Patent Publication Number: US-2021178074-A1

Title: Wearable automatic injection device for controlled delivery of therapeutic agents

Description:
RELATED APPLICATIONS 
     This application is related to and claims priority to U.S. Provisional Application Ser. No. 61/326,637, filed Apr. 21, 2010, the entire contents of which are expressly incorporated herein by reference in their entirety. 
    
    
     BACKGROUND 
     Automatic injection devices offer an alternative to manually-operated syringes for delivering therapeutic agents into patients&#39; bodies and allowing patients to self-administer injections. Automatic injection devices have been used to deliver medications under emergency conditions, for example, to administer epinephrine to counteract the effects of a severe allergic reaction. Automatic injection devices have also been described for use in administering anti-arrhythmic medications and selective thrombolytic agents during a heart attack (See, e.g., U.S. Pat Nos. 3,910,260; 4,004,577; 4,689,042; 4,755,169; and 4,795,433). Various types of automatic injection devices are also described in, for example, U.S. Pat. Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843; 5,102,393; 5,267,963; 6,149,626; 6,270,479; and 6,371,939; and International Patent Publication No. WO/2008/005315. 
     Conventionally, an automatic injection device houses a syringe and, when operated, causes the syringe to move forwardly and a needle to project from the housing so that a therapeutic agent contained in the syringe is ejected into a patient&#39;s skin. An automatic injection device typically includes a bung disposed within the syringe that, when actuated, moves within the syringe to expel the therapeutic agent from the syringe and into the patient&#39;s skin. 
     SUMMARY 
     Exemplary embodiments provide wearable automatic injection devices that may adhere to the skin or clothing of a patient and deliver a therapeutic agent into the patient&#39;s body by subcutaneous injection at slow, controlled injection rates, e.g., in a single slow bolus. Exemplary embodiments provide methods of assembling exemplary wearable automatic injection devices. Exemplary embodiments also provide methods of using wearable automatic injection devices worn by a patient for slow, controlled therapeutic agent delivery. Exemplary wearable automatic injection devices reduce or eliminate a burning sensation often felt or perceived by patients who use a conventional automatic injection device. Exemplary wearable automatic injection devices maintain the sterility of the therapeutic agent container (e.g., syringe), are easy to use, pre-fill capable, easy to manufacture, and/or do not require aseptic assembly. The wearable automatic injection devices provided by exemplary embodiments may adhere to the skin or clothing of the patient to deliver any therapeutic agent subcutaneously including, but not limited to, a biologic drug, such as, for example, an antibody, insulin, etc. 
     In accordance with an exemplary embodiment, a wearable automatic injection device is provided for providing a subcutaneous injection of a therapeutic agent into a patient. The device includes a housing comprising a patient contact portion securable to the patient. The device also includes an injection assembly moveably disposed in the housing holding a hypodermic injection needle for insertion into the patient, the injection assembly moveable between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing. The device also includes a vessel provided in the housing for holding the therapeutic agent, a plunger moveably disposed in the vessel for ejecting the therapeutic agent from the vessel into the injection assembly, and a plunger actuation mechanism for actuating the plunger within the vessel. The device also includes a retraction trigger responsive to a change of state of the wearable automatic injection device from an injection state to a post-injection state, and a retraction mechanism for automatically retracting the injection assembly from the extended position in the injection state to the retracted position in the post-injection state upon triggering by the retraction trigger. 
     In accordance with another exemplary embodiment, a method is provided for subcutaneously injecting a therapeutic agent into a patient. The method includes providing a wearable automatic injection device including a housing comprising a patient contact portion securable to the patient. The device also includes an injection assembly moveably disposed in the housing holding a hypodermic injection needle for insertion into the patient, the injection assembly moveable between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing. The device also includes a vessel provided in the housing for holding the therapeutic agent, a plunger moveably disposed in the vessel for ejecting the therapeutic agent from the vessel into the injection assembly, and a plunger actuation mechanism for actuating the plunger within the vessel. The device also includes a retraction trigger responsive to a change of state of the wearable automatic injection device from an injection state to a post-injection state, and a retraction mechanism for automatically retracting the injection assembly from the extended position in the injection state to the retracted position in the post-injection state upon triggering by the retraction trigger. The method includes securing the wearable automatic injection device to the skin of the patient or an article of clothing on the patient using the patient contact of the housing. The method also includes administering the therapeutic agent into the skin of the patient using the wearable automatic injection device. 
     In accordance with another exemplary embodiment, a wearable automatic injection device is provided for subcutaneously injecting a therapeutic agent into a patient. The device includes a housing and a cartridge assembly movably disposed within the housing. The cartridge includes a barrel portion for holding the therapeutic agent, and a hollow needle in fluid communication with the barrel portion for ejecting the therapeutic agent from the barrel portion. The cartridge also includes a bung for sealing the barrel portion and selectively applying pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge further includes a plunger actuator for applying pressure to the bung, and a trigger mechanism that actuates the plunger actuator to apply pressure to the bung when the cartridge is depressed from a ready position (in a pre-injection state) to a depressed position (in an injection state) inside the housing. The trigger mechanism actuates the plunger actuator such that the therapeutic agent is ejected from the barrel portion and into the patient at a controlled, slow rate with little or no burning sensation felt or perceived by the patient. The device also includes a fastener layer disposed on a patient contact surface to fasten the device to the skin or clothing of the patient or to an article of clothing of the patient. The fastener layer may include an adhesive for temporarily securing the wearable automatic injection device to the patient at least during the controlled injection of the therapeutic agent. 
     The wearable automatic injection device includes a retraction mechanism that retracts the cartridge from the depressed position to a retracted position (in a post-injection state). The wearable automatic injection device also includes a retraction trigger that activates the retraction mechanism, the retraction trigger trips when delivery of the therapeutic agent completes, or times out due an elapsed period of time, or when the wearable automatic injection device is removed from the patient, for example, before delivery of the therapeutic agent is completed. The wearable automatic injection device operates and functions entirely on mechanical principles or in combination with a controlled reaction to transition from any state (i.e., a pre-injection state, an injection state, a post-injection state), and controls the injection rate of the therapeutic agent over a time period that is selected for patient comfort, convenience or preference, or exceeds a time period for injection by a conventional automatic handheld device. In an exemplary embodiment, the time period of the injection by an exemplary wearable automatic injection device may range between about ten seconds and about twelve hours. In a preferred embodiment, the time period may range between about five minutes and about thirty minutes. 
     In another exemplary embodiment, a method is provided for subcutaneously injecting a therapeutic agent into a patient. The method includes providing a wearable automatic injection device comprising a housing and a cartridge assembly movably disposed within the housing. The cartridge includes a barrel portion for holding a therapeutic agent, and a hollow needle in fluid communication with the barrel portion for ejecting the therapeutic agent from the barrel portion. The cartridge also includes a bung for sealing the barrel portion and selectively applying pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge further includes a plunger actuator for applying pressure to the bung, and a trigger mechanism that actuates the plunger actuator to apply pressure to the bung when the cartridge is depressed from a ready position (in a pre-injection state) to a depressed position (in an injection state) inside the housing. The trigger mechanism actuates the plunger actuator such that the therapeutic agent is ejected from the barrel portion and into the patient at a controlled, slow rate and substantially free of any burning sensation. 
     The method also includes depressing the cartridge from the ready position to a depressed position within the housing. Depressing the cartridge automatically causes the injection needle that is used to pierce the patient&#39;s skin to project from an opening in the housing to penetrate the skin of the patient, and actuates the plunger actuator to apply pressure to the bung such that the therapeutic agent is delivered into the patient at a controlled, slow rate and substantially free of any burning sensation. 
     The method further includes automatically retracting the cartridge from the depressed to a retracted position (in a post-injection state) in the housing when delivery of the therapeutic agent is completed, or times out due to an elapsed period of time, or when the wearable automatic injection device is removed from the skin or clothing of the patient, for example, before delivery of the therapeutic agent is completed. 
     In an exemplary embodiment, a wearable automatic injection device is provided. The wearable automatic injection device provides a subcutaneous injection of a therapeutic agent into a patient. The wearable automatic injection device includes a housing having a patient contact portion securable to the patient and an interior portion defined by a plurality of walls and defining at least one open end opposing the patient contact portion. The wearable automatic injection device also includes a cartridge assembly movably disposed within the interior portion of the housing and movable from any of a ready position, an injection position, and a retraction position. The wearable automatic injection device further includes a trigger mechanism responsive to a change in state of the wearable automatic injection device from a pre-injection state to an injection state to actuate a plunger actuator disposed in the cartridge assembly to begin ejection of a therapeutic agent from the cartridge assembly, and a retraction trigger responsive to a change of state of the wearable automatic injection device from the injection state to a post-injection state. The wearable automatic injection device also includes a retraction mechanism responsive to the retraction trigger to automatically retract the cartridge assembly from the patient when the automatic injection device enters the post-injection state. 
     In another exemplary embodiment, a method of subcutaneously injecting a therapeutic agent into a patient is provided. The method includes securing to a patient a wearable automatic injection device comprising a housing having a patient contact portion securable to the patient and an interior portion defined by a plurality of walls and defining at least one open end opposing the patient contact portion and a cartridge assembly movably disposed within the interior portion of the housing and movable from any of a ready position, an injection position, and a retraction position, the cartridge assembly holding the therapeutic agent in a pre-fillable and/or pre-filled sterile manner The method also includes depressing the cartridge assembly downwardly towards the patient contact portion to cause the wearable automatic injection device to enter an injection state from a pre-injection state to automatically project a needle from a needle aperture in the housing and penetrate the skin of the patient and expel the therapeutic agent into the patient at a controlled rate. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings, in which: 
         FIG. 1A  illustrates a first end view and a first side view of an exemplary wearable device including a cartridge assembly in a packaged pre-injection state. 
         FIG. 1B  illustrates the first end view and the first side view of the exemplary device of  FIG. 1A  before an injection in a pre-injection state in which a needle cover covering the injection needle is removed in preparation for an injection. 
         FIG. 1C  illustrates the first end view and the first side view of the exemplary device of  FIG. 1A  during an injection in an injection state in which the patient&#39;s skin is pierced by the injection needle. 
         FIG. 1D  illustrates the first end view and the first side view of the exemplary device of  FIG. 1A  during an injection in an injection state in which a barrel portion of the device containing a dose of the therapeutic agent is deployed forwardly within the housing of the device. 
         FIG. 1E  illustrates the first end view and the first side view of the exemplary device of  FIG. 1A  during an injection in an injection state in which a bung of the device is actuated by a plunger actuator to expel the dose of the therapeutic agent from the barrel portion. 
         FIG. 1F  illustrates the first end view and the first side view of the exemplary device of  FIG. 1A  after an injection in a post-injection state in which the injection needle is retracted within the housing of the device. 
         FIG. 2A  illustrates a first end view and a first side view of an exemplary wearable device including a syringe assembly in a packaged pre-injection state. 
         FIG. 2B  illustrates the first end view and the first side view of the exemplary device of  FIG. 2A  before an injection in a pre-injection state in which a needle cover covering the injection needle is removed in preparation for an injection. 
         FIG. 2C  illustrates the first end view and the first side view of the exemplary device of  FIG. 2A  during an injection in an injection state in which the patient&#39;s skin is pierced by the injection needle. 
         FIG. 2D  illustrates the first end view and the first side view of the exemplary device of  FIG. 2A  during an injection in an injection state in which a barrel portion of the device containing a dose of the therapeutic agent is deployed forwardly within the housing of the device. 
         FIG. 2E  illustrates the first end view and the first side view of the exemplary device of  FIG. 2A  during an injection in an injection state in which a bung of the device is actuated by a plunger actuator to expel the dose of the therapeutic agent from the barrel portion. 
         FIG. 2F  illustrates the first end view and the first side view of the exemplary device of  FIG. 2A  after an injection in a post-injection state in which the injection needle is retracted within the housing of the device. 
         FIG. 3  is a flow chart of an exemplary method of assembling an exemplary wearable automatic injection device. 
         FIG. 4  is a flow chart of an exemplary method of using an exemplary automatic wearable injection device. 
         FIG. 5  is a flow chart of an exemplary method of using an exemplary wearable automatic injection device to inject a therapeutic agent into a patient. 
         FIG. 6A  illustrates an exemplary wearable automatic injection device suitable for linear insertion into a patient in a pre-injection state. 
         FIG. 6B  illustrates the exemplary device of  FIG. 6A  in an injection state ready to inject or injecting a dose of a therapeutic agent into a patient. 
         FIG. 6C  illustrates the exemplary device of  FIGS. 6A and 6B  in a post injection state after it has completed injecting the therapeutic agent into the patient or removed from the patient prior to completion of the injecting of the therapeutic agent. 
         FIG. 7A  illustrates an exemplary wearable automatic injection device suitable for rotary insertion in a pre-injection state ready for use by a patient. 
         FIG. 7B  illustrates the exemplary device of  FIG. 7A  in an injection state ready to inject or injecting a dose of a therapeutic agent into a patient. 
         FIG. 7C  illustrates the exemplary device of  FIGS. 7A and 7B  in a post-injection state after it has completed injecting the therapeutic agent into the patient or removed from the patient prior to completion of the injecting of the therapeutic agent. 
         FIG. 8  is a flow chart of an exemplary method of assembling an exemplary wearable automatic injection device. 
         FIG. 9  is a flow chart of an exemplary method of using an exemplary wearable automatic injection device. 
         FIG. 10  is a flow chart of an exemplary method of using an exemplary wearable automatic injection device to inject a therapeutic agent into a patient. 
         FIG. 11  illustrates an exemplary barrel portion in which a distal end of the barrel portion bears an injection needle that extends substantially along the longitudinal axis of the barrel portion. 
         FIG. 12  illustrates an exemplary barrel portion in which a distal end of the barrel portion bears an injection needle that extends at about 90 degrees relative to the longitudinal axis of the barrel portion. 
         FIG. 13  illustrates an exemplary needle assembly in which an exemplary adapter couples a syringe needle to an injection needle. 
         FIG. 14  illustrates an exemplary needle assembly in which a fluid conduit couples a syringe needle to an injection needle. 
         FIG. 15  illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle. 
         FIG. 16  illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle. 
         FIG. 17  illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle. 
         FIG. 18A  illustrates a perspective view of an exemplary wearable automatic injection device. 
         FIG. 18B  illustrates a disassembled view showing the components of the exemplary device of  FIG. 18A . 
         FIG. 19A  illustrates a side view of an exemplary wearable automatic injection device. 
         FIG. 19B  illustrates a perspective view showing the components of the device of  FIG. 19A . 
         FIG. 20A  illustrates a perspective view of an exemplary wearable automatic injection device. 
         FIG. 20B  illustrates a top view of the device of  FIG. 20A . 
         FIG. 20C  illustrates a side view of the transfer mechanism of the device of  FIG. 20A . 
         FIG. 21A  illustrates a perspective view of an exemplary wearable automatic injection device including an exemplary cartridge assembly. 
         FIG. 21B  illustrates a sectional view of the exemplary cartridge assembly of 
         FIG. 21A  taken along a longitudinal axis. 
         FIG. 21C  illustrates a transparent top view of the exemplary device of  FIG. 21A . 
         FIG. 22  illustrates an exemplary syringe or cartridge actuator that may be used to advance a barrel portion and/or the cartridge assembly from a retraction position to an extended position within the housing of a wearable automatic injection device. 
         FIG. 23  illustrates an exemplary syringe or cartridge actuator including a first portion, a second portion and a hinge portion provided between the first and second portions. 
         FIG. 24  illustrates a schematic of a portion of an exemplary automatic injection device including a plunger actuation mechanism that employs a fusee and a viscous damping mechanism. 
         FIG. 25  illustrates a wearable automatic injection device may include a platform, a slideable carriage coupled to the platform, and a cartridge assembly mounted on the slideable carriage. 
         FIG. 26  illustrates a wearable automatic injection device may include a platform, a slideable carriage coupled to the platform, and a cartridge assembly mounted on the slideable carriage. 
         FIG. 27  is a top view through a cover of an exemplary automatic injection device including a plunger actuation mechanism for automatically actuating a bung in a barrel portion. 
         FIG. 28  is a side view of the exemplary automatic injection device of  FIG. 27  showing a fusee and a damping mechanism. 
         FIG. 29  is a perspective view through a cover of the exemplary automatic injection device of  FIG. 27 . 
         FIG. 30  illustrates x and y coordinates (in inches) of cam profiles for: (i) the combination of spring  1  and a viscous damper, (ii) the combination of spring  1  and an escapement, (iii) the combination of spring  2  and a viscous damper, and (iv) the combination of spring  2  and an escapement. 
         FIG. 31  illustrates a graph of therapeutic agent flow rates (in milliliters per minute) versus time (in seconds) delivered by: (i) the combination of spring  1  and a viscous damper, (ii) the combination of spring  1 , a viscous damper and a cam spool, (iii) the combination of spring  1  and an escapement, (iv) the combination of spring  1 , an escapement and a cam spool, (v) the combination of spring  2  and a viscous damper, (vi) the combination of spring  2 , a viscous damper and a cam spool, (vii) the combination of spring  2  and an escapement, (viii) the combination of spring  2 , an escapement and a cam spool, and (ix) and an ideal flow rate in which the therapeutic agent is delivered at a substantially constant rate. 
         FIG. 32  illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) delivered by the combinations of components of  FIG. 31 . 
         FIG. 33  illustrates a graph of the volume of therapeutic agent (in milliliters) against time (in seconds) delivered using: (i) a G damping mechanism having a damping coefficient of about 10.3 lbf*s/in with a gear ratio of 4:1, (ii) a B damping mechanism having a damping coefficient of about 15.1 lbf*s/in with a gear ratio of 4:1, (iii) a K damping mechanism having a damping coefficient of about 18.9 lbf*s/in with a gear ratio of 4:1, (iv) a V damping mechanism having a damping coefficient of about 24.9 lbf*s/in with a gear ratio of 4:1, (v) a G damping mechanism having a damping coefficient of about 25.1 lbf*s/in with a gear ratio of 6.25:1, (vi) a B damping mechanism having a damping coefficient of about 37.0 lbf*s/in with a gear ratio of 6.25:1, (vii) a K damping mechanism having a damping coefficient of about 46.2 lbf*s/in with a gear ratio of 6.25:1, (viii) a V damping mechanism having a damping coefficient of about 60.7 lbf*s/in with a gear ratio of 6.25:1, (ix) a G damping mechanism having a damping coefficient of about 164 lbf*s/in with a gear ratio of 16:1, (x) a B damping mechanism having a damping coefficient of about 242 lbf*s/in with a gear ratio of 16:1, (xi) a K damping mechanism having a damping coefficient of about 303 lbf*s/in with a gear ratio of 16:1, (xii) a V damping mechanism having a damping coefficient of about 398 lbf*s/in with a gear ratio of 16:1, and (xiii) an ideal flow rate in which the therapeutic agent is delivered at a substantially constant rate. 
         FIG. 34  illustrates a graph of exemplary damper torques (that may be back-calculated from the displacement of the plunger actuator) against damper speeds (in rpm) for G, B, K and V model dampers having increasing damping coefficients. 
         FIG. 35  illustrates a graph of the volume of therapeutic agent (in milliliters) against time (in seconds) delivered by different exemplary syringes using a V model damper having a damping coefficient of about 24.9 lbf*s/in and an exemplary gear ratio of 4:1. 
         FIG. 36  illustrates a graph of the volume of therapeutic agent (in milliliters) delivered and the diameter of the fusee or cam spool (in inches) versus the time (in seconds). 
         FIG. 37  illustrates a graph of the volume of therapeutic agent (in milliliters) delivered versus time (in seconds) achieved by: (i) a first damper at room temperature, (ii) the first damper at about 40 degrees Fahrenheit (in a refrigerator), (iii) a second damper, (iv) the second damper at about 0 degree Fahrenheit (in a freezer), (v) a third damper having manufacturing variability relative to the first and second dampers, and (vi) a fourth damper having manufacturing variability relative to the first and second dampers. 
         FIG. 38  illustrates a schematic of a portion of an exemplary automatic injection device including a plunger actuation mechanism that employs a fusee and an escapement mechanism. 
         FIG. 39  illustrates an exemplary plunger actuation mechanism that employs one or more linear biasing mechanism to provide a force for expressing a therapeutic agent from the barrel portion of a wearable automatic injection device. 
         FIG. 40  illustrates an exemplary plunger actuation mechanism that employs one or more clock springs to provide a force for expressing a therapeutic agent from the barrel portion of a wearable automatic injection device. 
         FIG. 41  is a schematic of an exemplary automatic injection device including a plunger actuation mechanism that employs one or more fluid circuits. 
         FIG. 42  is an exemplary automatic injection device that employs one or more fluid circuits to perspective view a force to a bung for expressing a dose of a therapeutic agent from a barrel portion. 
         FIG. 43  illustrates a graph of the cumulative amount of therapeutic agent (in grams) against time (in seconds) as delivered by an exemplary delivery system at an exemplary delivery pressure of about 16.5 psi. 
         FIG. 44  illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) against time (in seconds) as delivered by an exemplary delivery system including a first flow restrictor. 
         FIG. 45  illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) against time (in seconds) as delivered by an exemplary delivery system including a second flow restrictor. 
         FIG. 46  is a schematic drawing of an exemplary automatic injection device that employs one or more fluid circuits to provide a force for expressing a therapeutic agent from a cartridge assembly. 
         FIG. 47  is a top view of the exemplary device of  FIG. 46 . 
         FIG. 48  illustrates a top view of an exemplary automatic injection device which shows a conduit coupling the master cylinder to a flow restrictor, a conduit coupling the flow restrictor to the bung, and a conduit coupling the master cylinder to a retraction mechanism via a valve. 
         FIG. 49  illustrates a schematic diagram of the device of  FIG. 48 . 
         FIG. 50  illustrates a graph of the pressure after a check valve and behind a bung (in psi) versus time (in seconds) in an exemplary embodiment. 
         FIG. 51  illustrates a side view of an exemplary automatic injection device in which the housing of the wearable automatic injection device includes a skin sensor foot. 
         FIGS. 52A and 52B  illustrate an exemplary needle protection system that maintains an injection needle in a retracted position within a housing of an exemplary automatic injection system. 
         FIGS. 53A and 53B  illustrate another exemplary needle protection system provided in an exemplary automatic injection system. 
         FIG. 54  illustrates another exemplary needle protection system provided in of an exemplary automatic injection system. 
         FIG. 55  illustrates another exemplary needle protection system provided in an exemplary automatic injection system. 
     
    
    
     DETAILED DESCRIPTION 
     Subcutaneous injection is a primary mode of therapeutic agent delivery and involves administering a bolus of a therapeutic agent into a patient. Subcutaneous injections are highly effective in administering various therapeutic agents including insulin, vaccines, and drugs such as morphine. Automatic injection devices offer an alternative to a syringe for delivering a therapeutic agent and allow patients to self-administer subcutaneous injections of therapeutic agents. Conventional automatic injection devices include hand held automatic injection devices and patch pumps, which are self-adhesive, patient-mounted auto-injectors. In use, a patch pump containing a therapeutic agent is mounted onto the skin or clothing of a patient and triggered to inject the therapeutic agent into the patient. Conventional patch pumps are typically filled by a patient prior to use. In addition, certain conventional patch pumps have an exposed needle inside the pump, and thus require secondary sterile packaging to maintain sterility. 
     Studies have shown that there is a direct correlation between the injection rate of certain therapeutic agents and the pain perceived by a patient upon injection of the therapeutic agents or agents. Some therapeutic agents cause pain, e.g., a burning or stinging sensation when injected rapidly into the patient. The pain sensation may be the result of a physiological response of the patient&#39;s skin to the subcutaneous injection of a therapeutic agent. Large volumes of any therapeutic agent, greater than one milliliter, may also cause pain when injected into the skin. Antibodies, and portions thereof, are exemplary therapeutic agents that are least painful when delivered at slow injection rates. Currently, there are no commercially viable conventional patch pumps that effectively address the discomfort associated with fast injection rates of hand held automatic injection devices. 
     Exemplary embodiments are described below with reference to certain illustrative embodiments. While exemplary embodiments are described with respect to using a wearable automatic injection device to provide an injection of a dose of a liquid medication, one of ordinary skill in the art will recognize that exemplary embodiments are not limited to the illustrative embodiments and that exemplary automatic injection devices may be used to inject any suitable substance into a patient. In addition, components of exemplary automatic injection devices and methods of making and using exemplary automatic injection devices are not limited to the illustrative embodiments described below. 
     A syringe assembly of exemplary automatic injections devices may contain a dose of a TNFa inhibitor. In an exemplary embodiment, the TNFa inhibitor may be a human TNFa antibody or antigen-biding portion thereof. In an exemplary embodiment, the human TNFa antibody or antigen-binding portion thereof may be adalimumab or golimumab. 
     Exemplary embodiments provide wearable automatic injection devices that may adhere to the skin or clothing of the patient and deliver a therapeutic agent into patient by subcutaneous injection at slow, controlled injection rates, e.g., in a single slow bolus. The slow, controlled injection rates achieved by exemplary devices minimize the pain sensation associated with a volume of a therapeutic agent entering into the patent&#39;s tissue. Exemplary time durations for slow delivery achieved by exemplary devices may range from about 5 minutes to about 30 minutes, but are not limited to this exemplary range. Exemplary volumes of therapeutic agent deliverable by exemplary devices may range from about 0.8 milliliters to about 1 milliliter, but are not limited to this exemplary range. In addition, exemplary devices may advantageously minimize inflections in the delivery profile against time of the therapeutic agent. 
     Exemplary embodiments minimize the size envelope of exemplary automatic injection devices, and provide scalable solutions with configurable delivery times and delivery profiles that may be used for a range of therapeutic agent viscosities. 
     Exemplary embodiments provide wearable automatic injection devices that deliver a therapeutic agent into a patient by subcutaneous injection at slow, controlled injection rates, e.g., in a single slow bolus without battery power or other components requiring electrical current or charge to operate. Exemplary embodiments also provide methods of using the wearable automatic injection devices for slow, controlled therapeutic agent delivery. The wearable automatic injection devices provided by exemplary embodiments are pre fillable prior to delivery to the patient, maintain sterility of the therapeutic agent and all subcutaneous contact surfaces (i.e., a hypodermic needle and one or more septums) to avoid the need for aseptic assembly and address the perceived patient discomfort due to injection by conventional hand held automatic injection devices. Exemplary wearable automatic injection devices include a primary therapeutic barrel portion that maintains sterility and therefore requires no aseptic assembly. Exemplary wearable automatic injection devices are disposable, easy to use, pre-fill capable, and may substantially or completely eliminate the burning sensation often experienced by a patient that uses a wearable automatic injection device. The wearable automatic injection devices provided by exemplary embodiments can be used to deliver any therapeutic agent that may be delivered subcutaneously including, but not limited to, an antibody or insulin, etc. 
     I. Definitions 
     Certain terms are defined in this section to facilitate understanding of exemplary embodiments. 
     The wearable automatic injection device of exemplary embodiments may include a “therapeutically effective amount” or a “prophylactically effective amount” of an antibody or antibody portion of the invention. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the antibody, antibody portion, or other TNFα inhibitor may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody, antibody portion, or other TNFα inhibitor to elicit a desired response in the patient. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody, antibody portion, or other TNFα inhibitor are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in patients prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. 
     The terms “substance” and “therapeutic agent” refer to any type of drug, biologically active agent, biological substance, chemical substance or biochemical substance that is capable of being administered in a therapeutically effective amount to a patient employing exemplary automatic injection devices. Exemplary substances include, but are not limited to, agents in a liquid state. Such agents may include, but are not limited to, adalimumab (HUMIRA®) and proteins that are in a liquid solution, e.g., fusion proteins and enzymes. Examples of proteins in solution include, but are not limited to, Pulmozyme (Dornase alfa), Regranex (Becaplermin), Activase (Alteplase), Aldurazyme (Laronidase), Amevive (Alefacept), Aranesp (Darbepoetin alfa), Becaplermin Concentrate, Betaseron (Interferon beta-1b), BOTOX (Botulinum Toxin Type A), Elitek (Rasburicase), Elspar (Asparaginase), Epogen (Epoetin alfa), Enbrel (Etanercept), Fabrazyme (Agalsidase beta), Infergen (Interferon alfacon-1), Intron A (Interferon alfa-2a), Kineret (Anakinra), MYOBLOC (Botulinum Toxin Type B), Neulasta (Pegfilgrastim), Neumega (Oprelvekin), Neupogen (Filgrastim), Ontak (Denileukin diftitox), PEGASYS (Peginterferon alfa-2a), Proleukin (Aldesleukin), Pulmozyme (Dornase alfa), Rebif (Interferon beta-1a), Regranex (Becaplermin), Retavase (Reteplase), Roferon-A (Interferon alfa-2), TNKase (Tenecteplase), and Xigris (Drotrecogin alfa), Arcalyst (Rilonacept), NPlate (Romiplostim), Mircera (methoxypolyethylene glycol-epoetin beta), Cinryze (C1 esterase inhibitor), Elaprase (idursulfase), Myozyme (alglucosidase alfa), Orencia (abatacept), Naglazyme (galsulfase), Kepivance (palifermin) and Actimmune (interferon gamma-1b). 
     A protein in solution may also be an immunoglobulin or antigen-binding fragment thereof, such as an antibody or antigen-binding portion thereof. Examples of antibodies that may be used in an exemplary automatic injection device include, but are not limited to, chimeric antibodies, non-human antibodies, human antibodies, humanized antibodies, and domain antibodies (dAbs). In an exemplary embodiment, the immunoglobulin or antigen-binding fragment thereof, is an anti-TNFa and/or an anti-IL-12 antibody (e.g., it may be a dual variable domain immunoglobulin (DVD) IgTM). Other examples of immunoglobulins or antigen-binding fragments thereof that may be used in the methods and compositions of exemplary embodiments include, but are not limited to, 1D4.7 (anti-IL-12/IL-23 antibody; Abbott Laboratories); 2.5(E)mg1 (anti-IL-18; Abbott Laboratories); 13C5.5 (anti-IL-13 antibody; Abbott Laboratories); J695 (anti-IL-12; Abbott Laboratories); Afelimomab (Fab 2 anti-TNF; Abbott Laboratories); HUMIRA (adalimumab) Abbott Laboratories); Campath (Alemtuzumab); CEA-Scan Arcitumomab (fab fragment); Erbitux (Cetuximab); Herceptin (Trastuzumab); Myoscint (Imciromab Pentetate); ProstaScint (Capromab Pendetide); Remicade (Infliximab); ReoPro (Abciximab); Rituxan (Rituximab); Simulect (Basiliximab); Synagis (Palivizumab); Verluma (Nofetumomab); Xolair (Omalizumab); Zenapax (Daclizumab); Zevalin (Ibritumomab Tiuxetan); Orthoclone OKT3 (Muromonab-CD3); Panorex (Edrecolomab); Mylotarg (Gemtuzumab ozogamicin); golimumab (Centocor); Cimzia (Certolizumab pegol); Soliris (Eculizumab); CNTO 1275 (ustekinumab); Vectibix (panitumumab); Bexxar (tositumomab and I131 tositumomab); and Avastin (bevacizumab). 
     Additional examples of immunoglobulins, or antigen-binding fragments thereof, that may be used in the methods and compositions of exemplary embodiments include, but are not limited to, proteins comprising one or more of the following: the D2E7 light chain variable region (SEQ ID NO: 1), the D2E7 heavy chain variable region (SEQ ID NO: 2), the D2E7 light chain variable region CDR3 (SEQ ID NO: 3), the D2E7 heavy chain variable region CDR3 (SEQ ID NO:4), the D2E7 light chain variable region CDR2 (SEQ ID NO: 5), the D2E7 heavy chain variable region CDR2 (SEQ ID NO: 6), the D2E7 light chain variable region CDR1 (SEQ ID NO: 7), the D2E7 heavy chain variable region CDR1 (SEQ ID NO: 8), the 2SD4 light chain variable region (SEQ ID NO: 9), the 2SD4 heavy chain variable region (SEQ ID NO: 10), the 2SD4 light chain variable CDR3 (SEQ ID NO: 11), the EP B12 light chain variable CDR3 (SEQ ID NO: 12), the VL10E4 light chain variable CDR3 (SEQ ID NO: 13), the VL100A9 light chain variable CDR3 (SEQ ID NO: 14), the VLL100D2 light chain variable CDR3 (SEQ ID NO: 15), the VLL0F4 light chain variable CDR3 (SEQ ID NO: 16), the LOES light chain variable CDR3 (SEQ ID NO: 17), the VLLOG7 light chain variable CDR3 (SEQ ID NO: 18), the VLLOG9 light chain variable CDR3 (SEQ ID NO: 19), the VLLOH1 light chain variable CDR3 (SEQ ID NO: 20), the VLLOH10 light chain variable CDR3 (SEQ ID NO: 21), the VL1B7 light chain variable CDR3 (SEQ ID NO: 22), the VL1C1 light chain variable CDR3 (SEQ ID NO: 23), the VL0.1F4 light chain variable CDR3 (SEQ ID NO: 24), the VL0.1H8 light chain variable CDR3 (SEQ ID NO: 25), the LOE7. A light chain variable CDR3 (SEQ ID NO: 26), the 2SD4 heavy chain variable region CDR (SEQ ID NO: 27), the VH1B11 heavy chain variable region CDR (SEQ ID NO: 28), the VH1D8 heavy chain variable region CDR (SEQ ID NO: 29), the VH1A11 heavy chain variable region CDR (SEQ ID NO: 30), the VH1B12 heavy chain variable region CDR (SEQ ID NO: 31), the VH1E4 heavy chain variable region CDR (SEQ ID NO: 32), the VH1F6 heavy chain variable region CDR (SEQ ID NO: 33), the 3C-H2 heavy chain variable region CDR (SEQ ID NO: 34), and the VH1-D2.N heavy chain variable region CDR (SEQ ID NO: 35). 
     The term “human TNFα” (abbreviated herein as hTNFα, or simply hTNF) refers to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules. The structure of hTNFα is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J. M., et al. (1987) Biochem.26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228. The term human TNFα is intended to include recombinant human TNFα (rhTNFα), which can be prepared by standard recombinant expression methods or purchased commercially (R &amp; D Systems, Catalog No. 210-TA, Minneapolis, Minn.). TNFα is also referred to as TNF. 
     The term “TNFα inhibitor” refers to an agent that interferes with TNFα activity. The term also includes each of the anti-TNFα human antibodies (used interchangeably herein with TNFα antibodies) and antibody portions described herein as well as those described in U.S. Pat. Nos. 6,090,382; 6,258,562; 6,509,015; 7,223,394; and 6,509,015. In one embodiment, the TNFα inhibitor used in the invention is an anti-TNFα antibody, or a fragment thereof, including infliximab (Remicade®, Johnson and Johnson; described in U.S. Pat. No. 5,656,272); CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody); CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment); an anti-TNF dAb (Peptech); CNTO 148 (golimumab; Centocor, See WO 02/12502 and U.S. Pat. Nos. 7,521,206 and 7,250,165); and adalimumab (HUMIRA® Abbott Laboratories, a human anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7). Additional TNF antibodies that may be used in the invention are described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380. In another embodiment, the TNFα inhibitor is a TNF fusion protein, e.g., etanercept (Enbrel®, Amgen; described in WO 91/03553 and WO 09/406476). In another embodiment, the TNFα inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono). 
     In one embodiment, the term “TNFα inhibitor” excludes infliximab. In one embodiment, the term “TNFα inhibitor” excludes adalimumab. In another embodiment, the term “TNFα inhibitor” excludes adalimumab and infliximab. 
     In one embodiment, the term “TNFα inhibitor” excludes etanercept, and, optionally, adalimumab, infliximab, and adalimumab and infliximab. 
     In one embodiment, the term “TNFα antibody” excludes infliximab. In one embodiment, the term “TNFα antibody” excludes adalimumab. In another embodiment, the term “TNFα antibody” excludes adalimumab and infliximab. 
     The term “antibody” refers to immunoglobulin molecules generally comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the invention are described in further detail in U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015. 
     The term “antigen-binding portion” of an antibody (or simply “antibody portion”) refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hTNFα). Fragments of a full-length antibody can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature 341:544-546), which consists of a VH or VL domain; (vi) an isolated complementarity determining region (CDR); and (vii) a dual variable domain immunoglobulin (DVD-Ig). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); See e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also encompassed within the term “antigen-binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (See e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). The antibody portions of the invention are described in further detail in U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015. 
     The term “recombinant human antibody” refers to all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (See e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germ line immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line repertoire in vivo. 
     Such chimeric, humanized, human, and dual specific antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT International Application No. PCT/US86/02269; European Patent Application No. 184,187; European Patent Application No. 171,496; European Patent Application No. 173,494; PCT International Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent Application No. 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw et al. (1988) J. Natl. Cancer Inst. 80:1553-1559; Morrison (1985) Science 229:1202-1207; Oi et al. (1986) BioTechniques 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141:4053-4060, Queen et al. (1989) Proc. Natl. Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,761; 5,693,762; WO 90/07861; and U.S. Pat. No. 5,225,539. 
     The term “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNFα and is substantially free of antibodies that specifically bind antigens other than hTNFα). An isolated antibody that specifically binds hTNFα may have cross-reactivity to other antigens, such as TNFα molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. 
     The term “neutralizing antibody” (or an “antibody that neutralized hTNFα activity”) refers to an antibody whose binding to hTNFα results in inhibition of the biological activity of hTNFα. This inhibition of the biological activity of hTNFα can be assessed by measuring one or more indicators of hTNFα biological activity, such as hTNFα-induced cytotoxicity (either in vitro or in vivo), hTNFα-induced cellular activation and hTNFα binding to hTNFα receptors. These indicators of hTNFα biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art (See U.S. Pat. No. 6,090,382). Preferably, the ability of an antibody to neutralize hTNFα activity is assessed by inhibition of hTNFα-induced cytotoxicity of L929 cells. As an additional or alternative parameter of hTNFα activity, the ability of an antibody to inhibit hTNFα-induced expression of ELAM-1 on HUVEC, as a measure of hTNFα-induced cellular activation, can be assessed. 
     The term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Example 1 of U.S. Pat. 6,258,562 and Jönsson et al. (1993) Ann. Biol. Clin. 51:19; Jönsson et al. (1991) Biotechniques 11:620-627; Johnsson et al. (1995) J. Mol. Recognit. 8:125; and Johnnson et al. (1991) Anal.Biochem.198:268. 
     The term “Koff” refers to the off rate constant for dissociation of an antibody from the antibody/antigen complex. 
     The term “Kd” refers to the dissociation constant of a particular antibody-antigen interaction. 
     The term “IC50” refers to the concentration of the inhibitor required to inhibit the biological endpoint of interest, e.g., neutralize cytotoxicity activity. 
     The term “dose” or “dosage” refers to an amount of a substance, such as a TNFα inhibitor, which is administered to a patient preferably using the wearable automatic injection device of the invention. In one embodiment, the dose comprises an effective amount, for example, including, but not limited to, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, and 160 mg, of the TNFα inhibitor adalimumab. 
     The term “dosing” refers to the administration of a substance (e.g., an anti-TNFα antibody) to achieve a therapeutic objective (e.g., treatment of rheumatoid arthritis). 
     The term “dosing regimen” describes a treatment schedule for a substance, such as a TNFα inhibitor, e.g., a treatment schedule over a prolonged period of time and/or throughout the course of treatment, e.g. administering a first dose of a TNFα inhibitor at week 0 followed by a second dose of a TNFα inhibitor on a biweekly dosing regimen. 
     The term “biweekly dosing regimen”, “biweekly dosing”, and “biweekly administration” refer to the time course of administering a substance (e.g., an anti-TNFα antibody) to a patient to achieve a therapeutic objective, e.g., throughout the course of treatment. The biweekly dosing regimen is not intended to include a weekly dosing regimen. Preferably, the substance is administered every 9 to 19 days, more preferably, every 11 to 17 days, even more preferably, every 13 to 15 days, and most preferably, every 14 days. In one embodiment, the biweekly dosing regimen is initiated in a patient at week 0 of treatment. In another embodiment, a maintenance dose is administered on a biweekly dosing regimen. In one embodiment, both the loading and maintenance doses are administered according to a biweekly dosing regimen. In one embodiment, biweekly dosing includes a dosing regimen wherein doses of a TNFα inhibitor are administered to a patient every other week beginning at week 0. In one embodiment, biweekly dosing includes a dosing regimen where doses of a TNFα inhibitor are administered to a patient every other week consecutively for a given time period, e.g., 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks, etc. Biweekly dosing methods are also described in U.S. 2003/0235585. 
     The term “combination” as in the phrase “a first agent in combination with a second agent” includes co-administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent. 
     The term “concomitant” as in the phrase “concomitant therapeutic treatment” includes administering an agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third, or additional substances are co-administered. A concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second substance or additional substances, wherein the second or additional agents, for example, may have been previously administered. A concomitant therapeutic treatment method may be executed step-wise by different patients. For example, one subject may administer to a patient a first agent and a second subject may to administered to the patient a second substance, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first substance (and additional substances) are after administration in the presence of the second substance (and additional substances). The actor and the patient may be the same entity (e.g., human). 
     The term “combination therapy” refers to the administration of two or more therapeutic substances, e.g., an anti-TNFα antibody and another drug. The other drug(s) may be administered concomitant with, prior to, or following the administration of an anti-TNFα antibody. 
     The term “treatment” refers to therapeutic treatment, as well as prophylactic or suppressive measures, for the treatment of a disorder, such as a disorder in which TNFα is detrimental, e.g., rheumatoid arthritis. 
     The term “patient” or “user” refers to any type of animal, human or non-human, that may be injected a substance using exemplary automatic injection devices. 
     The terms “wearable automatic injection device” and “wearable autoinjector” refer to a device worn by a patient that enables the patient to self-administer a therapeutically effective dose of a therapeutic agent by either fastening the wearable device directly to his or her skin or fastening the wearable device to an article of clothing that allows penetration of a hypodermic needle, wherein the wearable device differs from a conventional syringe by the inclusion of a mechanism for automatically delivering the therapeutic agent to the patient by injection when the mechanism is engaged. 
     The terms “syringe” and “cartridge” encompass a sterile barrel portion that is filled with a dose of a therapeutic agent prior to distribution or sale to a patient or other non-medical professional for administration of the therapeutic agent to a patient. In an exemplary embodiment, a distal end of the barrel portion of a syringe may be coupled to a sterile hypodermic needle. In an exemplary embodiment, a distal end of the barrel portion of a cartridge may not be coupled to a needle. That is, in exemplary embodiments, a syringe may be a cartridge with a pre-attached hollow needle coupled to its barrel portion. 
     Exemplary embodiments described herein with reference to a syringe assembly may also be implemented using a cartridge assembly. Similarly, exemplary embodiments described herein with reference to a cartridge assembly may also be implemented using a syringe assembly. 
     The term “vessel” refers to either a syringe or cartridge that may be used in an exemplary wearable automatic injection device for holding a dose of a therapeutic agent. 
     The term “injection needle” refers to a needle in a wearable automatic injection device that is inserted into a patient&#39;s body to deliver a dose of a therapeutic agent into the patient&#39;s body. In an exemplary embodiment, the injection needle may be directly coupled to or in contact with a syringe or a cartridge assembly that holds the dose of the therapeutic agent. In another exemplary embodiment, the injection needle may be indirectly coupled to the syringe or cartridge assembly, for example, via a syringe needle and/or a transfer mechanism that provides fluid communication between the syringe or cartridge and the injection needle. 
     The term “syringe needle” refers to a needle in a wearable automatic injection device that is coupled to or in contact with a syringe or a cartridge assembly for conveying a dose of a therapeutic agent from the syringe or cartridge assembly to an injection needle which, in turn, delivers the therapeutic agent into a patient&#39;s body. In an exemplary embodiment, the syringe needle is not inserted into the patient&#39;s body. In another exemplary embodiment, the syringe needle may be inserted into the patient&#39;s body. 
     In an exemplary wearable automatic injection device including a syringe assembly, the syringe needle may be coupled directly to the barrel portion of the syringe and may be in fluid communication with the barrel portion. In an exemplary wearable automatic injection device including a cartridge assembly, the syringe needle may be provided separately from the barrel portion of the cartridge, for example, within an injection button or a transfer mechanism. During an injection stage, the syringe needle may be inserted into a distal end of the barrel portion of the cartridge to establish fluid communication between the syringe needle and the barrel portion. 
     The term “pre-injection state” refers to a state of a wearable automatic injection device prior to the start of delivery of a therapeutic agent contained in the device. 
     The term “injection state” refers to one or more states of a wearable automatic injection device during the delivery of a therapeutic agent contained in the device. 
     The term “post-injection state” refers to completion of delivery of a therapeutically effective dose of a therapeutic agent contained in the device and to removal of the device from the patient prior to completion of delivery of a therapeutically effective dose of the therapeutic agent. 
     The term “slow” refers to a delivery rate of a volume of a therapeutic agent. In an exemplary embodiment, a volume of about 0.1 milliliters to about 1 milliliter or more may be delivered in a delivery time period of about ten seconds to about twelve hours. In a preferred embodiment, the delivery time period may range from about five minutes to about thirty minutes. 
     The term “clothing” refers to any suitable covering on a patient&#39;s body to which an exemplary wearable automatic injection device may be coupled or attached. The article of clothing may thus form an intermediate layer between the device and the patient&#39;s skin and may be used to indirectly couple the device to the patient&#39;s skin. In an exemplary embodiment, the article of clothing may be snug clothing on the patient&#39;s body, for example, nylon stockings. In another exemplary embodiment, the article of clothing may be a covering on the patient&#39;s skin including, but not limited to, a medical tape, a bandage, and the like. In another exemplary embodiment, the article of clothing may be a coupling mechanism that adheres the device in the proximity of the patient&#39;s skin including, but not limited to, a sleeve that may fit round a portion of the patient&#39;s body, a belt, a strap (e.g., a Velcro strap), and the like. 
     II. Exemplary Embodiments 
     Certain exemplary wearable automatic injection devices are described with reference to  FIGS. 1-10 . Certain exemplary needle systems that may be used in exemplary wearable automatic injection devices to convey a therapeutic agent are described with reference to  FIGS. 11-23 . Certain exemplary plunger actuation systems that may be used in exemplary wearable automatic injection devices to expel a therapeutic agent from a syringe or cartridge are described with reference to  FIGS. 24-51 . Certain exemplary needle protection systems that may be used in exemplary wearable automatic injection devices to maintain an injection needle in a retracted position in a post-injection state are described with reference to  FIGS. 52-55 . 
     Exemplary wearable automatic injection devices may employ a syringe assembly (as illustrated in  FIGS. 1A-1F ) or a cartridge assembly (as illustrated in  FIGS. 2A-2F ) for holding a dose of a therapeutic agent that may be delivered into a patient&#39;s body through an injection needle. 
       FIGS. 1A-1F  illustrate an exemplary embodiment of a wearable automatic injection device  100  including a syringe assembly that may be used to inject a dose of a therapeutic agent into the body of a patient.  FIG. 1A  illustrates a first end view and a first side view of the exemplary wearable device  100  in a packaged pre-injection state.  FIG. 1B  illustrates the first end view and the first side view of the exemplary device  100  in a pre-injection state in which a needle shield covering the injection needle is removed in preparation for an injection.  FIG. 1C  illustrates the first end view and the first side view of the exemplary device  100  during an injection in an injection state in which the patient&#39;s skin is pierced by the injection needle.  FIG. 1D  illustrates the first end view and the first side view of the exemplary device  100  during an injection in an injection state in which the barrel portion containing the dose of the therapeutic agent is deployed forwardly within the housing of the device  100 .  FIG. 1E  illustrates the first end view and the first side view of the exemplary device  100  during an injection in an injection state in which the bung is actuated by a plunger actuator to expel the dose of the therapeutic agent from the barrel portion.  FIG. 1F  illustrates the first end view and the first side view of the exemplary device  100  after an injection in a post-injection state in which the injection needle is retracted within the housing of the device  100 . 
     The wearable automatic injection device  100  may include a housing  102 . In an exemplary embodiment, the housing  102  may have an elongated configuration, although one of ordinary skill in the art will recognize that the housing  102  may have any suitable size, shape and configuration for housing a barrel portion containing a dose of a therapeutic agent to be injected. In an exemplary embodiment, the housing  102  may be formed of any suitable material including, but not limited to, plastic and other known materials. 
     The housing  102  of the wearable automatic injection device  100  may include an adhesive layer  124  disposed along a patient contact portion at the bottom of the housing  102  that is placed proximal to the skin of the patient or an article of clothing of the patient. In some exemplary embodiments, the adhesive layer  124  may be configured to be placed on the skin of the patient in order to attach the housing  102  to the patient to deliver the dose of the therapeutic agent. The adhesive layer  124  may include a non-adhesive tab  126  that is not adhesive. The non-adhesive tab  126  may be gripped by the patient and pulled to remove the wearable automatic injection device  100  from the skin or clothing of the patient. 
     Before the wearable automatic injection device  100  is put to use, e.g., in the package state illustrated in  FIG. 1A , the adhesive layer  124  may be covered by a protective film  128  which preserves the adhesive nature of the adhesive layer  124 . The protective film  128  may include a tab  130  which may be gripped by the patient and pulled to remove the protective film  128  from the adhesive layer  124 . This exposes the adhesive layer  124 , allowing the patient to attach the housing  102  to his or her skin or article of clothing by placing the side with the adhesive layer  124  on the skin or the article of clothing. 
     The housing  102  may house a syringe assembly extending substantially along a longitudinal axis L between a proximal end (farthest from the injection needle) and a distal end (nearest to the injection needle). The syringe assembly may include a barrel portion  106  for holding a dose  108  of a therapeutic agent to be injected into a patient&#39;s skin. The barrel portion  106  may extend substantially along the longitudinal axis between a proximal end (farthest from the injection needle) and a distal end (nearest to the injection needle). In an exemplary embodiment, the barrel portion  106  may be a substantially cylindrical member having a circular cross-section, although one of ordinary skill in the art will recognize that the barrel portion  106  may have any suitable shape or configuration. 
     In an exemplary embodiment, the barrel portion  106  may be stationary within the housing  102  so that the injection process does not result in the movement of the barrel portion  106  within and relative to the housing  102 . In another exemplary embodiment, the barrel portion  106  may initially, i.e., before an injection in a pre-injection state, be in a retracted position toward the proximal end of the device  100  (as illustrated in  FIGS. 1A-1C ), and may be actuated during an injection in an injection state to an extended position toward the distal end of the device  100 . 
     A bung  110  may be provided at the proximal end of the barrel portion  106  to seal the dose of the therapeutic agent within the barrel portion  106  and to apply a force to the dose to expel the dose from the barrel portion  106 . The bung  110  may be moveable within the barrel portion  106  toward the distal end of the barrel portion  106  in order to expel the dose from the barrel portion  106  during an injection in an injection state. In an exemplary embodiment, the bung  110  may be configured to perform both functions of sealing the dose and squeezing the dose out of the barrel portion  106 . In another exemplary embodiment, a bung may be provided to seal the dose within the barrel portion  106  and a separate piston or plunger rod may be provided to impart a force to the bung in order to squeeze the dose out of the barrel portion  106 . 
     The syringe assembly may include, at or near its distal end, a syringe stopper or a distal portion of the syringe  114  that may include a syringe needle  120  and a needle cover  134  for covering the syringe needle  120 . The needle cover  134  may include a soft needle shield, a rigid needle shield, or both. In an exemplary embodiment, the syringe needle  120  may be aligned parallel to the longitudinal axis L of the device  100 . The syringe needle  120  may have any suitable size, shape and configuration suitable for piercing a septum, and is not limited to the illustrative embodiment. 
     The syringe assembly may include, at or near its proximal end, a plunger actuator  112  for selectively actuating the bung  110  forwardly within the barrel portion  106  toward the distal end in order to inject the therapeutically effective dose contained in the barrel portion  106  into a patient&#39;s skin. The plunger actuator  112  may employ an energy storage and controlled energy release mechanism to actuate the bung  110 . In exemplary embodiments, the plunger actuator  112  may be located outside the barrel portion  106  or partly or fully within the barrel portion  106 . In an exemplary embodiments, the plunger actuator  112  may drive the bung  110  directly or indirectly though the use of a plunger disposed between the bung  110  and the plunger actuator  112 . 
     In an exemplary embodiment, the plunger actuator  112  may include a biasing mechanism, e.g., a spring, that is retracted before injection and that is released during injection to actuate the bung  110  forwardly within the barrel portion  106 . In another exemplary embodiment, the plunger actuator  112  may include a chemical gas generator, e.g., an expanding foam, that is in a non-expanded phase before injection and that expands during injection to actuate the bung  110  forwardly within the barrel portion  106 . In other exemplary embodiments, the plunger actuator  112  may employ hydraulic pressure of working fluids, gas pressure of compressed gases, osmotic pressure, hydrogel expansion, and the like. 
     In an exemplary embodiment, the plunger actuator  112  may be moved forwardly within the barrel portion  106  in a substantially linear manner, i.e., substantially constant speed. This may allow the dose to be delivered to the patient at a substantially constant delivery rate. The plunger actuator  112  may include or may be coupled to a damping mechanism that may be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during energy release by the plunger actuator  112 . The controlled release of energy may result in a substantially linear delivery profile, i.e., a substantially constant rate of delivery of the dose over time, and may prevent abrupt changes in the speed of the delivery. In an exemplary embodiment, a plunger actuator  112  may employ the hydraulic pressure of a working fluid and a damping mechanism may employ a flow restrictor placed in a fluid pathway between the working fluid and the bung  110 . In another exemplary embodiment, a plunger actuator  112  may employ a biasing mechanism and a damping mechanism may employ a viscous damper, a swiss lever escapement, a runaway escapement, and the like. In another exemplary embodiment, a plunger actuator  112  may employ a stepper motor connected to a gear drive system to provide a constant linear delivery profile. 
     The housing  102  of the wearable automatic injection device  100  may also house an injection button  116  bearing a hollow hypodermic injection needle  118  that is configured to pierce the patient&#39;s skin. In an exemplary embodiment, the injection needle  118  may be aligned orthogonally to the longitudinal axis L of the device  100 . In an exemplary embodiment, the injection needle  118  may be held in place by an injection needle carrier (not pictured) provided in the injection button  116  or separately from the injection button  116 . The injection needle  118  may have any suitable size, shape and configuration suitable for piercing the skin of the patient to deliver the therapeutic agent, and is not limited to the illustrative embodiment. Suitable needles may have a length configured or selected to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an exemplary embodiment, the injection needle  118  may have a length of about twelve mm and may be injected to a depth of about seven mm into the skin. In other exemplary embodiments, the injection needle  118  may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable injection needles may have a wall thickness suitable to provide sufficient mechanism strength, a diameter suitable to allow a desired flow rate of the injected substance while minimizing patient sensation, and a tip geometry suitable for the desired therapy while minimizing patient sensation. Suitable injection needles may be coated as needed to minimize patient sensation as allowed by therapy. The injection needle  118  may be covered and maintained in aseptic condition, i.e., sterile condition, by a needle cover  122 , for example, a rigid needle shield, a soft needle shield, or both. 
     The injection button  116  may also include a pierceable septum disposed in the vicinity of the syringe needle  120 . In a pre-injection state, the syringe needle  120  does not pierce the septum, thus prevent fluid communication between the barrel portion  106  and the syringe needle  120 . In an injection state, when pierced by a needle, for example, the syringe needle  120 , the septum may allow the dose to leave the barrel portion  106  and enter the syringe needle  120 . In an exemplary embodiment, one or more covers  115  may enclose the septum in a sterility barrier. The covers  115  may be pierced when the syringe needle  120  pierces the septum. 
     In an exemplary embodiment, the injection needle  118  and the syringe needle  120  may be coupled to and in fluid communication with each other via the body of the injection button  116 . In another exemplary embodiment, the injection needle  118  and the syringe needle  120  may be coupled to and in fluid communication with each other via one or more fluid conduits (not pictured). In another exemplary embodiment, the injection needle  118  and the syringe needle  120  may be directly coupled to and in fluid communication with each other. 
     In an exemplary embodiment, before an injection in a pre-injection state, the injection button  116  may be in a vertically raised position relative to the housing  102  such that the injection button  116  protrudes from the top of the housing  102 , as illustrated in  FIGS. 1A and 1B . In this position, the injection needle  118  may be retracted within the housing  102  and may not be inserted into the patient&#39;s skin. In this position, the syringe needle  120  may be aligned vertically below the septum in the syringe stopper  114  and may not pierce the septum. At the beginning of the injection process, the injection button  116  may be pressed downward, for example, by a user of the device or automatically. This may push the injection button  116  to a vertically depressed position relative to the housing  102  closer to the patient&#39;s skin such that the injection button  116  no longer protrudes from the top of the housing  102 , as illustrated in  FIGS. 1C-1E . In this position, the injection needle  118  may protrude from the bottom of the housing  102  and may be inserted into the patient&#39;s skin. In this position, the syringe needle  120  may be aligned with the septum in the syringe stopper  114  and may pierce the septum. 
     In an exemplary embodiment, the septum may initially be spaced from the injection button  116 . In this embodiment, the syringe needle  120  may pierce the septum when the syringe stopper  114  bearing the syringe needle  120  is advanced within the housing  102  toward the septum. That is, before an injection in a pre-injection state, the syringe needle  120  may be spaced from the septum such that there is no fluid communication between the barrel portion  106  and the injection needle  118  coupled to the injection button  116 . In an injection state, the barrel portion  106  may advance within the housing  102  toward the distal end of the device  100  such that that the syringe needle  120  may pierce the septum and establish fluid communication between the barrel portion  106  and the injection needle  118  coupled to the injection button  116 . This fluid communication may allow the dose of the therapeutic agent to flow from the barrel portion  106  into the patient&#39;s skin through the syringe needle  120  and the injection needle  118  when pressure is applied to the dose by the bung  110  during an injection in an injection state. 
     Referring now to  FIG. 1F , in an exemplary embodiment, the housing  102  of the wearable automatic injection device  100  may include a skin sensor foot  132 , which is a structure housed under or in the portion of the housing  102  proximal to the injection site. Prior to injection of the therapeutic agent and during injection, the skin sensor foot  132  is retained within or forms a portion of the underside of the housing  102 . When the wearable automatic injection device  100  is attached to the injection site and activated, the skin sensor foot  132  may be free to move but may be constrained by the injection site. When the wearable automatic injection device  100  is removed from the injection site, regardless of whether the drug delivery was completed, the skin sensor foot  132  is no longer constrained, and extends and projects outside the periphery of the housing  102 . This, in turn, trips a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle  120  which may also raise the injection button  116  from the vertically lowered position to the vertically raised position, so that the injection button  116  protrudes from the top of the housing  102  and the injection needle  118  is retracted within the housing  102 . 
       FIG. 1A  illustrates the wearable automatic injection device  100  in a pre-injection state, for example, as packaged, in which the barrel portion  106  may be pre-fillable and/or pre-filled with the dose  108  of the therapeutic agent and in a retracted position ready for use. The barrel portion  106  may contain the dose  108  of the therapeutic agent in the interior space defined between the wall or walls of the barrel portion  106  and the bung  110 . In an embodiment, the plunger actuator  112  may store energy that, when released, may actuate the bung  110 . The injection button  116  may be partially disposed within the housing  102  at the vertically raised position above the injection site, and the injection needle  118  may be retracted within the housing  102 . The protrusion of the injection button  116  out of the top of the housing  102  may provide a visual indication to the patient that the wearable automatic injection device  100  is not in operation. 
       FIG. 1B  illustrates the wearable automatic injection device  100  in a pre-injection state in which the needle cover  122  and the septum cover are removed. In exemplary embodiments, the protective film  128  may include a linking member that is connected to the needle cover  122 , the septum and syringe needle covers in the syringe stopper  114 . The linking member may include a tether or other linkage mechanism. When the protective film  128  is removed, the linking member of the protective film  128  may remove the needle cover  122  and the septum and syringe needle covers in the syringe stopper  114 . 
       FIG. 1C  illustrates the wearable automatic injection device  100  during an injection in an injection state in which the injection button  116  is in the vertically lowered position within the housing  102 . In the vertically lowered position, the injection button  116  may be disposed within the housing  102  at a depressed or vertically lowered location above the injection site, and the injection needle  118  may project from the bottom of the housing  102  through an aperture in the housing  102  so that it can penetrate the skin at the injection site. In the vertically lowered state, the injection button  116  may not protrude from the top of the housing  102 , which may provide a visual indication to the patient that the wearable automatic injection device  100  is in operation. 
       FIG. 1D  illustrates the wearable automatic injection device  100  during an injection in an injection state in which the barrel portion  106  containing the dose  108  of the therapeutic agent is deployed forwardly from a retracted position to an extended position within the housing of the device  100 . The advancement of the barrel portion  106  may bring the distal end of the barrel portion  106  or the syringe stopper  114  in the vicinity of or in contact with the injection button  116 . In an exemplary embodiment, the syringe needle  120  may pierce the septum held in the syringe stopper  114  in order to establish fluid communication between the barrel portion  106  and the injection needle  118 . 
       FIG. 1E  illustrates the wearable automatic injection device  100  during an injection in an injection state in which the plunger actuator  112  is triggered to move the bung  110 . Triggering of the plunger actuator  112  may release stored energy in the plunger actuator  112  in order to move the bung  110  within the barrel portion  106  toward the distal end of the device  100 . The movement of the bung  110  may eject the dose of the therapeutic agent from the barrel portion  106  through the distal end of the barrel portion  106 . Any suitable mechanism may be used to trigger the plunger actuator  112  including, but not limited to, a linking member that is coupled to and activated by the depression of the injection button  116  or by the removal of the needle cover  122 , a trigger button that may be used by the user, and the like. 
       FIG. 1F  illustrates the wearable automatic injection device  100  after an injection in a post-injection state, for example, after injecting a therapeutically effective dose of the therapeutic agent or removal of the wearable automatic injection device  100  from the patient before delivery of a therapeutically effective dose of the therapeutic agent, in which the injection button  116  is in the vertically raised position. In the vertically raised position, the injection button  116  may be disposed partly within the housing  102  at an elevated or vertically raised location above the injection site, and the injection needle  118  may be retracted within the housing  102 . A portion of the injection button  116  may project from the top of the housing  102  to provide a visual indication to the patient that the wearable automatic injection device assembly  100  is not in operation (i.e., in a post-injection state). The barrel portion  106  may be empty of the therapeutic agent and the plunger actuator  112  may no longer store energy. A skin sensor foot  132  may extend from the bottom of the housing  102  upon removal of the device  100  from the injection site. 
     The housing  102  may include a retraction mechanism that automatically raises the injection button  116  from the vertically lowered injection state (shown in  FIGS. 1C-1E ) to the vertically raised post-injection state (shown in  FIG. 1F ). In an exemplary embodiment, the retraction mechanism may include a biasing mechanism, e.g., a spring, that biases the syringe assembly away from the injection site when the retraction mechanism is triggered. 
     A retraction trigger, when activated, may trigger the retraction mechanism in order to raise the injection button  116  from the vertically lowered state to the vertically raised state. In an exemplary embodiment, the bung  110  and/or the plunger actuator  112  may include a linking member connected to the retraction trigger. The linking member may include a tether or other linkage mechanism. The linking member may be of a suitable length such that, when the bung  110  has been moved to the end of the barrel portion  106  (delivering a complete dose), the linking member triggers a latch that in turn trips the retraction trigger. In another exemplary embodiment, the extension of the skin sensor foot  132  from the bottom of the housing  102  may trip the retraction trigger. 
     In an exemplary embodiment, the retraction mechanism may include an end-of-dose retraction trigger that, when tripped, triggers the retraction mechanism. The end-of-dose retraction trigger may be tripped when the therapeutically effective dose of therapeutic agent in the wearable automatic injection device is delivered. In an exemplary embodiment, the end-of-dose retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon completed drug delivery. The retraction mechanism may also include an early-removal retraction trigger that, when tripped, triggers the retraction mechanism. The early-removal retraction trigger may be tripped when the wearable automatic injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is completely delivered. In an exemplary embodiment, the early-removal retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon removal of the wearable automatic injection device  100  from the injection site. The retraction mechanism is responsive to the end-of-dose retraction trigger and responsive to the early-removal retraction trigger to automatically retract the syringe assembly from the injection site. 
     In an exemplary embodiment, raising of the injection button  116  to the vertically raised position may cause the syringe needle  120  to bend upward, thus preventing undesirable reuse of the syringe needle and the wearable automatic injection device. 
       FIGS. 2A-2F  illustrate an exemplary embodiment of a wearable automatic injection device  200  including a cartridge assembly that may be used to inject a dose of a therapeutic agent into the body of a patient.  FIG. 2A  illustrates a first end view and a first side view of the exemplary wearable device  200  in a packaged pre-injection state.  FIG. 2B  illustrates the first end view and the first side view of the exemplary device  200  in a pre-injection state in which a needle shield covering the injection needle is removed in preparation for an injection.  FIG. 2C  illustrates the first end view and the first side view of the exemplary device  200  during an injection in an injection state in which the patient&#39;s skin is pierced by the injection needle.  FIG. 2D  illustrates the first end view and the first side view of the exemplary device  200  during an injection in an injection state in which the barrel portion containing the dose of the therapeutic agent is deployed forwardly within the housing of the device  200 .  FIG. 2E  illustrates the first end view and the first side view of the exemplary device  200  during an injection in an injection state in which the bung is actuated by a plunger actuator to expel the dose of the therapeutic agent from the barrel portion.  FIG. 2F  illustrates the first end view and the first side view of the exemplary device  200  after an injection in a post-injection state in which the injection needle is retracted within the housing of the device  200 . 
     The wearable automatic injection device  200  may include a housing  202 . In an exemplary embodiment, the housing  202  may have an elongated configuration, although one of ordinary skill in the art will recognize that the housing  202  may have any suitable size, shape and configuration for housing a barrel portion containing a dose of a therapeutic agent to be injected. In an exemplary embodiment, the housing  202  may be formed of any suitable material including, but not limited to, plastic and other known materials. 
     The housing  202  of the wearable automatic injection device  200  may include an adhesive layer  224  disposed along a patient contact portion at the bottom of the housing  202  that is placed proximal to the skin of the patient or an article of clothing of the patient. In some exemplary embodiments, the adhesive layer  224  may be configured to be placed on the skin of the patient in order to attach the housing  202  to the patient to deliver the dose of the therapeutic agent. The adhesive layer  224  may include a non-adhesive tab  226  that is not adhesive. The non-adhesive tab  226  may be gripped by the patient and pulled to remove the wearable automatic injection device  200  from the skin or clothing of the patient. 
     Before the wearable automatic injection device  200  is put to use, e.g., in the package state illustrated in  FIG. 2A , the adhesive layer  224  may be covered by a protective film  228  which preserves the adhesive nature of the adhesive layer  124 . The protective film  228  may include a tab  230  which may be gripped by the patient and pulled to remove the protective film  228  from the adhesive layer  224 . This exposes the adhesive layer  224 , allowing the patient to attach the housing  202  to his or her skin or article of clothing by placing the side with the adhesive layer  224  on the skin or the article of clothing. 
     The housing  202  may house a therapeutic agent cartridge assembly extending substantially along a longitudinal axis L between a proximal end (farthest from the injection needle) and a distal end (nearest to the injection needle). The cartridge assembly may include a barrel portion  206  for holding a dose  208  of a therapeutic agent to be injected into a patient&#39;s skin. The barrel portion  206  may extend substantially along the longitudinal axis between a proximal end (farthest from the injection needle) and a distal end (nearest to the injection needle). In an exemplary embodiment, the barrel portion  206  may be a substantially cylindrical member having a circular cross-section, although one of ordinary skill in the art will recognize that the barrel portion  206  may have any suitable shape or configuration. 
     In an exemplary embodiment, the barrel portion  206  may be stationary within the housing  202  so that the injection process does not result in the movement of the barrel portion  206  within and relative to the housing  202 . In another exemplary embodiment, the barrel portion  206  may initially, i.e., before an injection in a pre-injection state, be in a retracted position toward the proximal end of the device  200  (as illustrated in  FIGS. 2A-2C ), and may be actuated during an injection in an injection state to an extended position toward the distal end of the device  200 . 
     A bung  210  may be provided at the proximal end of the barrel portion  206  to seal the dose of the therapeutic agent within the barrel portion  206  and to apply a force to the dose to expel the dose from the barrel portion  206 . The bung  210  may be moveable within the barrel portion  206  toward the distal end of the barrel portion  206  in order to expel the dose from the barrel portion  206  during an injection in an injection state. In an exemplary embodiment, the bung  210  may be configured to perform both functions of sealing the dose and squeezing the dose out of the barrel portion  206 . In another exemplary embodiment, a bung may be provided to seal the dose within the barrel portion  206  and a separate piston may be provided to impart a force to the bung in order to squeeze the dose out of the barrel portion  206 . 
     The cartridge assembly may include, at or near its proximal end, a plunger actuator  212  for selectively actuating the bung  210  forwardly within the barrel portion  206  toward the distal end in order to inject the therapeutically effective dose contained in the barrel portion  206  into a patient&#39;s skin. The plunger actuator  212  may employ an energy storage and controlled energy release mechanism to actuate the bung  210 . In exemplary embodiments, the plunger actuator  212  may be located outside the barrel portion  206  or partly or fully within the barrel portion  206 . In an exemplary embodiment, the plunger actuator  212  may drive the bung  210  directly or indirectly though the use of a plunger disposed between the bung  210  and the plunger actuator  212 . 
     In an exemplary embodiment, the plunger actuator  212  may include a biasing mechanism, e.g., a spring, that is retracted before injection and that is released during injection to actuate the bung  210  forwardly within the barrel portion  206 . In another exemplary embodiment, the plunger actuator  212  may include a chemical gas generator, e.g., an expanding foam, that is in a non-expanded phase before injection and that expands during injection to actuate the bung  210  forwardly within the barrel portion  206 . In other exemplary embodiments, the plunger actuator  212  may employ hydraulic pressure of working fluids, gas pressure of compressed gases, osmotic pressure, hydrogel expansion, and the like. 
     In an exemplary embodiment, the plunger actuator  212  may be moved forwardly within the barrel portion  206  in a substantially linear manner, i.e., substantially constant speed. This may allow the dose to be delivered to the patient at a substantially constant delivery rate. The plunger actuator  212  may include or may be coupled to a damping mechanism that may be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during energy release by the plunger actuator  212 . The controlled release of energy may result in a substantially linear delivery profile, i.e., a substantially constant rate of delivery of the dose over time, and may prevent abrupt changes in the speed of the delivery. 
     In an exemplary embodiment, a plunger actuator  212  may employ one or more fluid circuits containing a working fluid in which the hydraulic pressure of the working fluid applies a force to the bung to move the bung within the barrel portion of the cartridge. A damping mechanism may employ a flow restrictor placed in the fluid circuit between a source of the working fluid and the bung. 
     In another exemplary embodiment, a plunger actuator  212  may employ a biasing mechanism, for example, a spiral spring or a helical compression spring. A damping mechanism may employ a viscous damper, a swiss lever escapement, a runaway escapement, and the like. 
     In another exemplary embodiment, a plunger actuator  212  may employ a stepper motor connected to a gear drive system to provide a constant linear delivery profile. 
     The cartridge assembly may include, at or near its distal end, a cartridge stopper  214  that may include a septum and a cover  215  for the septum. The septum may be a pierceable layer of material that is disposed adjacent to the distal end of the barrel portion  206  in order to seal the dose in the barrel portion  206 . When intact, the septum may seal the dose within the barrel portion  206 . When pierced by a needle, for example, a syringe needle, the septum may allow the dose to leave the barrel portion  206  and enter the syringe needle. The septum may be formed of a material that may be pierced by a syringe needle. A cover may be provided to protectively cover the septum from accidental piercing by the syringe needle when the device  200  is in the packaged pre-injection state as illustrated in  FIG. 2A . In an exemplary embodiment, the cartridge stopper  214  may also include a cover to protectively cover a syringe needle provided in the vicinity of the cartridge stopper  214 , thereby preventing accidental piercing of the septum by the syringe needle when the device  200  is in the packaged pre-injection state as illustrated in  FIG. 2A . 
     The housing  202  of the wearable automatic injection device  200  may also house an injection button  216  bearing a hollow hypodermic injection needle  218  that is configured to pierce the patient&#39;s skin. In an exemplary embodiment, the injection needle  218  may be aligned orthogonally to the longitudinal axis L of the device  200 . In an exemplary embodiment, the injection needle  218  may be held in place by an injection needle carrier (not pictured) provided in the injection button  216  or separately from the injection button  216 . The injection needle  218  may have any suitable size, shape and configuration suitable for piercing the skin of the patient to deliver the therapeutic agent, and is not limited to the illustrative embodiment. Suitable needles may have a length configured or selected to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an exemplary embodiment, the injection needle  218  may have a length of about twelve mm and may be injected to a depth of about seven mm into the skin. In other exemplary embodiments, the injection needle  218  may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable injection needles may have a wall thickness suitable to provide sufficient mechanism strength, a diameter suitable to allow a desired flow rate of the injected substance while minimizing patient sensation, and a tip geometry suitable for the desired therapy while minimizing patient sensation. Suitable injection needles may be coated as needed to minimize patient sensation as allowed by therapy. The injection needle  218  may be covered and maintained in a septic condition by a needle cover  222 , for example, a rigid needle shield, a soft needle shield, or both. 
     The injection button  216  may also bear a hollow syringe needle  220  configured to pierce the septum and establish fluid communication with the barrel portion  206 . In an exemplary embodiment, the syringe needle  220  may be aligned parallel to the longitudinal axis L of the device  200 . The syringe needle  220  may have any suitable size, shape and configuration suitable for piercing the septum and is not limited to the illustrative embodiment. 
     In an exemplary embodiment, the injection needle  218  and the syringe needle  220  may be coupled to and in fluid communication with each other via the body of the injection button  216 . In another exemplary embodiment, the injection needle  218  and the syringe needle  220  may be coupled to and in fluid communication with each other via one or more fluid conduits (not pictured). In another exemplary embodiment, the injection needle  218  and the syringe needle  220  may be directly coupled to and in fluid communication with each other. 
     In an exemplary embodiment, before an injection in a pre-injection state, the injection button  216  may be in a vertically raised position relative to the housing  202  such that the injection button  216  protrudes from the top of the housing  202 , as illustrated in  FIGS. 2A and 2B . In this position, the injection needle  218  may be retracted within the housing  202  and may not be inserted into the patient&#39;s skin. In this position, the syringe needle  220  may be aligned vertically above the septum in the cartridge stopper  214  and may not pierce the septum. At the beginning of the injection process, the injection button  216  may be pressed downward, for example, by a user of the device or automatically. This may push the injection button  216  to a vertically depressed position relative to the housing  202  closer to the patient&#39;s skin such that the injection button  216  no longer protrudes from the top of the housing  202 , as illustrated in  FIGS. 2C-2E . In this position, the injection needle  218  may protrude from the bottom of the housing  202  and may be inserted into the patient&#39;s skin. In this position, the syringe needle  220  may be aligned with the septum in the cartridge stopper  214  and may pierce the septum. 
     In an exemplary embodiment, the septum may initially be spaced from the injection button  216 . In this embodiment, the syringe needle  220  may pierce the septum when the cartridge stopper  214  bearing the septum is advanced within the housing  202  toward the injection button  216 . That is, before an injection in a pre-injection state, the syringe needle  220  may be spaced from the septum such that there is no fluid communication between the barrel portion  206  and the injection needle  218  coupled to the injection button  216 . In an injection state, the barrel portion  206  may advance within the housing  202  toward the distal end of the device  200  so that the syringe needle  220  may pierce the septum and establish fluid communication between the barrel portion  206  and the injection needle  218  coupled to the injection button  216 . This fluid communication may allow the dose of the therapeutic agent to flow from the barrel portion  206  into the patient&#39;s skin through the syringe needle  220  and the injection needle  218  when pressure is applied to the dose by the bung  210  during an injection in an injection state. 
     Referring now to  FIG. 2F , in an exemplary embodiment, the housing  202  of the wearable automatic injection device  200  may include a skin sensor foot  232 , which is a structure housed under or in the portion of the housing  202  proximal to the injection site. Prior to injection of the therapeutic agent and during injection, the skin sensor foot  232  is retained within or forms a portion of the underside of the housing  202 . When the wearable automatic injection device  200  is attached to the injection site and activated, the skin sensor foot  232  may be free to move but may be constrained by the injection site. When the wearable automatic injection device  200  is removed from the injection site, regardless of whether the drug delivery was completed, the skin sensor foot  232  is no longer constrained, and extends and projects outside the periphery of the housing  202 . This, in turn, trips a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle  220  which may also raise the injection button  216  from the vertically lowered position to the vertically raised position, so that the injection button  216  protrudes from the top of the housing  202  and the injection needle  218  is retracted within the housing  202 . 
       FIG. 2A  illustrates the wearable automatic injection device  200  in a pre-injection state, for example, as packaged, in which the barrel portion  206  may be pre-fillable and/or pre-filled with the dose  208  of the therapeutic agent and in a retracted position ready for use. The barrel portion  206  may contain the dose  208  of the therapeutic agent in the interior space defined between the wall or walls of the barrel portion  206  and the bung  210 . In an embodiment, the plunger actuator  212  may store energy that, when released, may actuate the bung  210 . The injection button  216  may be partially disposed within the housing  202  at the vertically raised position above the injection site, and the injection needle  218  may be retracted within the housing  202 . The protrusion of the injection button  216  out of the top of the housing  202  may provide a visual indication to the patient that the wearable automatic injection device  200  is not in operation. 
       FIG. 2B  illustrates the wearable automatic injection device  200  in a pre-injection state in which the needle cover  222  and the septum cover are removed. In exemplary embodiments, the protective film  228  may include a linking member that is connected to the needle cover  222  and the septum and syringe needle covers in the cartridge stopper  214 . The linking member may include a tether or other linkage mechanism. When the protective film  228  is removed, the linking member of the protective film  228  may remove the needle cover  222  and the septum and syringe needle covers in the cartridge stopper  214 . 
       FIG. 2C  illustrates the wearable automatic injection device  200  during an injection in an injection state in which the injection button  216  is in the vertically lowered position within the housing  202 . In the vertically lowered position, the injection button  216  may be disposed within the housing  202  at a depressed or vertically lowered location above the injection site, and the injection needle  218  may project from the bottom of the housing  202  through an aperture in the housing  202  so that it can penetrate the skin at the injection site. In the vertically lowered state, the injection button  216  may not protrude from the top of the housing  202 , which may provide a visual indication to the patient that the wearable automatic injection device  200  is in operation. 
       FIG. 2D  illustrates the wearable automatic injection device  200  during an injection in an injection state in which the barrel portion  206  containing the dose  208  of the therapeutic agent is deployed forwardly from a retracted position to an extended position within the housing of the device  200 . The advancement of the barrel portion  206  may bring the distal end of the barrel portion  206  or the cartridge stopper  214  in the vicinity of or in contact with the injection button  216 . In an exemplary embodiment, the syringe needle  220  may pierce the septum held in the cartridge stopper  214  in order to establish fluid communication between the barrel portion  206  and the injection needle  218 . 
       FIG. 2E  illustrates the wearable automatic injection device  200  during an injection in an injection state in which the plunger actuator  212  is triggered to move the bung  210 . Triggering of the plunger actuator  212  may release stored energy in the plunger actuator  212  in order to move the bung  210  within the barrel portion  206  toward the distal end of the device  200 . The movement of the bung  210  may eject the dose of the therapeutic agent from the barrel portion  206  through the distal end of the barrel portion  206 . Any suitable mechanism may be used to trigger the plunger actuator  212  including, but not limited to, a linking member that is coupled to and activated by the depression of the injection button  216  or by the removal of the needle cover  222 , a trigger button that may be used by the user, and the like. 
       FIG. 2F  illustrates the wearable automatic injection device  200  after an injection in a post-injection state, for example, after injecting a therapeutically effective dose of the therapeutic agent or removal of the wearable automatic injection device  200  from the patient before delivery of a therapeutically effective dose of the therapeutic agent, in which the injection button  216  is in the vertically raised position. In the vertically raised position, the injection button  216  may be disposed partly within the housing  202  at an elevated or vertically raised location above the injection site, and the injection needle  218  may be retracted within the housing  202 . A portion of the injection button  216  may project from the top of the housing  202  to provide a visual indication to the patient that the wearable automatic injection device assembly  200  is not in operation (i.e., in a post-injection state). The barrel portion  206  may be empty of the therapeutic agent and the plunger actuator  212  may no longer store energy. A skin sensor foot  232  may extend from the bottom of the housing  202  upon removal of the device  200  from the injection site. 
     The housing  202  may include a retraction mechanism that automatically raises the injection button  216  from the vertically lowered injection state (shown in  FIGS. 2C-2E ) to the vertically raised post-injection state (shown in  FIG. 2F ). In an exemplary embodiment, the retraction mechanism may include a biasing mechanism, e.g., a spring, that biases the cartridge assembly away from the injection site when the retraction mechanism is triggered. 
     A retraction trigger, when activated, may trigger the retraction mechanism in order to raise the injection button  216  from the vertically lowered state to the vertically raised state. In an exemplary embodiment, the bung  210  and/or the plunger actuator  212  may include a linking member connected to the retraction trigger. The linking member may include a tether or other linkage mechanism. The linking member may be of a suitable length such that, when the bung  210  has been moved to the end of the barrel portion  206  (delivering a complete dose), the linking member triggers a latch that in turn trips the retraction trigger. In another exemplary embodiment, the extension of the skin sensor foot  232  from the bottom of the housing  202  may trip the retraction trigger. 
     In an exemplary embodiment, the retraction mechanism may include an end-of-dose retraction trigger that, when tripped, triggers the retraction mechanism. The end-of-dose retraction trigger may be tripped when the therapeutically effective dose of therapeutic agent in the wearable automatic injection device is delivered. In an exemplary embodiment, the end-of-dose retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon completed drug delivery. The retraction mechanism may also include an early-removal retraction trigger that, when tripped, triggers the retraction mechanism. The early-removal retraction trigger may be tripped when the wearable automatic injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is completely delivered. In an exemplary embodiment, the early-removal retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon removal of the wearable automatic injection device  200  from the injection site. The retraction mechanism is responsive to the end-of-dose retraction trigger and responsive to the early-removal retraction trigger to automatically retract the cartridge assembly from the injection site. 
     In exemplary embodiments, the barrel portion of the wearable automatic injection device  100  (in  FIG. 1 )/ 200  (in  FIG. 2 ) may be pre-fillable and/or pre-filled with any volume of a therapeutic agent, e.g., a therapeutic antibody, desired for intradermal, subcutaneous, or intramuscular injections. In an exemplary embodiment, the barrel portion  106  may be pre-fillable and/or pre-filled with a volume of between about 0.1 milliliters and about 1.0 milliliters, although exemplary devices are not limited to this exemplary range of therapeutic agent volumes. 
     In exemplary embodiments, the wearable automatic injection device  100  (in  FIG. 1 )/ 200  (in  FIG. 2 ) may be used to inject a therapeutically effective amount of therapeutic agent over a period of time ranging from about ten seconds to about twelve hours. Certain other exemplary embodiments provide actuation devices and systems that cause actuation of the syringe plunger at a slow rate in order to deliver the therapeutic agent to a patient at a slow rate. Exemplary slow embodiments may deliver therapeutic agent volumes of about 0.1 milliliters to about 1 milliliter or more in about five minutes to about thirty minutes, although exemplary delivery rates are not limited to this exemplary range. 
     Exemplary embodiments may provide a linear delivery profile for the therapeutic agent so that the delivery rate is substantially constant over time. In some cases, a linear delivery profile may reduce discomfort experienced by the patient. In an exemplary embodiment, the therapeutic agent may be delivered in a single slow bolus. 
     The rate of delivery of the therapeutic agent may be dependent on the ambient temperature. At room temperature, i.e., about 72° F., the accuracy of the delivery time may range between about three percent and about ten percent. 
     Exemplary dimensions of exemplary devices are described with reference to Tables 1-6. However, one of ordinary skill in the art will recognize that the exemplary dimensions are provided for illustrative purposes, and that exemplary automatic injection devices are not limited to the illustrative dimensions. 
     In an exemplary embodiment, a wearable automatic injection device may have an exemplary length of about 4.37 inches, an exemplary width of about 2.12 inches, and an exemplary height of about 1.25 inches. In an exemplary embodiment, the diameter of the barrel portion is about 1.470 inches and the length of the barrel portion is about 2.520 inches. Tables 1-3 summarize the components of the length, width and height, respectively, for two exemplary types of the exemplary device. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Summary of components of the length of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Septum 
                 0.397 
                 0.272 
               
               
                 Needle 
                 0.500 
                 0.500 
               
               
                 Barrel portion 
                 2.520 
                 2.520 
               
               
                 Advance spring 
                 0.470 
                 0.322 
               
               
                 Hydraulic connection 
                 0.113 
                 0.113 
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Total 
                 4.370 
                 3.968 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Summary of components of the width of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Needle lock 
                 1.045 
                 0.935 
               
               
                 Barrel portion width 
                 0.470 
                 0.470 
               
               
                 Syringe lock 
                 0.235 
                 0.235 
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Total 
                 2.120 
                 1.880 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Summary of components of the height of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.100 
                 0.120 
               
               
                 Needle cover 
                 0.431 
                 0.431 
               
               
                 Septum 
                 0.400 
                 0.350 
               
               
                 Spring solid height 
                 0.200 
                 0.000 
               
               
                 Wall thickness 
                 0.185 
                 0.125 
               
               
                 Total 
                 1.316 
                 1.026 
               
               
                   
               
            
           
         
       
     
     In an exemplary embodiment, the diameter of the barrel portion in production may be increased from about 1.470 inches by about 0.125 inches, and the length of the barrel portion may be decreased in production from about 2.520 inches by about 0.732 inches. Tables 4-6 summarize the components of the length, width and height, respectively, for two exemplary types of the exemplary device. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Summary of components of the length of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Septum 
                 0.397 
                 0.272 
               
               
                 Needle 
                 0.500 
                 0.250 
               
               
                 Barrel portion 
                 2.520 
                 1.788 
               
               
                 Advance spring 
                 0.470 
                 0.322 
               
               
                 Hydraulic connection 
                 0.113 
                 0.113 
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Total 
                 4.370 
                 2.986 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Summary of components of the width of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Needle lock 
                 1.045 
                 0.935 
               
               
                 Barrel portion width 
                 0.470 
                 0.595 
               
               
                 Syringe lock 
                 0.235 
                 0.235 
               
               
                 Wall thickness 
                 0.185 
                 0.120 
               
               
                 Total 
                 2.120 
                 2.005 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Summary of components of the height of an exemplary device (inch) 
               
            
           
           
               
               
               
            
               
                 Element 
                 Type 1 
                 Type 2 
               
               
                   
               
               
                 Wall thickness 
                 0.100 
                 0.120 
               
               
                 Needle cover 
                 0.431 
                 0.493 
               
               
                 Septum 
                 0.400 
                 0.350 
               
               
                 Spring solid height 
                 0.200 
                 0.000 
               
               
                 Wall thickness 
                 0.185 
                 0.125 
               
               
                 Total 
                 1.316 
                 1.088 
               
               
                   
               
            
           
         
       
     
       FIG. 3  is a flow chart of an exemplary method  300  of assembling an exemplary automatic injection device  100 . In step  302 , a syringe or a cartridge assembly may be sterilized and assembled. In step  304 , an injection button may be sterilized and assembled. In step  306 , the barrel portion of the syringe or cartridge assembly may be filled with a dose of a therapeutic agent that is to be administered to a patient. In step  308 , a sterile bung may be placed in the barrel portion of the syringe or cartridge assembly to seal the therapeutic agent inside the barrel portion. The containment of the therapeutic agent inside the wearable automatic injection device by the sterile barrel portion and the sterile bung maintains sterility of the therapeutic agent. As such, in an exemplary embodiment, the remaining components of the wearable automatic injection device may be assembled in a non-sterile environment after the barrel portion is pre-fillable and/or pre-filled with the therapeutic agent. For example, in step  310 , a non-sterile plunger actuator, for example, a biasing mechanism may be inserted behind the bung. 
     In step  312 , the syringe or cartridge assembly may be inserted into a non-sterile housing. The housing may be pre-assembled with other non-sterile components, e.g., an adhesive layer, a protective film, a skin sensor foot, and the like. In step  314 , the injection button (with an enclosed sterile fluid path and one or more needles) may be inserted into the non-sterile housing. In exemplary embodiments, the barrel portion, the enclosed hypodermic injection needle, the syringe needle, the needle cover, and the bung may provide the sterility barrier for the therapeutic agent and the fluid path. Thus, once the barrel portion is filled with the therapeutic agent and the bung is inserted into the barrel portion, assembly of the remaining portions of the device does not require aseptic conditions. No therapeutic agent transfer steps need to be performed by the user. In step  316 , the assembled automatic injection device may be placed in an over-wrap, if necessary, and may then be commercially packaged for sale.  FIG. 1A  illustrates an exemplary embodiment of the assembled automatic injection device in the packaged pre-injection state. 
       FIG. 4  is a flow chart of an exemplary method  400  of using an exemplary automatic injection device. The wearable automatic injection device packaged and pre-fillable and/or pre-filled with a therapeutic agent may be generally stored in refrigerated storage before use. In step  402 , the packaged automatic injection device may be removed from storage. In step  404 , the wearable automatic injection device may be removed from its packaging and any over-wrap, and warmed to room temperature, e.g., by leaving the wearable device outside the packaging at room temperature or by warming the wearable device. In step  406 , the patient may confirm that the barrel portion contains a volume of the therapeutic agent through an therapeutic agent inspection window disposed in the device housing, and may also confirm the clarity of the therapeutic agent if necessary. 
     In step  408 , the injection site on the skin of the patient may be selected and prepared for the delivery of the therapeutic agent. In step  410 , the patient uses the wearable automatic injection device to inject the therapeutic agent into the injection site. The steps generally involved within step  410  are described below in connection with  FIG. 5 . In step  412 , after performing the injection, the wearable automatic injection device may be removed from the patient and discarded in an appropriate manner. 
       FIG. 5  is a flow chart of an exemplary method  500  of using an exemplary automatic injection device to inject a therapeutically effective amount of a therapeutic agent into a patient. Exemplary method  500  is a detailed outline of step  410  in  FIG. 4 . In step  502 , the patient removes the protective film that covers and protects the adhesive layer of the wearable automatic injection device. In some exemplary embodiments, removal of the protective film also removes the needle cover and the septum cover in the syringe or cartridge stopper. 
     In step  504 , the patient applies the patient contact portion of the wearable automatic injection device with the adhesive layer to the injection site (or an article of clothing around the injections site) so that the device is reliably retained on the injection site during the injection of the therapeutically effective dose of therapeutic agent. 
     In step  506 , once the wearable automatic injection device is attached to the injection site, the patient may depress the injection button from a vertically raised position in the pre-injection state to a vertically lowered position in the injection state within the housing. In the vertically raised position, the end of the injection button bearing the injection needle is retracted within the housing and is not exposed to the outside of the housing. When depressed, the end of the injection button bearing the injection needle is moved downward either linearly or rotationally within the housing so that the injection needle emerges from an aperture in the housing and is exposed. This allows the injection needle to penetrate the skin of the patient to an appropriate depth for injection of the therapeutic agent. The downward movement of the injection button in the housing may be linear (i.e., a vertical downward movement) or rotary (i.e., in a circular movement about a pivot point). 
     In an exemplary embodiment, the injection button is depressed into the housing by the patient manually pushing down the injection button. In another exemplary embodiment, the patient may activate an injection trigger, e.g., a trigger button located in a conveniently accessible location such as the top of the housing, which causes the injection trigger to automatically depress the injection button into the housing and in turn, cause the injection needle to pierce the skin of the patient. In an exemplary embodiment, pressing the injection trigger button may release a latch in the injection trigger that allows a spring to bias the injection button downwardly in the housing. The same motion of the injection button may cause the injection needle to be inserted into the injection site to an appropriate depth. 
     In step  508 , depressing the injection button may trigger a syringe or cartridge actuator that moves the syringe or cartridge assembly, more specifically, the barrel portion, forwardly within and relative to the housing from a retracted position (in which the distal end of the syringe or cartridge assembly is spaced from the injection button) to an extended position (in which the distal end of the syringe or cartridge assembly is adjacent to and/or in contact with the injection button). In another exemplary embodiment, the syringe or cartridge actuator is triggered not by depressing the injection button, but by the user activating a trigger, e.g., in the form of a trigger button. In an exemplary embodiment, movement of the syringe or cartridge assembly toward the injection button may cause the syringe needle to pierce the septum. 
     In step  510 , when the distal end of the barrel portion makes contact with the injection button, the plunger actuator may break the static friction (i.e., stiction) between the bung and the inside wall or walls of the barrel portion and cause the bung to move forwardly toward the syringe needle in the injection button to deliver the therapeutic agent via the injection needle. The plunger actuator may overcome the bung stiction in one step and actuate the bung in a subsequent step, or the plunger actuator may overcome the bung stiction and actuate the bung concurrently. Movement of the bung may cause the dose to be released through the syringe needle into the injection needle and thereby into the patient&#39;s skin. 
     In an exemplary embodiment, the forward advancement of the syringe or cartridge assembly within the housing and the forward advancement of the bung within the barrel portion may take place in separate steps. In another exemplary embodiment, the forward advancement of the syringe or cartridge assembly within the housing and the forward advancement of the bung within the barrel portion may take place in the same step, for example, simultaneously. 
     The rate of therapeutic agent delivery may depend on the characteristics of the plunger actuator. The plunger actuator may take the form of several exemplary embodiments. In some exemplary embodiments, the plunger actuator may employ means of energy storage and release, e.g., biasing mechanisms (including, but not limited to, one or more springs, for example, spiral springs or helical compression springs), compressed gases, chemical gas generators (such as expanding foams), osmotic pressure, hydrogel expansion, etc. A damping or control mechanism (including, but not limited to, a viscous damper or an escapement) may be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during energy release by the plunger actuator. A flow restrictor placed in a fluid pathway between the needle and the bung may be used to further regulate the rate of therapeutic agent delivery, e.g., where the plunger actuator delivers an unconstrained spring force via a working fluid. Thus, an appropriate plunger actuator and an appropriate control mechanism may be selected to deliver the dose at a controlled rate, e.g., in a single slow bolus free of or substantially free of any burning sensation to the patient. 
     In an exemplary embodiment, depressing the injection button may arm the retraction mechanism which, when triggered, retracts the injection button into the housing  102  after an injection in a post-injection state. 
     In step  512 , upon delivery of the therapeutically effective dose, the bung and/or the plunger actuator may trip the end-of-dose retraction trigger of the retraction mechanism. The bung and/or the plunger actuator may include a linking member connected to the end-of-dose retraction trigger. The linking member may include a tether or other linkage mechanism. The linking member may be of a suitable length such that, when the bung has been moved to the end of the syringe or cartridge assembly (delivering a complete dose), the linking member triggers a latch that in turn trips the retraction trigger. 
     In step  514 , once the end-of-dose retraction trigger is tripped, the retraction mechanism may retract the injection button upward inside the housing and away from the patient contact portion so that the syringe or cartridge assembly enters a post-injection state. In an exemplary embodiment, the movement of the injection button from the injection state to the post-injection state creates an audible sound, e.g., a “click,” which provides an aural indication of the completion of therapeutic agent delivery. Once retracted, the injection button protrudes outside the housing, which provides a visual indication of the state of the wearable automatic injection device, for example, completion of therapeutic agent delivery or a visual indication of the device in the post-injection state. 
     However, if the wearable device is removed from the skin of the patient before the completion of therapeutically effective dose of the therapeutic agent, the skin sensor foot may extend to the outside of the housing and trip the early-removal retraction trigger of the retraction mechanism. Once the early-removal retraction trigger is tripped, the retraction mechanism deploys the injection button upward in the housing away from the patient contact portion so that the syringe or cartridge assembly enters a post-injection state. In an exemplary embodiment, the plunger actuator may continue to move forwardly in the barrel portion toward the syringe needle when the device is removed from the patient before completion of delivery of a therapeutically effective dose of the therapeutic agent. 
     In step  516 , upon retraction, a needle lock engages with the injection needle to prevent redeployment of the injection needle to provide needle-stick protection. The needle lock may be a member that prevents the injection needle from exiting the housing once engaged, and may be located in the housing near the injection needle. Exemplary needle locks may include, but are not limited to, a plastic plate, a metal plate, a clip, etc. 
       FIGS. 6A-6C  illustrate an exemplary embodiment of a wearable automatic injection device  600  suitable for linear insertion of a needle into the skin of a patient. By linear insertion, the end of a cartridge assembly bearing a needle descends linearly within a housing of the wearable automatic injection device so that the needle is inserted into the patient. More specifically,  FIG. 6A  illustrates the exemplary wearable device in a Pre-Injection State, for example, as packaged;  FIG. 6B  illustrates the exemplary wearable device in an Injection State just before, while or just after it injects a therapeutic agent into a patient; and  FIG. 6C  illustrates the exemplary wearable device in a Post Injection State after it has completed delivery of the therapeutic agent into the patient or removed from the patient prior to completion of delivery of the therapeutic agent. 
     The wearable automatic injection device  600  includes a housing  635  for housing a therapeutic agent cartridge assembly  610 , containing a dose of a therapeutic agent to be injected subcutaneously into a patient. In an exemplary embodiment, the outside of the therapeutic agent cartridge assembly  610  may be provided with one or more ridges, and the inside of the housing  635  may be provided with one or more grooves or channels that provide a smooth pathway for the ridges of the cartridge assembly  610  as the cartridge assembly moves within the housing  635 . The one or more ridges on the outside of the cartridge assembly  610  may take the form of raised lines on the cartridge assembly  610 . The one or more grooves or channels on the inside of the housing  635  may take the formed of U-shaped depressed or trough-like lines. The top portion of the grooves or channels may be open so that the ridges may slide in and out of the top portion of the grooves or channels. In the linear insertion embodiment illustrated in  FIGS. 6A-6C , the ridges and grooves/channels may be straight lines. In the rotary insertion embodiment illustrated in  FIGS. 7A-7C , the ridges and grooves/channels may be lines that are curved about the center of rotation, i.e., the pivot point of the cartridge assembly  610 . 
     In another exemplary embodiment, the outside of the cartridge assembly  610  may not have any ridges, and the inside of the housing  635  may not have any grooves or channels. 
     The housing  635  preferably has an elongated configuration, though one of ordinary skill in the art will recognize that the housing  635  may have any suitable size, shape and configuration for housing a hypodermic needle couplable to a barrel portion of a therapeutic agent to be injected. The housing  635  may be formed of any suitable material including, but not limited to, plastic and other known materials. In another embodiment, the therapeutic agent cartridge  610  may be formed of any compatible material suitable for sterilization including, but not limited to, glass and other known materials. 
     The housing  635  includes an adhesive layer  640  disposed along a patient contact portion of the housing  635  that is placed proximal to the skin of the patient or an article of clothing of the patient. In some embodiments, the adhesive layer  640  is configured to be placed on the skin of the patient to attach the housing  635  to the patient to deliver a therapeutic agent. The adhesive layer  640  includes a non-adhesive tab  645  which is not adhesive. The non-adhesive tab  645  may be gripped by the patient and pulled to remove the adhesive layer  640  and thus the wearable automatic injection device  600  from the skin or clothing of the patient. 
     Before the wearable automatic injection device  600  is put to use, e.g., in the Pre-Injection state, the adhesive layer  640  is covered by a protective film  650  which preserves the adhesive nature of the adhesive layer  640 . The protective film  650  may include a tab  655  which may be gripped by the patient and pulled to remove the protective film  650  from the adhesive layer  640 . This exposes the adhesive layer  640 , allowing the patient to attach the housing  635  to his or her skin or article of clothing by placing the side with the adhesive layer  640  on the skin or the article of clothing. 
     In exemplary embodiments, the protective film  650  (in  FIG. 6A )/ 750  (in  FIG. 7A ) may include a linking member that is connected to the plunger actuator  630  (in  FIG. 6A )/ 730  (in  FIG. 7A ). The linking member may include a tether or other linkage mechanism. When the protective film  650  (in  FIG. 6A )/ 750  (in  FIG. 7A ) is removed, the linking member of the protective film  650  (in  FIG. 6A )/ 750  (in  FIG. 7A ) relieves static friction between the bung  615  (in  FIG. 6A )/ 715  (in  FIG. 7A ) and the interior wall of the barrel  605  (in  FIG. 6A )/ 705  (in  FIG. 7A ), and triggers the plunger actuator  630  (in  FIG. 6A )/ 730  (in  FIG. 7A ). 
     The therapeutic agent cartridge assembly  610  may include a hollow barrel portion  605  for holding a therapeutically effective dose of the therapeutic agent to be injected. The illustrative barrel portion  605  is substantially cylindrical in shape, although one of ordinary skill in the art will recognize that the barrel portion  605  may have any suitable shape or configuration. A bung  615  seals the dose of the therapeutic agent within the barrel portion  605 . 
     The therapeutic agent cartridge assembly  610  may also include a hollow hypodermic needle  625  connectable to or connected to, and in fluid communication with, the barrel portion  605 , through which the dose can be ejected by applying pressure to the bung  615 . The needle  625  may have any suitable size, shape and configuration suitable for piercing the skin of the patient to deliver the therapeutic agent subcutaneously, and is not limited to the illustrative embodiment. Suitable needles may have a length configured or selected to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an exemplary embodiment, needle  625  may have a length of about twelve mm and may be injected to a depth of about seven mm into the skin. In other exemplary embodiments, needle  625  may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable needles may have a wall thickness suitable to provide sufficient mechanism strength, a diameter suitable to allow a desired flow rate of the injected substance while minimizing patient sensation, and a tip geometry suitable for the desired therapy while minimizing patient sensation. Suitable needles may be coated as needed to minimize patient sensation as allowed by therapy. Needle  625  may be covered and maintained in a septic condition by a soft and rigid needle shield assembly  620 . 
     In the exemplary embodiment illustrated in  FIGS. 6A-6C , the needle  625  projects substantially at a right angle to the longitudinal axis of the wearable device  600 . In this exemplary embodiment, the barrel portion  605  includes an elbow  607  that extends substantially at a right angle to the longitudinal axis of the device  600 . In this embodiment, the needle  625  is connected to the elbow  607 . 
     The wearable automatic injection device  600  may include a plunger actuator  630  for selectively actuating the bung  615  forwardly toward the distal end of the therapeutic agent cartridge assembly  610  to inject the therapeutically effective dose contained in the barrel portion  605  into the patient. The plunger actuator  630  may employ an energy storage and controlled energy release mechanism to actuate the bung  615 . In an exemplary embodiment, the plunger actuator  630  may include a biasing mechanism, e.g., a spring, that is retracted before injection and that is released during injection to actuate the bung  615  forwardly in the barrel portion  605 . In another exemplary embodiment, the plunger actuator  630  may include a chemical gas generator, e.g., an expanding foam, that is in a non-expanded phase before injection and that expands during injection to actuate the bung  615  forwardly in the barrel portion  605  toward the distal end of the therapeutic agent cartridge assembly  610 . In other exemplary embodiments, the plunger actuator  630  may employ compressed gases, osmotic pressure, hydrogel expansion, etc. A damping mechanism may be used to absorb energy, for example, an initial release of energy, and to provide a controlled release of energy during energy release by the plunger actuator  630  (in  FIG. 6A )/ 730  (in  FIG. 7A ). A flow restrictor placed in a fluid pathway between the needle and the bung  615  (in  FIG. 6A )/ 715  (in  FIG. 7A ) may be used to further regulate the rate of therapeutic agent delivery, e.g., where the plunger actuator  630  (in  FIG. 6A )/ 730  (in  FIG. 7A ) delivers an unconstrained spring force. 
     In an exemplary embodiment, the plunger actuator  630  may be advanced forwardly inside the barrel portion  605  in a constant linear motion. Any number of mechanisms, internal or external to the wearable automatic injection device  600 , may be used to provide a constant linear motion including, but not limited to, a stepper motor connected to a gear drive system. Other exemplary mechanisms for providing a substantially constant linear motion in a controlled fashion are described with reference to  FIGS. 24-45 . 
     The bung  615  (in  FIG. 6A )/ 715  (in  FIG. 7A ) and/or the plunger actuator  630  (in  FIG. 6A )/ 730  (in  FIG. 7A ) may include a linking member connected to the retraction trigger. The linking member may include a tether or other linkage mechanism. The linking member may be of a suitable length such that, when the bung  615  (in  FIG. 6A )/ 715  (in  FIG. 7A ) has been moved to the end of the cartridge assembly  610  (in  FIG. 6A )/ 710  (in  FIG. 7A ) (delivering a complete dose), the linking member triggers a latch that in turn trips the retraction trigger. 
     Referring now to  FIG. 6C , in an exemplary embodiment, the housing  635  includes a skin sensor foot  660 , which is a structure housed under or in the portion of the housing  635  proximal to the injection site. Prior to injection of the therapeutic agent and during injection, the skin sensor foot  660  is retained within or forms a portion of the underside of the housing  635 . When the wearable automatic injection device  600  is attached to the injection site and activated, the skin sensor foot  660  may be free to move but may be constrained by the injection site. When the wearable automatic injection device  600  is removed from the injection site, regardless of whether the drug delivery was completed, the skin sensor foot  660  is no longer constrained, and extends and projects outside the periphery of the housing  635 . This, in turn, trips the removal retraction trigger. 
       FIG. 6A  illustrates the wearable automatic injection device  600  in a Pre-Injection State, for example, as packaged and ready for use or as ready for packaging. The device  600  may include a pre-fillable and/or pre-filled syringe or cartridge assembly. In an exemplary embodiment, in a pre-injection state, the syringe or cartridge assembly may be in a retracted position ready for use. In the Pre-Injection State, the therapeutic agent cartridge assembly  610  is partially disposed within the housing  635  at an elevated location distal from the injection site, and the needle  625  is retracted within the housing  635 . Visual indications to the patient that the wearable automatic injection device  600  is not in operation may include a portion of the therapeutic agent cartridge assembly  610  projecting outside the housing  635  in the pre-injection state. The barrel portion  605  contains a dose of a therapeutic agent which is contained by the interior space defined between the wall or walls of the barrel portion  605  and the bung  615 . In an embodiment, the plunger actuator  630  stores energy. 
       FIG. 6B  illustrates the wearable automatic injection device  600  in an Injection State ready to inject, injecting or just after injecting a therapeutically effective dose of a therapeutic agent, in which the therapeutic agent cartridge assembly  610  is in a depressed position. In the depressed position, the therapeutic agent cartridge assembly  610  is disposed within the housing  635  at a depressed location proximal to the injection site, and the needle  625  projects outside the housing  635  through an aperture in the housing  635  so that it can penetrate the skin at the injection site. In the Injection State, the therapeutic agent cartridge assembly  610  does not project outside the housing  635  to provide a visual indication to the patient that the wearable automatic injection device  600  is in operation. The plunger actuator  630  releases its stored energy to actuate the bung  615 . This cooperative movement of the plunger actuator  630  and the bung  615  ejects the therapeutic agent in the barrel portion  605  out through the needle  625 . 
       FIG. 6C  illustrates the wearable automatic injection device  600  in a Post Injection State, for example, after injecting a therapeutically effective dose of the therapeutic agent or removal of the wearable automatic injection device  600  from the patient before delivery of a therapeutically effective dose of the therapeutic agent, in which the therapeutic agent cartridge assembly  610  is in a retracted position. In the retracted position, the therapeutic agent cartridge assembly  610  is disposed within the housing  635  at an elevated location distal from the injection site, and the needle  625  is retracted within the housing  635 . A portion of the therapeutic agent cartridge assembly  610  projects outside the housing  635  to provide a visual indication to the patient that the wearable automatic injection device assembly  600  is not in operation (i.e., in a Post-Injection state). The barrel portion  605  may be empty of the therapeutic agent, and the plunger actuator  630  may no longer store energy. 
     The housing  635  includes a retraction mechanism that automatically raises the therapeutic agent cartridge assembly  610  from the Injection State (depressed position shown in  FIG. 6B ) to the Post-Injection state (retracted position shown in  FIG. 6C ). In an exemplary embodiment, the retraction mechanism may include a biasing mechanism, e.g., a spring, that biases the cartridge assembly away from the injection site when the retraction mechanism is triggered. 
     The retraction mechanism includes an end-of-dose retraction trigger that, when tripped, triggers the retraction mechanism. The end-of-dose retraction trigger is tripped when the therapeutically effective dose of therapeutic agent in the wearable automatic injection device is delivered. In an exemplary embodiment, the end-of-dose retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon completed drug delivery. The retraction mechanism also includes an early-removal retraction trigger that, when tripped, triggers the retraction mechanism. The early-removal retraction trigger is tripped when the wearable automatic injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is completely delivered. In an exemplary embodiment, the early-removal retraction trigger may include a latch, e.g., a flexible plastic hook, that is released upon removal of the wearable automatic injection device  600  from the injection site. The retraction mechanism is responsive to the end-of-dose retraction trigger and responsive to the early-removal retraction trigger to automatically retract the cartridge assembly from the injection site. 
       FIGS. 7A-7C  illustrate an exemplary embodiment of a wearable automatic injection device  700  suitable for rotary insertion of the needle into the skin of a patient. In rotary insertion, the end of a therapeutic agent cartridge assembly  710  bearing the needle  725  descends in a rotary fashion about a pivot point to insert the needle  725  into the skin of the patient. More specifically,  FIG. 7A  illustrates the exemplary wearable device in a Pre-Injection State, for example, as packaged with a pre-filled and curved sterile hypodermic needle and barrel portion holding a therapeutic agent;  FIG. 7B  illustrates the exemplary wearable device while in an Injection State just before, while or just after injecting a therapeutic agent into a patient; and  FIG. 7C  illustrates the exemplary wearable device in a Post Injection State after delivery of the therapeutic agent into the patient or removal of the wearable device from the patient prior to completing delivery of the therapeutic agent to the patient. 
     The therapeutic agent cartridge assembly  710  is rotatably movable within the housing  735  about a pivot point  765  in the housing. In an exemplary embodiment, the outside of the therapeutic agent cartridge assembly  710  may be provided with one or more ridges, and the inside of the housing  735  may be provided with one or more grooves or channels that provide a pathway for the ridges of the cartridge  710  as the cartridge moves within the housing  735  amongst the various states. In another exemplary embodiment, the outside of the cartridge assembly  710  is free of ridges, and the inside of the housing  735  is free of grooves or channels. 
     When the therapeutic agent cartridge assembly  710  is depressed into the housing  735 , the therapeutic agent cartridge assembly  710  moves rotatably downward about the pivot point  765  such that the needle  725  becomes exposed and penetrates the skin of the patient. In this exemplary embodiment, the needle  725  penetrates the skin of the patient at an angle offset from 90°. Similarly, when the therapeutic agent cartridge assembly  710  is retracted, the therapeutic agent cartridge assembly  710  moves rotatably upward about the pivot point  765  such that the needle  725  retracts within the housing  735 . The mechanism to implement this rotational motion of the therapeutic agent cartridge assembly  710  may be simpler and more robust than the mechanism required for the linear insertion of  FIGS. 6A-6C . 
     The needle  725  is curved, with a radius defined by the pivot point  765  and the distance from the needle  715  to the pivot point  765  along the longitudinal axis of the housing  735 . The curvature of the needle  725  increases the comfort of the patient during insertion of the needle. The needle  725  may be preferentially oriented with the sharp needle tip closest to the pivot point  765 . 
     Features in  FIGS. 7A-7C  similar to those illustrated in  FIGS. 6A-6C  are described above in connection with  FIGS. 6A-6C . 
     In exemplary embodiments, the therapeutic agent cartridge assembly  610  and  720  of  FIGS. 6A-6C and 7A-7C , respectively, may be pre-fillable and/or pre-filled with any volume of a therapeutic agent, e.g., a therapeutic antibody, desired for intradermal, subcutaneous, or intramuscular injections. In an exemplary embodiment, the cartridge assembly  610  and  720  may be pre-fillable and/or pre-filled with a volume of about 0.8-0.85 milliliters, although exemplary cartridge assemblies are not limited to these exemplary volumes. In another exemplary embodiment, the cartridge assembly  610  and  720  may be pre-fillable and/or pre-filled with a volume of about 1 milliliter or more. 
     In exemplary embodiments, the wearable automatic injection device  600  (in  FIG. 6A )/ 700  (in  FIG. 7A ) may be used to inject the therapeutically effective amount of therapeutic agent over a period of time ranging from about ten seconds to about twelve hours. In an exemplary embodiment, the therapeutic agent may be delivered at a fixed rate for a delivery time of between about five minutes and about thirty minutes. The wearable automatic injection device  600  (in  FIG. 6A )/ 700  (in  FIG. 7A ) may be used to inject a volume of therapeutic agent in a single slow bolus. 
     The rate of delivery of the therapeutic agent may be dependent on the ambient temperature. At room temperature, i.e., about 72° F., the accuracy of the delivery time may range between about three percent and about ten percent. 
       FIG. 8  is a flow chart of an exemplary method  800  of assembling an exemplary wearable automatic injection device  600  or  700 . In step  805 , the barrel portion  605 / 705 , needle  625 / 725  and needle shield  620 / 720  are sterilized. In step  810 , the barrel portion  605 / 705  is filled with a dose of the therapeutic agent that is to be administered to the patient. In step  815 , a sterile bung  615 / 715  is placed in the barrel portion  605 / 705  to seal the therapeutic agent inside the barrel portion  605 / 705 . The containment of the therapeutic agent inside the wearable automatic injection device  600  or  700  by the sterile barrel portion  605 / 705 , the sterile bung  615 / 715  and the needle shroud  620 / 720  maintains sterility of the therapeutic agent and the needle  625 / 725 . As such, the remaining components of the wearable automatic injection device may be assembled in a non-sterile environment after the barrel portion  605 / 705  is pre-filled with a therapeutic agent. For example, in step  820 , a non-sterile plunger actuator  630 / 730  is inserted behind the bung  615 / 715  in the therapeutic agent cartridge assembly  610 / 710 . 
     In step  825 , the therapeutic agent cartridge assembly  610 / 710  is inserted into a non-sterile housing  635 / 735 . The housing  635 / 735  may be pre-assembled with other non-sterile components, e.g., the adhesive layer  640 / 740 , the protective film  650 / 750 , the skin sensor foot  660 / 760 . In exemplary embodiments, the barrel portion  605 / 705 , the needle  625 / 725 , the needle shield  620 / 720  and the bung  615 / 715  of the therapeutic agent cartridge assembly  610 / 710  provide the sterility barrier for the therapeutic agent and the subcutaneous contact surfaces. Thus, once the barrel portion  605 / 705  is filled with the therapeutic agent, the plunger  615 / 715  is inserted into the barrel portion  605 / 705  and the needle shroud  620 / 720  is in place: assembly of the remaining portions of the therapeutic agent cartridge assembly  610 / 710  and assembly of the housing  635 / 735  do not require aseptic conditions. No therapeutic agent transfer steps need to be performed by the user.  FIGS. 6A and 7A  illustrate exemplary embodiments of the wearable assembled automatic injection device  600 / 700  in a Pre-Injection state. 
     In step  830 , the assembled wearable automatic injection device  600 / 700  may be placed in an over-wrap, if necessary, and is then commercially packaged for sale. 
       FIG. 9  is a flow chart of an exemplary method  900  of using an exemplary wearable automatic injection device  600  or  700 . The wearable automatic injection device  600 / 700  packaged and pre-filled with a therapeutic agent is generally stored in refrigerated storage before use. In step  905 , the packaged wearable automatic injection device  600 / 700  is removed from storage. In step  910 , the wearable automatic injection device  600 / 700  is removed from its packaging and any over-wrap and warmed to room temperature, e.g., by leaving the wearable device outside the packaging at room temperature or by warming the wearable device. In step  915 , the patient confirms the therapeutic agent cartridge assembly  610 / 710  includes a volume of the therapeutic agent in the wearable device  600 / 700  through an therapeutic agent inspection window disposed in the wearable device housing and may also confirm the clarity of the therapeutic agent, if necessary. In step  920 , the injection site on the skin of the patient is selected and prepared for the delivery of the therapeutic agent. In step  925 , the patient uses the wearable automatic injection device  600 / 700  to inject the therapeutic agent into the injection site. The steps generally involved within step  920  are described below in connection with  FIG. 10 . In step  930 , after the wearable automatic injection device  600 / 700  is removed from the patient, the removed wearable automatic injection device  600 / 700  is discarded in an appropriate manner 
       FIG. 10  is a flow chart of an exemplary method  1000  of using an exemplary wearable automatic injection device  600  or  700  to inject a therapeutically effective amount of a therapeutic agent into a patient. Exemplary method  1000  is a detailed outline of step  920  in  FIG. 9 . In step  1005 , the patient removes the protective film  650 / 750  that covers and protects the adhesive layer  640 / 740  of the wearable automatic injection device  600 / 700 . In some exemplary embodiments, removal of the protective film  650 / 750  also removes the needle shield  620 / 720  and exposes the needle  625 / 725  for injection. In some exemplary embodiments, removal of the protective film  650 / 750  also breaks static friction (i.e., stiction) between the bung  615 / 715  and the interior wall of the barrel  605 / 705  and triggers the plunger actuator  630 / 730 . In exemplary embodiments, the protective film  650 / 750  may include a linking member that is connected to the plunger actuator  630 / 730 . The linking member may include a tether or other linkage mechanism. When the protective film  650 / 750  is removed, the linking member of the protective film  650 / 750  relieves static friction between the bung  615 / 715  and the interior wall of the barrel  605 / 705 , and triggers the plunger actuator  630 / 730 . 
     In step  1010 , the patient applies the patient contact portion of the wearable automatic injection device  600 / 700  with the adhesive layer  640 / 740  to the injection site (or an article of clothing around the injections site) so that the wearable device is reliably retained on the injection site during the injection of the therapeutically effective dose of therapeutic agent. 
     In step  1015 , once the wearable automatic injection device  600 / 700  is attached to the injection site, the therapeutic agent cartridge assembly  610 / 710  is depressed from a ready position in the Pre-Injection State to a depressed position in the Injection State within the housing  635 / 735 . In the ready position, the end of the therapeutic agent cartridge assembly  610 / 710  bearing the needle  625 / 725  is retracted within the housing  635 / 735  and is not exposed to the outside of the housing. When depressed, the end of the therapeutic agent cartridge assembly  610 / 710  bearing the needle  625 / 725  is moved downward either linearly or rotationally within the housing  635 / 735  so that the needle  625 / 725  emerges from an aperture in the housing  635 / 735  and is exposed. This allows the needle  625 / 725  to penetrate the skin of the patient to an appropriate depth for injection of the therapeutic agent. The downward movement of the therapeutic agent cartridge assembly  610 / 710  in the housing  635 / 735  may be linear (i.e., a vertical downward movement) or rotary (i.e., in a circular movement about a pivot point).  FIGS. 6B and 7B  illustrate exemplary embodiments of the wearable automatic injection device  600  and  700  in an Injection state with the therapeutic agent cartridge  610 / 710  depressed into the housing  635 / 735  after step  1015  is performed. 
     In an exemplary embodiment, the therapeutic agent cartridge assembly  610 / 710  is depressed into the housing  635 / 735  by the patient manually pushing down the therapeutic agent cartridge assembly  610 / 710 . In another exemplary embodiment, the patient may activate an insertion trigger, e.g., an insertion trigger button located in a conveniently accessible location such as the top of the housing  635 / 735 , which causes an insertion trigger to automatically depress the therapeutic agent cartridge assembly  610 / 710  into the housing  635 / 735  and in turn, cause the needle  625 / 725  to pierce the skin of the patient. In an exemplary embodiment, pressing the insertion trigger button may release a latch in the insertion trigger that allows a spring to bias the cartridge assembly  610 / 710  downwardly in the housing  635 / 735 . The same motion of the cartridge assembly  610 / 710  may cause the needle  625 / 725  to be inserted into the injection site to an appropriate depth. 
     In an exemplary embodiment, depressing the therapeutic agent cartridge assembly  610 / 710  triggers the plunger actuator  630 / 730  to begin movement of the bung  615 / 715  to cooperatively inject the therapeutically effective dose into the patient. Depression of the therapeutic agent cartridge assembly  610 / 710  causes the plunger actuator  630 / 730  to break the static friction (i.e., stiction) between the bung  615 / 715  and the inside wall or walls of the barrel portion  605 / 705  and cause the bung  615 / 715  to move forwardly toward the needle  625 / 725  in the therapeutic agent cartridge assembly  610 / 710  to deliver the therapeutic agent via the needle  625 / 725 . The plunger actuator  630 / 730  may overcome the bung stiction in one step and actuate the bung in a subsequent step, or the plunger actuator  630 / 730  may overcome the bung stiction and actuate the bung concurrently. In another exemplary embodiment, the plunger actuator  630 / 730  is triggered not by depressing the therapeutic agent cartridge, but by the user activating an injection trigger, e.g., in the form of an injection trigger button. 
     The rate of therapeutic agent delivery may depend on the characteristics of the plunger actuator  630 / 730 . The plunger actuator  630 / 730  may take the form of several exemplary embodiments. In some exemplary embodiments, the plunger actuator  630 / 730  may employ means of energy storage and release, e.g., biasing mechanisms (such as springs), compressed gases, chemical gas generators (such as expanding foams), osmotic pressure, hydrogel expansion, etc. A damping mechanism may be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during energy release by the plunger actuator  630 / 730 . A flow restrictor placed in a fluid pathway between the needle and the bung  615 / 715  may be used to further regulate the rate of therapeutic agent delivery, e.g., where the plunger actuator  630 / 730  delivers an unconstrained spring force. Thus, an appropriate plunger actuator  630 / 730  and an appropriate flow restrictor may be selected to deliver the dose at a controlled rate, e.g., in a single slow bolus free of or substantially free of any burning sensation to the patient. 
     In an exemplary embodiment, depressing the therapeutic agent cartridge assembly  610 / 710  also arms the retraction mechanism which, when triggered, retracts the therapeutic agent cartridge assembly  610 / 710  into the housing  635 / 735 . 
     In step  1020 , the therapeutic agent cartridge assembly  610 / 710  is retracted from the depressed position to a retracted position in a Post-Injection State so that it protrudes outside the housing  635 / 735  and the needle  625 / 725  is retracted within the housing  635 / 735  or protected by the skin sensor foot  660 / 760  or both.  FIGS. 6C and 7C  illustrate exemplary embodiments of automatic injection device  600  and  700 , respectively, in a retracted position after step  1020 . Step  1020  is performed either when the therapeutically effective dose of therapeutic agent is delivered or when the wearable automatic injection device  600 / 700  is removed from the injection site before the therapeutically effective dose is completely delivered. 
     Upon delivery of the therapeutically effective dose, the bung  615 / 715  and/or the plunger actuator  630 / 730  trips the end-of-dose retraction trigger of the retraction mechanism. The bung  615 / 715  and/or the plunger actuator  630 / 730  may include a linking member connected to the retraction trigger. The linking member may include a tether or other linkage mechanism. The linking member may be of a suitable length such that, when the bung  615 / 715  has been moved to the end of the cartridge assembly  610 / 710  (delivering a complete dose), the linking member triggers a latch that in turn trips the retraction trigger. 
     Once the end-of-dose retraction trigger is tripped, the retraction mechanism deploys the therapeutic agent cartridge assembly  610 / 710  upward inside the housing  635 / 735  and away from the patient contact portion so that the therapeutic agent cartridge assembly  610 / 710  enters a Post-Injection State. In an exemplary embodiment, the movement of the therapeutic agent cartridge assembly  610 / 710  from the injection state to the post-injection state creates an audible sound, e.g., a “click,” which provides an aural indication of the completion of therapeutic agent delivery. Once retracted, the therapeutic agent cartridge assembly  610 / 710  protrudes outside the housing  635 / 735  (as shown in  FIGS. 6C and 7C ), which provides a visual indication of the state of the wearable automatic injection device  600 / 700 , for example, completion of therapeutic agent delivery or a visual indication of the device in the Post-Injection State. 
     However, if the wearable device  600 / 700  is removed from the skin of the patient before the completion of therapeutically effective dose of the therapeutic agent, the skin sensor foot  660 / 760  extends to the outside of the housing  635 / 735  and trips the early-removal retraction trigger of the retraction mechanism. Once the early-removal retraction trigger is tripped, the retraction mechanism deploys the therapeutic agent cartridge assembly  610 / 710  upward in the housing  635 / 735  away from the patient contact portion so that the therapeutic agent cartridge assembly  610 / 710  is returned to a retracted position. In an exemplary embodiment, the plunger actuator  630 / 730  may continue to move forwardly in the therapeutic agent cartridge  610 / 720  toward the needle  625 / 725  when the wearable device  600 / 700  is removed from the patient before completion of delivery of a therapeutically effective dose of the therapeutic agent. 
     In step  1025 , upon retraction, an automatic needle lock engages with the injection needle  625 / 725  to prevent redeployment of the needle  625 / 725  to provide needle-stick protection. The needle lock may be a member that prevents the needle  625 / 725  from exiting the housing  635 / 735  once engaged, and may be located in the housing  635 / 735  near the needle  625 / 725 . Exemplary needle locks may include, but are not limited to, a plastic plate, a metal plate, a clip, etc. 
     III. Exemplary Needle Systems 
     Exemplary embodiments provide different exemplary needle assemblies for injecting a dose of a therapeutic agent into a patient&#39;s skin. In some exemplary embodiments, an injection needle, coupled to a barrel portion of an exemplary automatic injection device containing the dose, may be inserted into the patient&#39;s skin to inject the dose into the patient&#39;s skin. In other exemplary embodiments, a syringe needle may be coupled to a barrel portion containing the dose to conduct the dose out of the barrel portion, and an injection needle coupled to the syringe needle may be inserted into the patient&#39;s skin to inject the dose into the patient&#39;s skin. 
     In some exemplary embodiments, as illustrated in  FIGS. 11 and 12 , a syringe may include a barrel portion and an injection needle coupled to a distal end of the barrel portion. The injection needle may be inserted into the patient&#39;s skin to deliver a therapeutic agent contained in the barrel portion of the syringe. The injection needle may be aligned at any suitable angle relative to the longitudinal axis of the barrel portion ranging from about 0 degrees to about 180 degrees. 
       FIG. 11  illustrates an exemplary syringe  1100  suitable for use in an exemplary automatic injection device. The syringe  1100  includes a barrel portion  1102  configured to hold a dose of a therapeutic agent and extending between a proximal end and a distal end along a longitudinal axis L. A distal end of the barrel portion  1102  is coupled to an injection needle  1104  that extends along the longitudinal axis L. 
       FIG. 12  illustrates an exemplary syringe  1200  suitable for use in an exemplary automatic injection device. The syringe  1200  includes a barrel portion  1202  configured to hold a dose of a therapeutic agent and extending between a proximal end and a distal end along a longitudinal axis L. A distal end of the barrel portion  1202  may include an elbow portion  1204  that extends substantially at 90 degrees from the longitudinal axis L. A distal end of the elbow portion  1204  is coupled to an injection needle  1206  that extends substantially at 90 degrees from the longitudinal axis L. One of ordinary skill in the art will recognize that exemplary automatic injection devices may include injection needles that extend along the longitudinal axis L of the syringe or that extend at any suitable angle relative to the longitudinal axis L of the syringe. Exemplary angles may include, but are not limited to, about 70 degrees to about 110 degrees. 
     In some exemplary embodiments, as illustrated in  FIGS. 13 and 14 , a syringe may include a barrel portion and an injection needle coupled to a distal end of the barrel portion. The injection needle may be inserted into a patient&#39;s skin to deliver a therapeutic agent contained in the barrel portion of the syringe. The injection needle may be aligned at any suitable angle relative to the longitudinal axis of the barrel portion ranging from about 0 degrees to about 180 degrees. 
     In some exemplary embodiments, as illustrated in  FIGS. 13 and 14 , a syringe may include a barrel portion and an injection needle coupled directly or indirectly to a distal end of the barrel portion. The syringe needle may convey a therapeutic agent contained in the barrel portion of the syringe to the injection needle, and the injection needle may deliver the therapeutic agent into a patient&#39;s skin. A coupling between the syringe needle and the injection needle may be provided by one or more intermediate components. An exemplary coupling component may include, for example, an adapter, provided between the distal end of the barrel portion and the injection needle. 
       FIG. 13  illustrates an exemplary syringe  1300  suitable for use in an exemplary automatic injection device. The syringe  1300  includes a barrel portion  1302  configured to extend from a proximal end to a distal end along a longitudinal axis L and configured to hold a dose of a therapeutic agent. A distal end of the barrel portion  1302  is coupled to a hollow syringe needle  1304 . The syringe needle  1304  is, in turn, coupled to a hypodermic injection needle  1306  through an exemplary intermediate adapter  1308 . More specifically, a proximal portion of the adapter  1308  is coupled to the syringe needle  1304  and a distal portion of the adapter  1308  is coupled to the injection needle  1306 . The adapter  1308  may establish a substantially πdegree alignment between the longitudinal axis L of the barrel portion  1302  and the hypodermic injection needle  1306 . 
     The exemplary adapter  1308  is a component that includes a first portion  1310  that extends from the barrel portion  1302  substantially parallel to the longitudinal axis L, and a second portion  1312  that extends from the first portion  1310  substantially perpendicular to the longitudinal axis L. More specifically, a proximal end of the first portion  1310  is coupled to a distal end of the barrel portion  1302 . In an exemplary embodiment, the proximal end of the first portion  1310  may envelope the distal end of the barrel portion  1302 . A distal end of the first portion  1310  is coupled to a proximal end of the second portion  1312 . A distal end of the second portion  1312  is coupled to a proximal end of the injection needle  1306 . In an exemplary embodiment, the first portion  1310  and the second portion  1312  of the adapter  1308  may be formed integrally. 
     Exemplary adapters may be formed of a rigid material including, but not limited to, plastic materials, steel, and the like. Exemplary adapters may alternatively be formed of a flexible material including, but not limited to, rubber and the like. 
     The configuration of the adapter  1308  coupled to the injection needle  1306  allows the injection needle  1306  to extend at about πdegrees relative to the longitudinal axis L of the syringe. This configuration simplifies the manufacturing of the wearable automatic injection device as it eliminates the need for a bent injection needle. The exemplary injection needle  1306  maintains a low profile against the patient while allowing for proper insertion into the patient&#39;s skin during an injection in an injection state. One of ordinary skill in the art will recognize that exemplary injection needles may be bent from the longitudinal axis of the syringe to any suitable angle not limited to about πdegrees, e.g., about 70 degrees to about 110 degrees. 
     In some exemplary embodiments, one or more fluid conduits may be disposed between the syringe needle and the injection needle to allow a flow of the therapeutic agent from the barrel portion to the injection needle through the syringe needle. Any suitable fluid conduit or fluid transfer mechanism may be used to establish the one or more fluid conduits between the syringe needle and the injection needle. In an exemplary embodiment, a pierceable septum in its intact state may separate the syringe needle from fluid communication from the injection needle. When the syringe needle pierces the septum during an injection in an injection state, fluid communication may be established between the syringe needle and the injection needle through the fluid conduit. 
       FIG. 14  illustrates a portion of an exemplary automatic injection device in which a fluid conduit couples a syringe needle and an injection needle. The device includes a syringe or cartridge assembly having a barrel portion  1400  holding a dose of a therapeutic agent. A distal end of the barrel portion  1400  is coupled to a syringe needle  1402 . A transfer mechanism  1404  is provided in contact with or in the vicinity of the syringe needle  1402 , and also in contact with or in the vicinity of an injection needle (not pictured). The transfer mechanism  1404  includes a fluid conduit or passageway  1406  that establishes fluid communication between the syringe needle  1402  and the injection needle. 
     In an exemplary embodiment, the transfer mechanism  1404  includes a pierceable septum  1408  that separates the syringe needle  1402  from the fluid conduit  1406  in the transfer mechanism  1404  before an injection in a pre-injection state. In an exemplary embodiment, during an injection in an injection state, the syringe or cartridge may be moved toward the transfer mechanism  1404  so that the syringe needle  1402  pierces the septum  1408  to create a fluid communication path among the barrel portion  1400 , the fluid conduit  1406  of the transfer mechanism  1404 , and the injection needle. The therapeutic agent may thereby flow out of the barrel portion  1400  through the syringe needle  1402  into the fluid conduit  1406 . The therapeutic agent may then be transmitted through the fluid conduit  1406  into the injection needle for delivery of the therapeutic agent to a patient. 
       FIG. 15  illustrates an exemplary transfer mechanism  1500  for providing a fluid conduit  1502  between a syringe needle (not pictured) and an injection needle (not pictured). The fluid conduit  1502  may include a centrally extending channel  1504  through which the therapeutic agent flows from the syringe needle to the injection needle, and raised wall portions  1506  extending along the edges of the channel  1504  in order to constrain the fluid to the channel  1504 . The fluid conduit  1502  may take any suitable form and dimension. In the illustrative embodiment, the fluid conduit  1502  has a first substantially straight portion  1508  aligned at about πdegrees from a second substantially straight portion  1510 . 
     The fluid conduit  1502  may include a fluid inlet  1512  for entry of the therapeutic agent from the syringe needle, and a fluid outlet  1514  for exit of the therapeutic agent into the injection needle. The fluid inlet  1512  may be coupled directly or indirectly to the proximal end of a syringe needle. In an exemplary embodiment, a pierceable septum (not pictured) may be provided at the fluid inlet  1512  to prevent fluid flow from the syringe needle when the septum is intact, and to allow fluid flow from the syringe needle when the septum is pierced by the syringe needle. The fluid outlet  1514  may be coupled directly or indirectly to the distal end of the injection needle in order to establish a fluid flow path between the fluid conduit  1502  and the injection needle. 
     Alternatively,  1512  may be used as the fluid outlet and  1514  may be used as the fluid inlet. In this exemplary embodiment, fluid inlet  1514  may be coupled directly or indirectly to a syringe needle, and fluid outlet  1512  may be coupled directly or indirectly to an injection needle. 
     The transfer mechanism  1500  may be formed of two housing portions  1516  and  1518  stacked together. In an exemplary embodiment, the fluid conduit  1502  may be formed on the surface of portion  1516 , and portion  1518  may be stacked over the fluid conduit  1502  so as to seal the edges of the fluid conduit  1502  in order to prevent fluid leakage from the fluid conduit. Compression between the two housing portions  1516  and  1518  may be provided by one or more mechanical interlocking mechanism, for example, one or more fasteners, snaps, chemical bonding, ultrasonic welding, and others. 
     The fluid conduit  1502  may be formed on the surface of the housing portion  1516  using any suitable technology. In an exemplary embodiment, the raised wall portions  1506  of the fluid conduit  1502  may be formed of a low durometer material molded as a gasket to seal the flow path of the therapeutic agent. In another exemplary embodiment, laser welding may be used to trace a path around the perimeter of the channel  1504  in order to simultaneously create a seal around the channel  1504  and bond the two housing portions  1516  and  1518  together. 
       FIG. 16  illustrates an exemplary transfer mechanism  1600  for providing a fluid conduit  1602  between a syringe with a syringe needle  1604  coupled to a barrel portion  1606  and an injection needle (not pictured). The transfer mechanism  1600  may include a first portion  1608  having a septum  1610  provided in the vicinity of the syringe needle  1604 . 
     The first portion  1608  of the transfer mechanism  1600  may include an internal hollow space for accommodating the therapeutic agent and an inlet port  1612  coupled to one end of a hollow tube  1614 . Another end of the hollow tube  1614  is coupled directly or indirectly (for example, through a second portion similar to first portion  1608 ) to the injection needle. The hollow tube  1614  provides a fluid path from the syringe needle  1604  to the injection needle. The hollow tube  1614  may take any suitable form, alignment and dimension. In the illustrative embodiment, the hollow tube  1614  extends substantially at right angles to the longitudinal axis of the barrel portion  1606 . 
     In an exemplary embodiment, the transfer mechanism  1600  may be moveable upward and/or downward along the vertical axis. In this embodiment, before an injection in a pre-injection state (for example, when the syringe needle is covered by a needle cover), the transfer mechanism  1600  may be in a vertically raised position above the syringe needle  1604  such that the syringe needle  1604  is not aligned with the septum  1610  in the transfer mechanism  1600 , thereby preventing fluid communication between the syringe needle  1604  and the transfer mechanism  1600 . At the beginning of an injection (for example, upon removal of the syringe cover from the syringe needle  1604 ), the transfer mechanism  1600  may be automatically lowered to a vertically lowered position such that the syringe needle  1604  becomes aligned with the septum  1610  in the transfer mechanism  1600 , thus allowing the syringe needle  1604  to pierce the septum  1610 . Exemplary embodiments may provide any suitable actuation mechanism for lowering the transfer mechanism  1600  from the vertically raised position to the vertically lowered position at the beginning of an injection. 
     In an exemplary embodiment, the syringe needle  1604  may be initially coupled to or provided immediately adjacent to the first portion  1608 . In another embodiment, the syringe may be in a retraction position within the wearable automatic injection device and the syringe needle  1604  may be initially separated from the first portion  1608  of the transfer mechanism  1600 . In this embodiment, before an injection in a pre-injection state, the syringe needle  1604  may be separated from the septum  1610  in the first portion  1608  and may not be in fluid communication with the transfer mechanism  1600 . At the beginning of an injection, the syringe may be moved forwardly by a cartridge or syringe actuator to an extended position within the device, and the syringe needle  1604  may pierce the septum  1610 , allowing the therapeutic agent to flow from the barrel portion  1606  to the transfer mechanism  1600 . Exemplary embodiments may provide any suitable syringe or cartridge actuation mechanism for advancing the barrel portion and/or the cartridge assembly within the housing between the retracted position and the extended position in order to pierce the septum and convey the therapeutic agent to the patient&#39;s skin through the injection needle. 
     An advantage of the exemplary transfer mechanism  1600  is that the motions of the syringe needle  1604  and the injection needle are decoupled and independent from each other. For example, the mechanism coupling the syringe needle  1604  to the inlet port  1612  need not take into consideration how this coupling would affect the outlet of the transfer mechanism  1600  coupled to the injection needle. 
       FIG. 17  illustrates an exemplary transfer mechanism  1700  for providing a fluid conduit between a syringe having a syringe needle  1704  coupled to a barrel portion  1706  and an injection needle (not pictured). The transfer mechanism  1700  may include an inlet portion (not pictured) couplable to the syringe needle  1704  and an outlet portion (not pictured) couplable to the injection needle. A hollow tube  1708 , for example, a jumper tube, may be used to couple the inlet portion of the transfer mechanism to the outlet portion of the transfer mechanism. The hollow tube  1708  provides a fluid path from the syringe needle  1704  to the injection needle. The hollow tube  1708  may take any suitable form, alignment and dimension. In the illustrative embodiment, the hollow tube  1708  extends substantially at right angles to the longitudinal axis of the barrel portion  1706 . 
     In an exemplary embodiment, the inlet portion of the transfer mechanism  1700  may include a septum (not pictured) provided in the vicinity of the syringe needle  1704 . Piercing of the septum by the syringe needle  1704  may establish fluid communication between the barrel portion  1706  and the transfer mechanism  1700 . In an exemplary embodiment, the outlet portion of the transfer mechanism may include a septum (not pictured) provided in the vicinity of the injection needle. Piercing of the septum by the injection needle may establish fluid communication between the transfer mechanism  1700  and the patient&#39;s skin. 
     In an exemplary embodiment, the transfer mechanism  1700  may be moveable upward and/or downward along the vertical axis. In this embodiment, before an injection in a pre-injection state (for example, when the syringe needle is covered by a needle cover), the transfer mechanism  1700  may be in a vertically raised position above the syringe needle  1704  such that the syringe needle  1704  is not aligned with the septum in the transfer mechanism  1700 , thereby preventing fluid communication between the syringe needle  1704  and the transfer mechanism  1700 . At the beginning of an injection (for example, upon removal of the syringe cover from the syringe needle  1704 ), the transfer mechanism  1700  may be automatically lowered to a vertically lowered position such that the syringe needle  1704  becomes aligned with the septum in the transfer mechanism  1700 , thus allowing the syringe needle  1704  to pierce the septum. Exemplary embodiments may provide any suitable actuation mechanism for lowering the transfer mechanism  1700  from the vertically raised position to the vertically lowered position at the beginning of an injection. 
     In an exemplary embodiment, the syringe needle  1704  may be initially coupled to or provided immediately adjacent to the first portion  1708 . In another embodiment, the syringe may be in a retraction position within the wearable automatic injection device and the syringe needle  1704  may be initially separated from the transfer mechanism  1700 . In this embodiment, before an injection in a pre-injection state, the syringe needle  1704  may be separated from the septum and may not be in fluid communication with the transfer mechanism  1700 . At the beginning of an injection, the syringe may be moved forwardly by a cartridge or syringe actuator to an extended position within the device, and the syringe needle  1704  may pierce the septum, allowing the therapeutic agent to flow from the barrel portion  1706  to the transfer mechanism  1700 . Exemplary embodiments may provide any suitable syringe or cartridge actuation mechanism for advancing the barrel portion and/or the cartridge assembly within the housing between the retracted position and the extended position in order to pierce the septum and convey the therapeutic agent to the patient&#39;s skin through the injection needle. 
     In the exemplary embodiments illustrated in  15 - 17 , a tight and reliable fluid path conveys the therapeutic agent from the barrel portion of a syringe or cartridge through a pierced septum and a tube or channel in a transfer mechanism and eventually into an injection needle. This configuration allows the syringe needle assembly and the injection needle assembly to move independently of each other, which facilitates retraction of the injection needle into the housing in a post-injection state after an injection has been performed, while leaving the syringe needle in a position in which it pierces the septum. 
       FIGS. 18A and 18B  illustrate an exemplary wearable automatic injection device including a syringe and an exemplary transfer mechanism.  FIG. 18A  illustrates a perspective view of the device.  FIG. 18B  illustrates a disassembled view showing the components of the device. The automatic injection device  1800  includes a housing portion  1802  that includes an adhesive layer  1804  at a patient contact region that may be removed to attach the device to a patient&#39;s body or clothing. 
     The housing portion  1802  holds a syringe  1806  in a stationary or moveable manner in the device  1800 . The syringe  1806  holds a dose of a therapeutic agent and that is coupled to a syringe needle  1808  at its distal end. The syringe needle  1808  may extend substantially along the longitudinal axis of the syringe  1806 . In a packaged pre-injection state, the syringe needle  1808  may be covered by a syringe needle cover  1805 , which may be removed by a patient before an injection. In an injection state, the syringe needle  1808  may be uncovered. In an exemplary embodiment, removal of the adhesive layer  1804  may also remove the syringe needle cover  1805 . 
     An injection button  1810  is provided in the vicinity of the syringe needle  1808 . The injection button  1810  includes holds an injection needle  1812  at substantially 90 degrees relative to the syringe needle  1808 , and includes a transfer mechanism that provides a fluid conduit between the syringe needle  1808  and the injection needle  1812 . In a packaged pre-injection state, the injection needle  1812  may be covered by an injection needle cover  1813 , which may be removed by a patient before an injection. In an injection state, the injection needle  1812  may be uncovered. In an exemplary embodiment, removal of the adhesive layer  1804  may also remove the injection needle cover  1813 . 
     The injection button  1810  also includes a septum  1811  that prevents the syringe needle  1808  from establishing fluid communication with the fluid conduit in the injection button  1810 . A cover  1813  may be provided to cover the septum  1811  in a pre-injection state, which may be removed by a patient before an injection. In an exemplary embodiment, the septum cover  1813  and the syringe needle cover  1805  may be coupled so that removal of one also removes the other. 
     In an exemplary embodiment, in a pre and post-injection state, the syringe needle cover  1805  may cover the syringe needle  1808 , and the injection button  1810  may be in a vertically raised position as displaced by the syringe needle cover  1805  such that the injection needle  1812  is retracted within the housing  1802 . In this state, the septum  1811  of the injection button  1810  may be vertically above the syringe needle  1808 . In addition, the syringe  1806  may be in a retracted position along the longitudinal axis of the assembly  1806  spaced from the septum  1811  of the injection button  1810 . 
     When the syringe needle cover  1805  is removed from the syringe needle  1808 , the injection button  1810  is lowered to a vertically lowered position such that the injection needle  1812  protrudes outside the housing  1802  into the patient contact region. In an exemplary embodiment, the injection button  1810  may be automatically lowered by the removal of the syringe needle cover  1805 . In another exemplary embodiment, the injection button  1810  is lowered by the patient pushing downward on the injection button  1810 . 
     In an exemplary embodiment, the lowering of the injection button  1810  aligns the syringe needle  1808  with the septum  1811  of the injection button  1810 . The lowering of the injection button  1810  also triggers a syringe actuator that advances the syringe  1806  along its longitudinal axis toward the septum  1811  of the injection button  1810 . This causes the syringe needle  1808  to pierce the septum  1811  and establish fluid communication with the injection needle  1812 . 
       FIGS. 19A and 19B  illustrate an exemplary wearable automatic injection device including a syringe and an exemplary transfer mechanism.  FIG. 19A  illustrates a side view of the device.  FIG. 19B  illustrates a perspective view showing the components of the device. The automatic injection device  1900  includes a housing  1902  holding a syringe  1904  in a stationary of moveable manner relative to the housing  1902 . An injection button  1906  is provided in the housing  1902  in the vicinity of the syringe  1904  and holds an injection needle (not pictured). The housing  1902  includes an adhesive layer  1908  for attachment at a patient contact region. 
     Other components in the device  1900  similar to the components in the device  1800  are described with reference to  FIGS. 18A and 18B . 
       FIGS. 20A-20C  illustrate an exemplary wearable automatic injection device including a cartridge assembly and an exemplary transfer mechanism.  FIG. 20A  illustrates a perspective view of the device.  FIG. 20B  illustrates a top view of the device.  FIG. 20C  illustrates a side view of the transfer mechanism of the device. The automatic injection device  2000  includes a housing  2002  having an adhesive layer  2003  for attachment at a patient contact region. The housing  2002  holds a cartridge  2004  in a stationary or moveable manner relative to the housing  2002 . The cartridge  2004  is configured to hold a dose of a therapeutic agent. 
     An injection button  2006  is provided in the housing  2002  in the vicinity of the cartridge  2004 . The injection button  2006  may hold or be coupled to an injection needle  2008  extending substantially at πdegrees relative to the longitudinal axis of the cartridge  2004  and a syringe needle  2010  extending substantially parallel to the longitudinal axis of the cartridge  2004 . The injection button  2006  may form or include a transfer mechanism that establishes fluid communication between the cartridge  2004  to the injection needle  2008  through the syringe needle  2010 . 
     The injection button  2006  may include a housing engagement portion  2012  that engages with a housing portion  2014  when the injection button  2006  is pressed down during an injection in an injection state. In an exemplary embodiment illustrated in  FIG. 20C , the engagement between the housing engagement portion  2012  and the housing portion  2014  causes the housing portion  2014  to move parallel to the longitudinal axis of the cartridge  2004  toward the distal end of the cartridge  2004 , thus allowing the syringe needle  2010  to establish fluid communication with the barrel portion of the cartridge  2004 . In another exemplary embodiment, the engagement between the housing engagement portion  2012  and the housing portion  2014  causes the cartridge  2004  to move parallel to the longitudinal axis of the cartridge  2004  toward the syringe needle  2010 , thus allowing the syringe needle  2010  to establish fluid communication with the barrel portion of the cartridge  2004 . 
     Other components in the device  2000  similar to the components in the device  1800  are described with reference to  FIGS. 18A and 18B . 
       FIGS. 21A-21C  illustrate an exemplary wearable automatic injection device including an exemplary cartridge assembly.  FIG. 21A  illustrates a perspective view of the exemplary wearable automatic injection device.  FIG. 21B  illustrates a sectional view of the cartridge assembly taken along a longitudinal axis.  FIG. 21C  illustrates a transparent top view of the transfer mechanism of the device. The automatic injection device  2100  includes a housing  2102  having an adhesive layer  2103  for attachment at a patient contact region. The housing  2102  holds a cartridge  2104  in a stationary or moveable manner relative to the housing  2102 . The cartridge  2104  is configured to hold a dose of a therapeutic agent. A proximal end of the cartridge  2104  includes a bung  2106  and a distal end of the cartridge  2104  includes a septum  2108  that cooperatively seal the dose within the cartridge  2104 . 
     An injection button  2110  is provided in the housing  2102  in the vicinity of the cartridge  2104 . The injection button  2110  holds an injection needle at a proximal end that extends substantially at πdegrees relative to the longitudinal axis of the cartridge  2104 . The injection button  2110  is coupled to a transfer mechanism  2111  that holds a syringe needle  2112  in the vicinity of the cartridge  2104 . The syringe needle  2112  extends substantially parallel to the longitudinal axis of the cartridge  2104 . The transfer mechanism  2111  includes a fluid conduit to establish fluid communication between the cartridge  2104  to the injection needle  2108  through the syringe needle  2110 . In a pre-injection state, the syringe needle  2112  may extend partly into a distal end of the cartridge  2104  but may be spaced from the septum  2108 . In an injection state, the bung  2106  may be moved within the cartridge  2104  such that the fluid pressure in the cartridge  2104  moves the septum  2108  forward toward the syringe needle  2112 . This causes the syringe needle  2112  to pierce the septum  2108  and establishes fluid communication between the cartridge  2104  and the injection needle through the syringe needle  2112 . 
     Other components in the device  2100  similar to the components in the device  1800  are described with reference to  FIGS. 18A and 18B . 
       FIG. 22  illustrates an exemplary syringe or cartridge actuator  2200  that may be used to advance a syringe  2202  or a cartridge assembly from a retraction position to an extended position within the housing of a wearable automatic injection device. A proximal end of the barrel portion and/or the cartridge assembly may be coupled to a biasing member  2204 , for example, a drive spring, that applies a force on the barrel portion of the syringe and/or the cartridge assembly to move the barrel portion and/or the cartridge assembly toward a septum in a transfer mechanism (not pictured). The syringe or cartridge actuator  2200  may counter the biasing force of the biasing member, and may hold and lock the barrel portion and/or the cartridge assembly in a retracted position in a stable and reliable manner. 
     When triggered, the syringe or cartridge actuator  2200  may allow the barrel portion and/or the cartridge assembly to move forward toward the septum under the force of the biasing member. In an exemplary embodiment, the syringe or cartridge actuator  2200  may be configured and/or set to a certain distance to control the level of triggering force required to advance the barrel portion and/or the cartridge assembly from the retracted position to the extended position. 
     Any suitable trigger mechanism may be used to trigger the syringe or cartridge actuation systems. In an exemplary embodiment, the trigger mechanism may automatically trigger the syringe or cartridge actuation system when the wearable automatic injection device moves from a pre-injection state to an injection state. In an exemplary embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the syringe or cartridge assembly and the injection needle may provide a trigger force to trigger the plunger actuation system. In another exemplary embodiment, the forward movement of the syringe or cartridge assembly within the housing to establish a fluid path between the syringe or cartridge assembly and the injection needle may provide a trigger force to trigger the syringe or cartridge system. In another exemplary embodiment, the syringe or cartridge system may be manually triggered by a user. 
     Before an injection in a pre-injection state, a needle cover, for example, a soft and rigid needle shield assembly (not pictured), provided at the distal end of the syringe may protectively cover the syringe needle. At this stage, since the syringe needle is covered with the needle cover, the distal end of the syringe has a first greater diameter. As such, the transfer mechanism including the septum is maintained in a vertically raised position above the needle cover, and the septum is not aligned with the syringe needle. When the needle cover is removed from the syringe in preparation for an injection (for example, manually by a user or by an automatic mechanism), the transfer mechanism is allowed to lower to a vertically lowered position since it is not longer kept displaced by the rigid needle shield, and the septum in the transfer mechanism is aligned with the syringe needle. The removal of the needle cover thus lowers the transfer mechanism from its raised position to its lowered position. The lowering of the transfer mechanism, in turn, applies a trigger force to the syringe or cartridge actuator  2200  and operates as the trigger mechanism for the syringe or cartridge actuator  2200 . 
       FIG. 23  illustrates an exemplary syringe or cartridge actuator  2300  including a first portion  2302 , a second portion  2304  and a hinge portion  2306  provided between the first and second portions. The hinge portion  2306  allows the first and second portions to rotate about the hinge relative to each other. In different rotational configurations, the first and second portions may have exemplary angles of between about 0 degrees and about 180 degrees between each other. The actuator  2300  may be coupled to the syringe and to the septum and/or the transfer mechanism. When the septum and/or transfer mechanism is in its first raised position, the actuator  2300  may hold the syringe in place in its retracted position. When the septum and/or transfer mechanism is in its second lowered position, the actuator  2300  may release the syringe so that the biasing member may push the syringe forward to its extended position in order to pierce the septum. 
     IV. Exemplary Plunger Actuation Systems and Needle Retraction Systems 
     Exemplary embodiments provide plunger actuation systems for actuating a bung in a barrel portion of a wearable automatic injection device so that the bung moves forwardly within the barrel portion and expels a dose of a therapeutic agent contained in the barrel portion. Any suitable trigger mechanism may be used to trigger the plunger actuation systems. In an exemplary embodiment, the trigger mechanism may automatically trigger the plunger actuation system when the wearable automatic injection device moves from a pre-injection state to an injection state. In an exemplary embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the syringe or cartridge assembly and the injection needle may provide a trigger force to trigger the plunger actuation system. In another exemplary embodiment, the forward movement of the syringe or cartridge assembly within the housing to establish a fluid path between the syringe or cartridge assembly and the injection needle may provide a trigger force to trigger the plunger actuation system. In another exemplary embodiment, the plunger actuation system may be manually triggered by a user. 
     Certain other exemplary embodiments provide plunger actuation devices and systems that cause actuation of the syringe plunger at a slow rate in order to deliver the therapeutic agent to a patient at a slow rate. Exemplary slow embodiments may deliver therapeutic agent volumes of about 0.1 milliliters to about 1 milliliter or more in about five minutes to about thirty minutes, although exemplary delivery rates are not limited to this exemplary range. 
     Exemplary embodiments may provide a linear delivery profile for the therapeutic agent so that the delivery rate is substantially constant over time. In some cases, a linear delivery profile may reduce discomfort experienced by the patient. 
       FIG. 24  illustrates a schematic of a portion of an exemplary automatic injection device  2400  including a plunger actuation mechanism that employs a fusee and a viscous damping mechanism. The wearable automatic injection device  2400  includes a housing  2402  having a platform  2410  that is a mechanical structure for holding a syringe or cartridge assembly  2404  in place within the wearable automatic injection device  2400 . The syringe or cartridge  2404  includes a barrel portion for holding a dose of a therapeutic agent and a bung  2408  for sealing the dose within the barrel portion. A plunger actuation mechanism  2406  is provided for moving the bung  2408  within the barrel portion for expelling the dose from the barrel portion. A damping mechanism  2422 , for example, a viscous damper, is provided to regulate the motion of the bung  2408  so that the therapeutic agent is delivered in a linear fashion, i.e., at a substantially constant flow rate. A gear train  2420  including one or more gears may be provided to couple the plunger actuation mechanism  2406  to the damping mechanism  2422 . The gear train  2420  may include any number of suitable gears to provide any suitable gearing ratio. 
     The platform  2410  of the wearable automatic injection device  2400  may be stationary or moveable. In an exemplary embodiment, the platform  2410  may be a substantially box-shaped or cylindrical structure with an internal space for accommodating the syringe or cartridge  2404 . The peripheral walls surrounding the internal space may be configured to hold a syringe or a cartridge assembly  2404  in place. The platform  2410  may include one or more clamping mechanism  2412  for holding the syringe or cartridge  2404  in place. The platform  2410  may also include a flange bearing  2414  provided at the proximal end of the syringe or cartridge  2404 . A flange provided at the proximal end of the syringe or cartridge  2404  may slide backward against the flange bearing  2414 . 
     In an exemplary embodiment, the platform  2410  may hold the syringe or cartridge  2404  stationary within and relative to the platform  2410 . In another exemplary embodiment, the platform  2410  may allow the syringe or cartridge  2404  to move relative to the platform  2410 , for example, toward or away from a fluid transfer mechanism (not pictured). In this exemplary embodiment, the internal space of the platform  2410  may include one or more grooves, tracks or channels for facilitating the movement of the syringe or cartridge  2404  within the platform  2410 . In an exemplary embodiment, the platform  2410  may include a window  2416 , for example, a cutout or a transparent portion, in order to allow the patient to view the syringe or cartridge  2404 . 
     One or more plunger actuators  2406  may be provided in the vicinity of the syringe or cartridge  2404  for storing energy and providing a force for driving a bung  2408  within the syringe or cartridge  2404  toward the distal end of the syringe or cartridge  2404 . In an exemplary embodiment, a plunger actuator  2406 , for example, a helical compression spring, may be used to drive the bung  2408 . The plunger actuator  2406  may be provided at least partly within the syringe or cartridge  2404 . Before an injection in a pre-injection state, the plunger actuator  2406  may be maintained in a compressed state. At the beginning of an injection or during an injection in an injection state, the plunger actuator  2406  may be allowed to expand from the compressed state to a released state. The expansion of the plunger actuator  2406  may push the bung  2408  toward the distal end of the syringe or cartridge  2404 , thus expressing the therapeutic agent from the syringe or cartridge  2404 . Advantageously, the configuration of the plunger actuator  2406  within the syringe or cartridge  2404  does not add to the length of the housing required to hold the syringe or cartridge  2404 . However, in some exemplary embodiments, the plunger actuator  2406  may not provide a constant force to drive the bung  2408 . 
     In another exemplary embodiment, a spiral spring may be used to drive the bung  2408 . The spiral spring may be provided outside but alongside the syringe or cartridge  2404  of within the platform  2410 , which may add to the space requirement of the housing  2402 . Before an injection in a pre-injection state, the spring may be maintained in a compressed state. At the beginning of an injection or during an injection in an injection state, the spring may be allowed to expand from the compressed state to a released state. The expansion of the spring may push the bung  2408  toward the distal end of the syringe or cartridge  2404 , thus expressing the therapeutic agent from the syringe or cartridge  2404 . Advantageously, the spiral spring may provide a substantially constant force to drive the bung  2408 . 
     One or more damping mechanisms may be provided for regulating the release of energy in the plunger actuator  2406  in order to control the delivery rate and/or the delivery time for delivering the therapeutic agent. In an exemplary embodiment, to achieve a slow and/or controlled delivery, the plunger actuator  2406  is prevented from accelerating without resistance from its compressed state to a released state. The movement of the plunger actuator  2406  may be maintained at a constant speed, for example, by providing linear damping values. Any suitable mechanism may be used to provide resistance against the acceleration of the plunger actuator  2406 . In an exemplary embodiment, a rotary viscous damper  2422  may be used to resist the acceleration of the plunger actuator  2406 . The viscous damper  2422  may use one or more viscous fluids, for example, silicon grease, to provide resistance. The viscous damper  2422  may include a stationary housing holding a solid rotating element called a “rotor.” The outer circumference of the rotor may include a plurality of teeth configured to be engaged by the teeth of a gear in the gear train  2420 . The rotor may be surrounded by a thin film of a viscous fluid that is sealed inside the housing. The rotation of the rotor may provide resistance against the acceleration of the plunger actuator  2406  by shearing the viscous fluid. In an exemplary embodiment, the viscous damper  2422  may be replaced with a different viscous damper providing a different level of damping. 
     The force required to turn the rotary viscous damper  2422  is described with reference to a coordinate system x where x=0 is at the free length of a spring. If m is the inertia of the system, c is the damping coefficient, and k is the spring constant, then: 
     
       
         
           
             
               
                 
                   
                     
                       m 
                        
                       
                           
                       
                        
                       
                         x 
                         ¨ 
                       
                     
                     + 
                     
                       c 
                        
                       
                           
                       
                        
                       
                         x 
                         . 
                       
                     
                     + 
                     kx 
                   
                   = 
                   
                     
                       0 
                       ⇒ 
                       
                         x 
                         ¨ 
                       
                     
                     = 
                     
                       
                         1 
                         m 
                       
                        
                       
                         [ 
                         
                           
                             
                               - 
                               c 
                             
                              
                             
                                 
                             
                              
                             
                               x 
                               . 
                             
                           
                           - 
                           kx 
                         
                         ] 
                       
                     
                   
                 
               
               
                 
                   ( 
                   1 
                   ) 
                 
               
             
             
               
                 
                   
                     
                       x 
                       ¨ 
                     
                     + 
                     
                       2 
                        
                       
                           
                       
                        
                       ζ 
                        
                       
                           
                       
                        
                       
                         ω 
                         0 
                       
                        
                       
                         x 
                         . 
                       
                     
                     + 
                     
                       
                         ω 
                         0 
                         2 
                       
                        
                       x 
                     
                   
                   = 
                   0 
                 
               
               
                 
                   ( 
                   2 
                   ) 
                 
               
             
           
         
       
     
     where natural frequency: 
     
       
         
           
             
               
                 
                   
                     ω 
                     0 
                   
                   = 
                   
                     
                       k 
                       m 
                     
                   
                 
               
               
                 
                   ( 
                   3 
                   ) 
                 
               
             
           
         
       
     
     and where damping ratio: 
     
       
         
           
             
               
                 
                   ζ 
                   = 
                   
                     c 
                     
                       2 
                        
                       
                         mk 
                       
                     
                   
                 
               
               
                 
                   ( 
                   4 
                   ) 
                 
               
             
           
         
       
     
     If the damping is driven by a rotary damper, the torque T required to turn the dampener may be assumed to be linearly proportional to the angular velocity by some constant C: 
       T=C θ {dot over (θ)}  (5)
 
     If the rotary damper is coupled to the plunger actuator by a gear train of reduction N and a spool of diameter D, then: 
     
       
         
           
             
               
                 
                   
                     x 
                     . 
                   
                   = 
                   
                     
                       
                         
                           D 
                           
                             2 
                              
                             N 
                           
                         
                          
                         
                           θ 
                           . 
                         
                       
                       ∴ 
                       
                         θ 
                         . 
                       
                     
                     = 
                     
                       
                         
                           2 
                            
                           N 
                            
                           
                               
                           
                            
                           
                             x 
                             . 
                           
                         
                         D 
                       
                        
                       
                           
                       
                        
                       and 
                     
                   
                 
               
               
                 
                   ( 
                   6 
                   ) 
                 
               
             
             
               
                 
                   
                     T 
                     spool 
                   
                   = 
                   
                     
                       
                         
                           F 
                           x 
                         
                          
                         D 
                       
                       2 
                     
                     = 
                     
                       NT 
                       = 
                       
                         
                           
                             NC 
                             θ 
                           
                            
                           
                             θ 
                             . 
                           
                         
                         = 
                         
                           
                             
                               2 
                                
                               
                                 N 
                                 2 
                               
                                
                               
                                 C 
                                 θ 
                               
                             
                             D 
                           
                            
                           
                             x 
                             . 
                           
                         
                       
                     
                   
                 
               
               
                 
                     
                 
               
             
             
               
                 
                   
                     ∴ 
                     
                       F 
                       x 
                     
                   
                   = 
                   
                     
                       
                         
                           
                             4 
                              
                             
                               N 
                               2 
                             
                              
                             
                               C 
                               θ 
                             
                           
                           
                             D 
                             2 
                           
                         
                          
                         
                           x 
                           . 
                         
                       
                       ∴ 
                       
                         c 
                         x 
                       
                     
                     = 
                     
                       
                         4 
                          
                         
                           N 
                           2 
                         
                          
                         
                           C 
                           θ 
                         
                       
                       
                         D 
                         2 
                       
                     
                   
                 
               
               
                 
                     
                 
               
             
           
         
       
     
     In another exemplary embodiment, an escapement may be used to resist the acceleration of the plunger actuator  2406 . The escapement may use a known period of oscillation of a balance wheel and a spiral hairspring to incrementally release the energy of a main spring. An escapement may provide a dependable design and linearity in the release of the energy. In another exemplary embodiment, a runaway escapement may be used to resist the acceleration of the plunger actuator  2406 . In another exemplary embodiment, a swiss lever escapement may be used to resist the acceleration of the plunger actuator  2406 . 
     A gear train  2420  may be provided for coupling the plunger actuator  2406  to the regulating device  2422 , i.e., the viscous damper or the escapement. The gear train  2420  may include a shaft  2424  may be coupled to the housing  2402  of the wearable automatic injection device  2400  with a close slip fit. In an exemplary embodiment, the shaft  2424  may support a cylindrical structure  2426 , for example, a spool or a shaft, and a gear  2428  that is provided below the spool  2426 . In an exemplary embodiment, the spool  2426  may be a cam spool or a fusee. One or more snap rings  2430  may be used to retain the spool  2426  and the gear  2428  on the shaft  2424 . The spool  2426  and the gear  2428  may be provided around the shaft  2424  such that the centers of rotation of the spool  2426  and the gear  2428  are aligned with each other and with the shaft  2424 . The spool  2426  and the gear  2428  may be cooperatively coupled to each other and to the shaft  2424  such that the gear  2428  and the spool  2426  may rotate together on the shaft  2424 . In an exemplary embodiment, the spool  2426  and the gear  2428  may be taken off from the shaft  2424  and replaced with a different set of spools and gears. The plunger actuator  2406  may be coupled to the gear train, for example, the spool  2426 , using one or more tethers or cables  2442 . 
     In an exemplary embodiment, the spool  2426  may be any suitable rotating mechanism including, but not limited to, a constant diameter spool, a cam spool or fusee. If a cam or fusee is used, the outer diameter of the cam or fusee may vary with linear displacement D. Taking the equation for the linear damping coefficient and holding the gear reduction N and the rotary damping coefficient constant yields: 
     
       
         
           
             
               
                 
                   
                     c 
                     x 
                   
                   = 
                   
                     
                       
                         4 
                          
                         
                           N 
                           2 
                         
                          
                         
                           C 
                           θ 
                         
                       
                       
                         D 
                         2 
                       
                     
                     = 
                     
                       a 
                       
                         D 
                         x 
                         2 
                       
                     
                   
                 
               
               
                 
                   ( 
                   7 
                   ) 
                 
               
             
           
         
       
     
     where a is constant. Substituting the above into the equation of motion and assuming that the first derivative of χ is constant, yields: 
     
       
         
           
             
               
                 
                   
                     D 
                     x 
                   
                   = 
                   
                     
                       
                         
                           
                             
                               - 
                               a 
                             
                              
                             
                                 
                             
                              
                             
                               x 
                               . 
                             
                           
                           k 
                         
                       
                        
                       
                         x 
                         
                           - 
                           
                             1 
                             2 
                           
                         
                       
                     
                     - 
                     
                       
                         C 
                         1 
                       
                        
                       
                         x 
                         
                           - 
                           b 
                         
                       
                     
                     + 
                     
                       C 
                       2 
                     
                   
                 
               
               
                 
                   ( 
                   8 
                   ) 
                 
               
             
           
         
       
     
     where C 1 , C 2  and b are constants that may be varied in order to make the velocity approximately constant. Plugging this variable into the equation of motion and solving for x as a function of time, x may be substituted into equation (8) to determine D as a function of time, D t . The instantaneous velocity may be represented as: 
     
       
         
           
             
               
                 
                   
                     x 
                     . 
                   
                   = 
                   
                     
                       
                         
                           
                             D 
                             t 
                           
                           2 
                         
                          
                         
                           φ 
                           . 
                         
                       
                       ⇒ 
                       
                         φ 
                         . 
                       
                     
                     = 
                     
                       
                         
                           
                             2 
                              
                             
                                 
                             
                              
                             
                               x 
                               . 
                             
                           
                           
                             D 
                             t 
                           
                         
                         ⇒ 
                         
                           φ 
                           t 
                         
                       
                       = 
                       
                         
                           ∫ 
                           0 
                           t 
                         
                          
                         
                           
                             
                               2 
                                
                               
                                   
                               
                                
                               
                                 x 
                                 . 
                               
                             
                             
                               D 
                               t 
                             
                           
                            
                           dt 
                         
                       
                     
                   
                 
               
               
                 
                   ( 
                   9 
                   ) 
                 
               
             
           
         
       
     
     where ϕ is the angular position of the cam or fusee. D t  and ϕ t  are the polar coordinates of the cam profile. 
     Exemplary embodiments may couple the plunger actuator  2406  to a bung in the barrel portion of a syringe or cartridge using any suitable mechanism. If a compression spring is used as the plunger actuator  2406 , one or more tethers or cables may be used to couple the plunger actuator  2406  to the bung. If a spiral spring is used as the plunger actuator  2406 , spur gearing may be used to couple the plunger actuator  2406  to the bung. The torque generated the spiral spring by may be coupled to the bung using a pinion to push a flexible rack around the corner of the syringe or cartridge. 
     In an exemplary embodiment, the spool  2426  may be in contact with and/or coupled to a ratchet  2434  and pawl  2436 . A torsion spring (not pictured) may be provided below the pawl  2436  to preload the pawl  2436  against the ratchet  2434 . When the spool  2426  is being wound during assembly of the wearable automatic injection device  2400 , the torsion spring may be held in place. After the spool  2426  is wound and before an injection in a pre-injection state, the ratchet  2434  and pawl  2436  may hold the spool  2426  in place and prevent rotational movement of the spool  2426 . This holds the tether  2442  in place which, in turn, maintains the plunger actuator  2406  in its compressed state, preventing movement of the plunger. At the beginning of an injection or during an injection in an injection state, the pawl  2436  may be rotated to disengage the ratchet  2434 , for example, by a user or automatically upon the pressing of an injection button. This allows the spool  2426  to rotate under the pulling force of the tether  2442  caused by the spring force of the plunger actuator  2406 . The spring force of the plunger actuator  2406  pulls the tether  2442  toward the distal end of the syringe or cartridge  2404 . 
     One or more additional gears may be provided in contact with and/or coupled to the gear coupled to the spool  2426 , thus forming a gear train  2438 . Each gear in the gear train  2438  may be provided on a corresponding shaft coupled to the housing  2402  of the wearable automatic injection device  2400 . In an exemplary embodiment, the gears in the gear train  2438  may be taken off from their corresponding shafts and replaced with a different set of gears. One of ordinary skill in the art will recognize that other exemplary devices may include fewer or more gears. 
     The gear train  2438  may be coupled to the viscous damper  2422  or an escapement that resists acceleration of the bung  2408 . That is, the gear train may couple the viscous damper  2422  or an escapement to the tether  2442  holding the bung  2408  so that, when the bung  2408  is moved under the force of the plunger actuator  2406 , acceleration of the plunger actuator  2406  is resisted by the viscous damper  2422  or the escapement. 
     In an exemplary embodiment, the gear train  2438  may be coupled to an encoding device  2440 , for example, a rotary encoder, that detects and logs the angular displacement or position of the gear train and the corresponding time. A computing device may be associated with the wearable automatic injection device to determine the position of the syringe plunger based on the data obtained by the encoding device  2440 . The computing device may also determine the flow rate of the therapeutic agent from the syringe or cartridge  2404  and the corresponding time based on the data obtained by the encoding device  2440 . The computing device may be provided integrally with the encoding device  2440  or separately from the encoding device  2440 . During assembly and testing of the wearable automatic injection device, the encoding device  2440  may be used to evaluate different gear trains, viscous dampers and biasing elements, validate mathematical models and account for variables not addressed in the mathematical models. During use of the wearable automatic injection device to perform an injection, the encoding device  2440  may be used to indicate one or more conditions to the user, for example, the flow rate of the therapeutic agent, malfunction of the device (for example, if the flow rate is too high or too low), and the like. 
     In an exemplary embodiment illustrated in  FIGS. 25 and 26 , a wearable automatic injection device may include a syringe assembly moveable relative to a platform in the device. The wearable automatic injection device includes a platform  2500 , a slideable carriage  2502  coupled to the platform  2500 , and a syringe  2504  mounted on the slideable carriage  2502 . A distal end of the syringe  2504  may be coupled to a syringe needle  2512 . The syringe  2504  may include a barrel portion  2506  containing a dose of a therapeutic agent sealed by a bung  2508 . A plunger actuator  2510  may be provided in the vicinity or in contact with the bung  2508  for moving the bung  2508  forwardly within the barrel portion  2506 . In an exemplary embodiment, the plunger actuator  2510  may include a biasing mechanism coupled by a tether to a gear train and thereby to a damping mechanism. 
     The device may also include an injection button bearing an injection needle (not pictured) and including a pierceable septum that may be pierced by the syringe needle  2512 . The septum may be coupled directly or through a conduit to the injection needle such that, when pierced by the syringe needle  2512 , the septum establishes fluid communication between the barrel portion  2506  and the injection needle. 
     In an exemplary embodiment, in a pre-injection state, the syringe needle  2512  may already pierce the septum and be in fluid communication with the injection needle. During an injection in an injection state, the dose of the therapeutic agent may be expelled from the barrel portion  2506  when the plunger actuator  2510  is activated to move the bung  2508  forwardly within the barrel portion  2506 . In this embodiment, the carriage  2502  may be stationary on the platform  2500 . 
     In another exemplary embodiment, in a pre-injection state, the syringe needle  2512  may be spaced from the septum and may not be in fluid communication with the injection needle. During an injection in an injection state, the syringe  2504  may be moved forwardly within and relative to the platform  2500  toward the septum in order to pierce the septum with the syringe needle  2512 . In this exemplary embodiment, the carriage  2502  may be moveable and may move relative to the platform  2500  toward the septum. 
     In an exemplary embodiment, a tether  2516  may be used to couple the plunger actuator  2510  to a gear train  2518 . The gear train  2518  may in turn be coupled to a damping mechanism  2520  for providing a linear delivery profile of the therapeutic agent. In a pre-injection state, a lockout mechanism  2522  may hold the gear train  2518  in place and prevent rotation of the gears. This causes the tether  2516  to hold the plunger actuator  2510  in place and prevents release of the plunger actuator  2510 , thereby preventing movement of the bung  2508 . During an injection in an injection state, the lockout mechanism  2522  may be released, for example, manually by a user or automatically, thereby allowing the gears  2518  to rotate under the biasing force of the plunger actuator  2510 . This may allow the moveable carriage  2502  to automatically move toward the septum, which results in the syringe needle  2512  piercing the septum. The bung  2508  may also move within the barrel portion  2506  toward the septum under the biasing force of the plunger actuator  2510  to expel the dose through the syringe needle  2512 . 
       FIGS. 27-29  illustrate a schematic of a portion of an exemplary automatic injection device that may include a syringe assembly that is stationary relative to the housing of the device. The wearable automatic injection device  2800  includes a plunger actuation mechanism for automatically actuating a bung  2802  in a barrel portion  2804 .  FIG. 27  is a top view through a cover of the device  2800 .  FIG. 28  is a side view of the device  2800 .  FIG. 29  is a perspective view through a cover of the device  2800 . 
     The plunger actuation mechanism may include a biasing mechanism  2806  that operates as the plunger actuator. In an exemplary embodiment, one or more tethers or cables  2812  may be used to couple the biasing mechanism  2806  to a stage  3  gear  2810 , for example a fusee, that unwinds to allow the biasing mechanism  2806  to expand. A stage  1  damper  2808 , for example, a viscous damper or an escapement, regulates the movement of the bung  2802  during an injection in an injection state in order to achieve a linear flow rate of the therapeutic agent. One or more stage  2  gears and pinions  2814  may be used to couple the stage  3  gear  2810  and the stage  1  damper  2808 . 
     Table 7 summarizes exemplary features of an exemplary stage  1  damper, an exemplary stage  2  gear, an exemplary stage  2  pinion and an exemplary stage  3  gear that may be used in exemplary automatic injection devices. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Exemplary features of exemplary plunger actuation components 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Stage 3  
                 Stage 2  
                 Stage 2  
                 Stage 1 
               
               
                   
                 Gear 
                 Pinion 
                 Gear 
                 Damper 
               
               
                   
               
               
                 Diametral 
                 72  
                 72  
                 31.75  
                 31.75  
               
               
                 pitch 
                 teeth/in 
                 teeth/in 
                 teeth/in 
                 teeth/in 
               
               
                 Number  
                 50 teeth 
                 18 teeth 
                 16 teeth 
                 11 teeth 
               
               
                 of teeth 
                   
                   
                   
                   
               
               
                 Face width 
                 0.100 in 
                 0.100 in 
                 0.050 in 
                 0.118 in 
               
               
                 Tooth  
                 14.5 deg 
                 14.5 deg 
                 14.5 deg 
                 14.5 deg 
               
               
                 profile 
                   
                   
                   
                   
               
               
                 Material 
                 Nylon 
                 Nylon 
                 Nylon 
                 Acetal 
               
               
                 Pitch  
                 0.694 in 
                 0.250 in 
                 0.504 in 
                 0.346 in 
               
               
                 diameter 
                   
                   
                   
                   
               
               
                 Circular  
                 0.044  
                 0.044  
                 0.099  
                 0.099  
               
               
                 pitch 
                 in/tooth 
                 in/tooth 
                 in/tooth 
                 in/tooth 
               
               
                 Yield  
                 11.8 ksi 
                 11.8 ksi 
                 11.8 ksi 
                 10.2 ksi 
               
               
                 strength 
                   
                   
                   
                   
               
               
                 Lewis form 
                 0.346 
                 0.270 
                 0.255 
                 0.192 
               
               
                 factor 
                   
                   
                   
                   
               
               
                 Torque 
                 8.5 oz-in 
                 3.1 oz-in 
                 3.1 oz-in 
                 2.1 oz-in 
               
               
                 Tangential 
                 1.53 lbf 
                 1.53 lbf 
                 0.76 lbf 
                 0.76 lbf 
               
               
                 force 
                   
                   
                   
                   
               
               
                 Radial  
                 0.39 lbf 
                 0.39 lbf 
                 0.20 lbf 
                 0.20 lbf 
               
               
                 force 
                   
                   
                   
                   
               
               
                 Safety  
                 3.71 
                 2.90 
                 6.25 
                 9.62 
               
               
                 factor 
                   
                   
                   
                   
               
               
                 Total  
                 4.04 
                   
                   
                   
               
               
                 gearing 
               
               
                   
               
            
           
         
       
     
     Failure analysis was performed on the exemplary plunger actuation mechanism. In an exemplary embodiment, the gear train (including the stage  2  gear) is designed assuming a Lewis bending failure mode which assumes that the gear tooth is a simple cantilever with tooth contact occurring at the tip. The results of the failure analysis summarized in Table 7 indicate that the minimum factor of safety for the gear train is 3 and that the total gear ratio is 4.04. 
     Different combinations of different types of plunger actuators (spring  1  and spring  2 ), spools (constant-diameter spool or cam spool), and damping mechanisms (viscous damper or escapement) were tested to determine their effect on the delivery rate of the therapeutic agent.  FIG. 30  illustrates x and y coordinates (in inches) of cam profiles for: (i) the combination of spring  1  and a viscous damper, (ii) the combination of spring  1  and an escapement, (iii) the combination of spring  2  and a viscous damper, and (iv) the combination of spring  2  and an escapement. 
       FIG. 31  illustrates a graph of therapeutic agent flow rates (in milliliters per minute) versus time (in seconds) delivered by: (i) the combination of spring  1  and a viscous damper, (ii) the combination of spring  1 , a viscous damper and a cam spool, (iii) the combination of spring  1  and an escapement, (iv) the combination of spring  1 , an escapement and a cam spool, (v) the combination of spring  2  and a viscous damper, (vi) the combination of spring  2 , a viscous damper and a cam spool, (vii) the combination of spring  2  and an escapement, (viii) the combination of spring  2 , an escapement and a cam spool, and (ix) and an ideal flow rate in which the therapeutic agent is delivered at a substantially constant rate.  FIG. 32  illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) delivered by the combinations of components of  FIG. 31 . 
       FIGS. 31 and 32  show that a substantially linear flow rate of the therapeutic agent may be achieved by the use of a cam spool or a fusee. The use of an escapement, versus a viscous damper, may be used to improve the linearity of the flow rate. The total delivery time of the therapeutic agent may be controlled by configuring the gearing ratio. 
     Different combinations of exemplary dampers and exemplary gear ratios in exemplary plunger actuation mechanisms were tested. The exemplary dampers included: (i) damping mechanism G, (ii) damping mechanism B, (iii) damping mechanism K, and (iv) damping mechanism V. The exemplary gear ratios included: (i) 4:1, (ii) 6.25:1, and (iii) 16:1.  FIG. 33  illustrates a graph of the volume of therapeutic agent (in milliliters) against time (in seconds) delivered using: (i) a G damping mechanism having a damping coefficient of about 10.3 lbf*s/in with a gear ratio of 4:1, (ii) a B damping mechanism having a damping coefficient of about 15.1 lbf*s/in with a gear ratio of 4:1, (iii) a K damping mechanism having a damping coefficient of about 18.9 lbf*s/in with a gear ratio of 4:1, (iv) a V damping mechanism having a damping coefficient of about 24.9 lbf*s/in with a gear ratio of 4:1, (v) a G damping mechanism having a damping coefficient of about 25.1 lbf*s/in with a gear ratio of 6.25:1, (vi) a B damping mechanism having a damping coefficient of about 37.0 lbf*s/in with a gear ratio of 6.25:1, (vii) a K damping mechanism having a damping coefficient of about 46.2 lbf*s/in with a gear ratio of 6.25:1, (viii) a V damping mechanism having a damping coefficient of about 60.7 lbf*s/in with a gear ratio of 6.25:1, (ix) a G damping mechanism having a damping coefficient of about 164 lbf*s/in with a gear ratio of 16:1, (x) a B damping mechanism having a damping coefficient of about 242 lbf*s/in with a gear ratio of 16:1, (xi) a K damping mechanism having a damping coefficient of about 303 lbf*s/in with a gear ratio of 16:1, (xii) a V damping mechanism having a damping coefficient of about 398 lbf*s/in with a gear ratio of 16:1, and (xiii) an ideal flow rate in which the therapeutic agent is delivered at a substantially constant rate. 
       FIG. 33  shows that increasing the damping coefficient for the same gear ratio increases the delivery time of the same volume of therapeutic agent. In some cases, increasing the damping coefficient makes the delivery rate more linear. For example, for the 6:25:1 gear ratio, the highest damping coefficient of about 60.7 lbf*s/in yields linear delivery rate than the lower damping coefficients. 
       FIG. 34  illustrates a graph of exemplary damper torques (that may be back-calculated from the displacement of the plunger actuator) against damper speeds (in rpm) for G, B, K and V model dampers having increasing damping coefficients. The dots indicate the actual torque values and the dotted lines indicate the assumed manufacturer damping torque values, which indicates that the manufacturer values were underestimated. The data indicate that the torque values were substantially linear in the range of between 0 and about 20 rpm. This is evidenced by the high correlation coefficient for the linear fit equations shown in the graph. Using the new linear fit equations for the damper torque provided by the linear fit adjusts the damping coefficient and includes a static torque value. Substituting these new values into a computer model allows for a close approximation of the system response. 
     Since the static torque is multiplied by the gear ratio and subtracts directly from the spring force, it may be desirable to choose the highest rate damper and the lowest gearing ratio in an exemplary embodiment, for example, the V model damper and a 4:1 gearing ratio.  FIG. 35  illustrates a graph of the volume of therapeutic agent (in milliliters) against time (in seconds) delivered by different exemplary syringes using a V model damper having a damping coefficient of about 24.9 lbf*s/in and an exemplary gear ratio of 4:1. 
     After adjusting the computer models to reflect the measured damper torque, a fusee was designed to linearize the delivery rate of therapeutic agent.  FIG. 36  illustrates a graph of the volume of therapeutic agent (in milliliters) delivered and the diameter of the fusee or cam spool (in inches) versus the time (in seconds). Since the diameter of the fusee changes over the delivery, the angular position data was numerically integrated along the fusee curve to yield the linear position data of the plunger actuator at each data point. 
       FIG. 36  shows that the actual measured delivery rate is about 10% slower than that predicted by the model but is nearly constant as evidenced by the high correlation coefficient (0.9995). The discrepancy between the measured and predicted data may be explained by inefficiencies in the gearing, for example, areas where the gearing binds may be seen as sharp changes in slope in the graph. The discrepancy may also be explained by the tether coupling the fusee to the plunger actuator not being perfectly in line with the plunger actuator, or the spring rate of the plunger actuator being lower in reality than calculated. Regardless of the source of error, reducing the spring rate of the plunger actuator by about 5% may produce a near perfect correlation (1.0). 
     Different exemplary damping mechanisms were tested at different temperatures to determine the effect of temperature on the damping effect, i.e., the linearity of the delivery of the therapeutic agent. The viscous rotary damping torque is dependent on the viscosity of the silicon grease inside the rotary damper. The viscosity of the silicon grease depends in part on the temperature of the surrounding environment. Different exemplary damping mechanisms were also tested to determine the effect of manufacturing variability in the damping mechanisms on the damping effect, i.e., the linearity of the delivery of the therapeutic agent. Variations in damper manufacturing may affect the resisting torque provided by the damper. 
       FIG. 37  illustrates a graph of the volume of therapeutic agent (in milliliters) delivered versus time (in seconds) achieved by: (i) a first damper at room temperature, (ii) the first damper at about 40 degrees Fahrenheit (in a refrigerator), (iii) a second damper, (iv) the second damper at about 0 degree Fahrenheit (in a freezer), (v) a third damper having manufacturing variability relative to the first and second dampers, and (vi) a fourth damper having manufacturing variability relative to the first and second dampers. 
       FIG. 37  shows that changes in temperature did not substantially affect the damping effect, i.e., the linearity of the delivery of the therapeutic agent. However, the delivery rate was affected in some cases by decreasing the temperature, for example, for the first damper. Similarly, manufacturing variability in the damping mechanisms did not substantially affect the damping effect, i.e., the linearity of the delivery of the therapeutic agent. However, the delivery rate was affected in some cases by manufacturing variability. The damper torque values varied by about 5% in the sample group tested. 
     Thus, one or more factors may be configured to control the linearity and/or the delivery rate of the therapeutic agent including, but not limited to, the gear ratio, the damping coefficient, manufacturing deviations in the damper, manufacturing deviations in the plunger actuator, and the like. In addition, other characteristics of the plunger actuator may be varied in order to control the linearity and/or the rate of the flow of the therapeutic agent. 
       FIG. 38  illustrates a schematic of a portion of an exemplary automatic injection device  2600  that employs a fusee and an escapement mechanism. The device  2600  includes a plunger actuation mechanism for automatically actuating a bung  2408  contained in a syringe or cartridge  2404 . In the exemplary plunger actuation mechanism, a runaway escapement  2602  may be used to resist the acceleration of the plunger actuator  2406  by providing linear damping. In the exemplary runaway escapement  2602 , an escape wheel is provided having a plurality of teeth on its circumferential periphery and a pallet is provided in the vicinity of the escape wheel. In an exemplary embodiment, the escape wheel may have 30 teeth, although exemplary escape wheels are not limited to 30 teeth. The escape wheel may be coupled to the spool  2426  via one or more gears forming a gear train. In an exemplary embodiment, a gearing ratio of 50:1 may couple the spool  2426  to the escape wheel, but other exemplary gearing ratios may be used. The pallet may have an adjustable mass moment of inertia by way of pin holes that may be filed with one or more pins, for example, steel dowel pins. 
     In operation, when torque is applied to the escape wheel, the escape wheel rotates and a tooth of the escape wheel imparts an impulse torque on the pallet such that the kinetic energy of the pallet is reversed. The tooth pushes aside an arm of the pallet. This causes the pallet to oscillate which frees the tooth of the escape wheel, simultaneously bringing the alternate arm of the pallet into interference with a second tooth of the escape wheel. As such, as the escape wheel rotates, its movement is arrested by periodic impact with the pallet, thus allowing the escape wheel to rotate only when the pallet is free to oscillate. As the torque applied to the escape wheel increases, the escape wheel imparts a stronger impulse to the pallet, thus increasing the oscillation speed pallet and therefore allowing the escape wheel to move more rapidly. 
     Assuming that the collisions between the teeth of the escape wheel and the pallet are perfectly elastic, the pallet absorbs, for each impact: 
       T=J{dot over (φ)} 2  
 
     The power dissipation of the pallet is directly proportion to the frequency of oscillation of the pallet w because two collisions occur between the escape wheel and the pallet for every oscillation of the pallet. Thus: 
       P=2ωJ{dot over (φ)} 2  
 
     Assuming an impulse time of zero, since the collisions are perfectly elastic, the magnitude of the angular velocity {dot over (φ)} may be assumed to be constant and related to φ max , the angular distance between collisions (in radians) may be represented by: 
       {dot over (φ)}=2ωφ max  
 
     Thus, 
       P=8Jω 3 φ max   2  
 
     The rotational speed of the escape wheel {dot over (θ)} is related to the number of teeth n and the oscillation frequency ω and may be represented as: 
     
       
         
           
             
               θ 
               . 
             
             = 
             
               
                 
                   
                     2 
                      
                     
                         
                     
                      
                     π 
                      
                     
                         
                     
                      
                     ω 
                   
                   n 
                 
                 ⇒ 
                 ω 
               
               = 
               
                 
                   n 
                    
                   
                       
                   
                    
                   
                     θ 
                     . 
                   
                 
                 
                   2 
                    
                   
                       
                   
                    
                   π 
                 
               
             
           
         
       
       
         
           
             Thus 
             , 
             
               
 
             
              
             
               P 
               = 
               
                 
                   J 
                    
                   
                       
                   
                    
                   
                     ϕ 
                     max 
                     2 
                   
                    
                   
                     n 
                     3 
                   
                    
                   
                     
                       θ 
                       . 
                     
                     3 
                   
                 
                 
                   π 
                   3 
                 
               
             
           
         
       
     
     Since P=C θ {dot over (θ)} 2  for a viscous rotary damper: 
     
       
         
           
             
               C 
               θ 
             
             = 
             
               
                 
                   
                     J 
                      
                     
                         
                     
                      
                     
                       ϕ 
                       max 
                       2 
                     
                      
                     
                       n 
                       3 
                     
                      
                     
                        
                       
                         θ 
                         . 
                       
                        
                     
                   
                   
                     π 
                     3 
                   
                 
                  
                 
                   
 
                 
                 ⇒ 
                 
                   F 
                   x 
                 
               
               = 
               
                 
                   
                     
                       ( 
                       
                         
                           2 
                            
                           nN 
                         
                         
                           π 
                            
                           
                               
                           
                            
                           D 
                         
                       
                       ) 
                     
                     3 
                   
                    
                   J 
                    
                   
                       
                   
                    
                   
                     ϕ 
                     max 
                     2 
                   
                    
                   
                      
                     
                       x 
                       . 
                     
                      
                   
                   * 
                   
                     x 
                     . 
                   
                 
                 = 
                 
                   
                     C 
                     x 
                   
                    
                   
                      
                     
                       x 
                       . 
                     
                      
                   
                   * 
                   
                     x 
                     . 
                   
                 
               
             
           
         
       
     
     which creates a non-linear differential equation. 
     In another exemplary plunger actuation mechanism, a swiss lever escapement may be used to resist the acceleration of the plunger actuator. Assuming a coordinate system in which 0=0 is at the equilibrium of a coil spring attached to a balance wheel. If damping is negligible in this system, then: 
         J{umlaut over (θ)}+kθ= 0 
     Where k is the torsional spring constant of the coil spring and J is the mass moment of inertia: 
       J=∫r 2 dm
 
     Where r is the distance from the center of rotation and m is mass, the natural frequency of the system is: 
     
       
         
           
             
               ω 
               0 
             
             = 
             
               
                 k 
                 J 
               
             
           
         
       
     
     If the escapement wheel has n teeth and a spur gear train of speed reduction N couples the escapement to a spool of diameter D, then the spool rotates at angular velocity: 
     
       
         
           
             
               φ 
               . 
             
             = 
             
               
                 2 
                  
                 
                     
                 
                  
                 π 
                  
                 
                     
                 
                  
                 
                   ω 
                   0 
                 
               
               nN 
             
           
         
       
     
     Taking the derivative of the equation relating θ to x: 
     
       
         
           
             
               d 
               dt 
             
              
             
               ( 
               
                 φ 
                 = 
                 
                   
                     2 
                      
                     
                       ( 
                       
                         x 
                         - 
                         
                           x 
                           0 
                         
                       
                       ) 
                     
                   
                   D 
                 
               
               ) 
             
           
         
       
     
     which yields: 
     
       
         
           
             
               φ 
               . 
             
             = 
             
               
                 2 
                  
                 
                     
                 
                  
                 
                   x 
                   . 
                 
               
               D 
             
           
         
       
       
         
           
             Thus 
             , 
             
               
 
             
              
             
               
                 x 
                 . 
               
               = 
               
                 
                   
                     π 
                      
                     
                         
                     
                      
                     D 
                      
                     
                         
                     
                      
                     
                       ω 
                       0 
                     
                   
                   nN 
                 
                 = 
                 
                   
                     
                       π 
                        
                       
                           
                       
                        
                       D 
                     
                     nN 
                   
                    
                   
                     
                       k 
                       J 
                     
                   
                 
               
             
           
         
       
     
     The components illustrated in  FIG. 38  that are common to  FIG. 24  are described with reference to  FIG. 24 . 
       FIG. 39  illustrates an exemplary plunger actuation mechanism  3900  that employs one or more linear biasing mechanisms to provide a force for expressing a therapeutic agent from the barrel portion  3902  of a wearable automatic injection device. The barrel portion  3902  extends longitudinally between a proximal end and a distal end, and is configured to hold a dose of a therapeutic agent. A distal end of the barrel portion  3902  is coupled to a syringe needle  3904 . A bung  3906  is provided moveably within the barrel portion  3902  to seal the dose of the therapeutic agent. 
     One or more linear springs  3908  are provided for providing a biasing force upon the bung  3906  in order to move the bung  3906  within the barrel portion  3902  toward the syringe needle  3904  during an injection in an injection state. A distal end of the linear spring  3908  is in the vicinity of and/or in contact with a plunger  3916  having a plurality of teeth configured for engagement with a damping mechanism. The plunger  3916  may be provided in the vicinity of and/or in contact with a distal end of a force transmission mechanism, for example, one or more ball bearings  3910 . 
     A distal end of the ball bearings  3910  may also be in the vicinity of and/or in contact with the bung  3906  such that the biasing force of the spring  3908  is transmitted to the bung  3906  through the ball bearings  3910 . The ball bearings  3910  may be enclosed in an enclosed track  3912  that restricts the lateral or sideway movement of the ball bearings  3910 . That is, the biasing force of the spring  3908  causes the plunger  3916  and, in turn, ball bearings  3910  to move substantially in a back or forth manner, i.e., toward or away from the bung  3906 . The use of the ball bearings  3910  allows redirection of the biasing force to the bung  3906  and allows minimization of the size of the device. When actuated, the spring  3908  exerts a biasing force in the direction of the bung  3906 . The biasing force is transmitted by the plunger  3916  and the ball bearings  3910  to the bung  3906  and causes the bung  3906  to move toward the syringe needle  3904  within the barrel portion  3902 . This causes the therapeutic agent to be expressed through the syringe needle  3904  to the exterior of the barrel portion  3902 . 
     A damping mechanism  3914 , for example, a rotary viscous damper, may be provided and associated with the spring  3908  and/or the plunger  3916  to regulate the rate of delivery of the therapeutic agent. The damper  3914  may include a hub and a plurality of teeth that extend in a radial manner about the hub. The teeth of the damper  3914  may be configured for engagement with the teeth of the plunger  3916 . The damper  3914  may provide a force proportional to the speed of movement of the plunger  3916  in order to regulate the delivery rate. As such, the exemplary system  3900  may be used to provide slow controlled delivery of the therapeutic agent by configuring the force provided by the spring  3908  and/or the properties of the damper  3914 . 
       FIG. 40  illustrates an exemplary plunger actuation mechanism  4000  that employs one or more clock springs to provide a force to a bung in a barrel portion in order to expel a therapeutic agent from the barrel portion. A biasing means  4002  is provided by a compression helical coil spring characterized by spring coils of progressively increasing diameter, such that when the spring is compressed, the coils nest one within the other in the manner of a clock spring, thereby taking up the minimum of space. A portion of the spring  4002  is in the vicinity of and/or in contact with a mechanical escapement mechanism  4004  so that the rotary biasing force of the spring  4002  is converted into a linear displacement of the mechanical escapement mechanism  4004 . The mechanical escapement mechanism  4004  may be in the vicinity of and/or in contact with the bung such that the biasing force of the spring  4002  is transmitted as a linear displacement to the bung through the motion of the mechanical escapement mechanism  4004 . That is, the biasing force of the spring  4002  causes the mechanical escapement mechanism  4004  to move substantially in a back or forth manner, i.e., toward or away from the bung. The use of the mechanical escapement mechanism  4004  allows redirection of the biasing force to the bung and allows minimization of the size of the device. 
     When actuated, the spring  4002  exerts a biasing force that is converted to a back and forth force by the mechanical escapement mechanism  4004  in the direction of the bung. The biasing force is transmitted directly or indirectly to the bung and causes the bung to move toward the needle within the barrel portion. This causes the therapeutic agent to be expressed through the needle to the exterior of the barrel portion. As such, the exemplary system  4000  may be used to provide slow controlled delivery of the therapeutic agent by configuring the force provided by the spring  4002  and/or the linear displacement provided by the mechanical escapement mechanism  4004 . The mechanical escapement mechanism  4004  may be configured to control, for example, the amount of advance per cycle. The spring  4002  may be sized to predominate over stick-slip forces. 
       FIGS. 41 and 42  illustrate an exemplary automatic injection device  4100  that employs a fluid-based plunger actuation mechanism in which the fluid pressure and/or movement of a working fluid is used to move a bung within the barrel portion of a syringe or cartridge. The plunger actuation mechanism includes one or more fluid circuits to provide a force to a bung for expressing a dose of a therapeutic agent from a barrel portion  4104  of a syringe or cartridge.  FIG. 41  is a schematic of the exemplary automatic injection device  4100  and  FIG. 40  is a perspective view of the exemplary automatic injection device  4100 . The wearable automatic injection device  4100  may include a pressure element  4106  that stores an incompressible working fluid that provides a fluid pressure. Exemplary working fluids may include, but are not limited to, water, air, oil, and the like. Exemplary pressure elements  4106  may include, but are not limited to, an elastic bladder, a master cylinder, a spring-loaded syringe, and the like. 
     The pressure element  4106  may be coupled to a flow restrictor  4108  via a tubing  4110 . The flow restrictor  4108  may restrict the flow of the working fluid so that the fluid pressure upstream of the flow restrictor is greater than the fluid pressure downstream of the flow restrictor. The flow restrictor  4108  may include an orifice of diameter ranging from about 0.001 inch to about 0.01 inch, but the diameters of exemplary flow restrictor orifices are not limited to this exemplary range. The orifice of the flow restrictor  4108  may have lengths ranging from about 10 mm to about 50 mm, but the lengths of exemplary flow restrictor orifices are not limited this exemplary range. 
     Exemplary embodiments may configure a number of characteristics of the delivery system to control the total delivery time of the therapeutic agent. Exemplary embodiments may also configure a number of characteristics of the delivery system based on the viscosity of the working fluid and/or the therapeutic agent. Exemplary characteristics may include, but are not limited to, the diameter of the orifice, the length of the orifice, the viscosity of the working fluid, and the like. For example, the diameter of the orifice of the flow restrictor may be decreased to increase the total delivery time. 
     The flow restrictor  4108  may also be coupled to the bung via a tubing  4112 . When the working fluid is released from the pressure element  4106  via the flow restrictor  4108 , the fluid pressure of the working fluid drives the bung forwardly within the barrel portion  4104  in order to expel the dose of the therapeutic agent from the barrel portion  4104 . 
     In an exemplary embodiment, before an injection in a pre-injection state, the working fluid may not be released from the pressure element  4106 . In this exemplary embodiment, a delivery trigger (not pictured) may be coupled to the pressure element  4106  so that, upon activation of the delivery trigger, the working fluid is released from the pressure element  4106  into the tubings  4110  and  4112 . The fluid pressure of the working fluid advances the bung within the barrel portion  4104 , thus injecting the dose into the patient&#39;s skin. Thus, the fluid circuit established by the flow of the working fluid and the flow restrictor may provide a regulated force to the bung. 
     In an exemplary embodiment, the dose is delivered in a linear delivery profile, i.e., at a substantially constant delivery rate. Linearity of the delivery profile may be achieved by the high pressure of the working fluid provided by the pressure element  4106  upstream of the flow restrictor  4108  and the damping effect provided by the flow restrictor  4108 . The pressure upstream of the flow restrictor  4108  may be maintained at a high level relative to projected stick-slip forces such that a highly damped system is achieved. For the bung to be moved forward within the barrel portion  4104 , the bung would need to pull a vacuum on the working fluid between the flow restrictor  4108  and the barrel portion  4104 , which is difficult to achieve to an appreciable extent because the working fluid is essentially incompressible. 
     Exemplary damped hydraulic delivery circuits allow movement of the bung via volumetric metering, rather than by a direct application of force, thereby minimizing stick-slip phenomena in the delivery profile of the therapeutic agent. 
     In an exemplary embodiment, an exemplary volume of 0.8 milliliters of therapeutic agent may be delivered at an exemplary delivery pressure of about 16.5 psi within an exemplary duration of about 12 minutes. In another exemplary embodiment, an exemplary volume of 0.8 milliliters of therapeutic agent may be delivered at an exemplary delivery pressure of about 5 psi within an exemplary duration of about 17 minutes. 
       FIG. 43  illustrates a graph of the cumulative amount of therapeutic agent (in grams) against time (in seconds) as delivered by an exemplary delivery system at an exemplary delivery pressure of about 16.5 psi.  FIG. 44  illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) against time (in seconds) as delivered by an exemplary delivery system including a first exemplary flow restrictor having an exemplary diameter of about 0.008 inches and an exemplary length of about 34.3 mm The total delivery time for delivering about 1 milliliters of a therapeutic agent was about twenty seconds.  FIG. 45  illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) against time (in seconds) as delivered by an exemplary delivery system including a second exemplary flow restrictor having an exemplary diameter of about 0.002 inches and an exemplary length of about 34.3 mm The total delivery time for delivering about 1 milliliters of a therapeutic agent was about 15 minutes. In the illustrative graphs, the delivery profile is substantially linear, i.e., substantially constant over time, and does not display an initial bolus or abrupt changes or inflections representative of inconsistent delivery rates. 
       FIG. 46  is a schematic drawing of an exemplary automatic injection device  4600  that employs one or more fluid circuits to provide a force for expressing a therapeutic agent from a cartridge assembly.  FIG. 47  is a top view of the exemplary device  4600 . The exemplary automatic injection device  4600  includes a barrel portion  4602  containing a dose of a therapeutic agent. A distal end of the barrel portion  4602  is provided in the vicinity of or coupled to a syringe needle (hidden by a needle cover  4604 ) that is protectively covered by a needle cover  4604 . The device  4600  includes an injection button that includes a septum and bears an injection needle (not pictured). In an exemplary embodiment, the device  4600  may include an injection needle carrier  4606  for holding the injection needle. In an exemplary embodiment, the injection needle may be extend substantially orthogonally to the plane of the device as illustrated, and may be held in place by the needle carrier  4606 . A needle lock  4608  may be provided for preventing the injection needle from exiting the housing once engaged and may be located in the housing near the injection needle. 
     In an exemplary embodiment, a syringe or cartridge actuator  4610  may be provided for advancing the barrel portion  4602  within the housing toward the septum. A trigger may be provided for triggering the syringe or cartridge actuator  4610 , for example, when the injection button is pressed down or when the needle cover  4604  is removed. 
     In this exemplary embodiment, a master cylinder  4612  containing a working fluid is provided for providing a fluid pressure to actuate a bung  4614  within the barrel portion  4602 . The master cylinder  4612  may be coupled to a delivery trigger  4616  that, when activated, releases the working fluid into fluid communication with the bung  4614  and allows the fluid pressure to advance the bung  4614  within the barrel portion  4602 . 
     Exemplary embodiments also provide needle retraction systems for retracting an injection needle from a vertically lowered position (or an extended or deployed position) outside the housing of the device at the patient contact region to a vertically raised position (or a retracted position) within the housing of the device. The wearable automatic injection device  4600  includes a retraction mechanism that automatically raises the injection button from a vertically depressed position within the housing during an injection in an injection state to a vertically raised position within the housing in a post-injection state after an injection. In an exemplary embodiment, the retraction mechanism may be a telescoping element. The master cylinder  4612  may be coupled to a retraction trigger that, when activated, releases the working fluid into fluid communication with the retraction trigger and allows the fluid pressure to activate the retraction mechanism. 
       FIG. 48  illustrates a top view of the device  4600  which shows a conduit  4802  coupling the master cylinder  4612  to a flow restrictor  4804 , a conduit  4806  coupling the flow restrictor  4804  to the bung in the barrel portion of the device, and a conduit  4808  coupling the master cylinder  4612  to a retraction mechanism  4810  via a valve  4812 , for example, a check valve.  FIG. 49  illustrates a schematic diagram of the device  4600 . 
     The check valve  4812  may have a suitable cracking pressure at or above which the check valve  4812  allows fluid into the conduit  4808  coupled to the retraction mechanism  4810 . In an exemplary embodiment, the cracking pressure is higher than the maximum fluid pressure in the conduit  4806  required to drive the bung during an injection in an injection state. Otherwise, undesirably, the needle retraction process may begin during or even before the injection. In an exemplary embodiment, the pressure in the conduit  4806  at the end of the movement of the bung during an injection in an injection state is higher than the cracking pressure. Otherwise, at the end of the movement of the bung, the pressure in the conduit  4808  may be insufficient to activate the retraction mechanism  4810 . The volume of the working fluid in the master cylinder  4612  is sufficient to deliver the entire dose of the therapeutic agent and to activate the retraction mechanism  4810 . 
     In an exemplary embodiment, the retraction mechanism  4810  and the check valve  4812  may be provided separately. In another exemplary embodiment, the retraction mechanism  4810  and the check valve  4812  may be provided as a single element, for example, as an inverting diaphragm. 
       FIG. 50  illustrates a graph of the pressure after the check valve and behind the bung (in psi) versus time (in seconds) in an exemplary embodiment. In an exemplary embodiment, the cracking pressure of the check valve may be about 7.5 psi and the diameter of the flow restrictor orifice may be about 0.008 inches. 
     During an injection in an injection state, the flow restrictor  4804  may cause the pressure in the conduit  4802  to be about 10 to about 15 psi, while the pressure in the conduit  4806  may be about 5 to about 6 psi. The check valve  4812  thus prevents any flow of the working fluid from entering the conduit  4808  while the bung is moving during the injection. Once the bung stops moving at the end of the injection, i.e., when the dose has been completely expelled from the barrel portion, the pressure in the conduit  4806  increases beyond 7.5 psi. This causes the check valve  4812  to open, allowing the working fluid to flow into the conduit  4808  which activates the retraction mechanism  4810 . The retraction mechanism  4810  in turn unlocks the needle lock and retracts the injection button/carrier  4606  bearing the injection needle. Because it is based on pressure equalization in the hydraulic circuit, the needle retraction process ensures that the entire dose is delivered before the injection needle is retracted, maximizes utilization of the therapeutic agent, and minimizes the overfill required in the barrel portion  4602 . 
     Any suitable trigger mechanism may be used to trigger the needle retraction systems. In an exemplary embodiment, the trigger mechanism may automatically trigger the needle retraction system when the wearable automatic injection device moves from an injection state to a post-injection state. In an exemplary embodiment, completion of the delivery of a therapeutically effective dose of the therapeutic agent may trigger the needle retraction system. In another exemplary embodiment, the removal of the device from the patient before completion of the delivery of a therapeutically effective dose of the therapeutic agent may trigger the needle retraction system. In another exemplary embodiment, the needle retraction system may be manually triggered by a user. 
       FIG. 51  illustrates a side view of an exemplary automatic injection device  5100  in which the housing  5102  of the wearable automatic injection device  5100  includes a skin sensor foot  5104 , which is a structure in an exemplary embodiment housed under or in the portion of the housing  5102  proximal to the injection site. In an exemplary embodiment, prior to injection of the therapeutic agent and during injection, the skin sensor foot  5104  is retained within or forms a portion of the underside of the housing  5102 . When the wearable automatic injection device  5100  is attached to the injection site and activated, the skin sensor foot  5104  may be free to move but may be constrained by the injection site. In an exemplary embodiment, when the wearable automatic injection device  5100  is removed from the injection site, regardless of whether the drug delivery was completed, the skin sensor foot  5104  is no longer constrained, and extends and projects outside the periphery of the housing  5102 . This, in turn, trips a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle which may also raise the injection button from the vertically lowered position to the vertically raised position, so that the injection button protrudes from the top of the housing  5102  and the injection needle is retracted within the housing  5102 . 
     V. Exemplary Needle Protection Systems 
     Exemplary embodiments provide different exemplary needle protection systems for maintaining the injection needle within the wearable automatic injection device in a post-injection state after an injection. Protection of the needle prevents accidental needle sticks from injuring the patient or any other humans in the vicinity of the wearable automatic injection device. 
       FIGS. 52A and 52B  illustrate an exemplary needle protection system  5200  that maintains an injection needle  5202  in a retracted position within a housing  5204  of an automatic injection system. The injection needle  5202  is movable relative to the housing  5204  away from or toward the patient&#39;s skin. When the needle  5202  is in a position within the housing  5204  farther from the patient&#39;s skin, the needle  5202  is in a retracted position and does not protrude outside the housing  5204 . When the needle  5202  is in a position within the housing  5204  closer to the patient&#39;s skin, the needle  5202  is in an inserted or deployed position and protrudes fully or partly from the housing  5204 . The housing  5204  may be provided with an aperture  5206  through which the needle  5202  may protrude outside the housing  5204 . 
     The needle protection system  5200  employs a barrier mechanism  5208  which prevents the needle  5202  from protruding from the housing  5204  in a pre-injection state before an injection and in a post-injection state after an injection when the needle  5202  is in the retracted position.  FIG. 52A  illustrates the system  5200  in which the needle  5202  is in an inserted or deployed position and protrudes fully or partly through the aperture  5206  outside the housing  5204 , for example, during an injection in an injection state. In this case, the barrier mechanism  5208  is displaced away from the aperture  5206  so that the aperture  5206  is open to the outside of the housing  5204 , and the needle  5202  is free to protrude through the aperture  5206  to the outside of the housing  5204 .  FIG. 52B  illustrates the system  5200  in which the needle  5202  is in a retracted position and does not protrude from the housing  5204 , for example, in a pre-injection state and a post-injection state. In this case, the barrier mechanism  5208  is aligned with and covers the aperture  5206  so that the aperture  5206  is no longer open to the outside of the housing  5204 , and the needle  5202  is not free to protrude through the aperture  5206  to the outside of the housing  5204 . In an exemplary embodiment, the barrier mechanism  5208  may be moved rotatably above a point of rotation between a first position in which it exposes the aperture  5206  (in  FIG. 52A ) to a second position in which it covers the aperture  5206  (in  FIG. 52B ). 
       FIGS. 53A and 53B  illustrate another exemplary needle protection system  5300  provided in the housing  5302  of an automatic injection system. The automatic injection system includes an injection needle  5304  that is movable relative to the housing  5302  away from or toward the patient&#39;s skin. When the needle  5304  is in a position within the housing  5302  farther from the patient&#39;s skin, the needle  5304  is in a retracted position and does not protrude outside the housing  5302 . When the needle  5304  is in a position within the housing  5302  closer to the patient&#39;s skin, the needle  5304  is in an inserted or deployed position and protrudes fully or partly from the housing  5302 . 
     The needle protection system  5300  includes a needle lockout sleeve  5306  provided in the vicinity of the injection needle  5304  for locking the injection needle in the retracted position in a pre-injection state and a post-injection state. The needle lockout sleeve  5306  may be coupled to a pin  5308  disposed in a slot  5310 . The pin  5308  may be in a first position (illustrated in  FIG. 53A ) relative to the slot  5310  in which the needle lockout sleeve  5306  locks the injection needle  5304  in the retracted position within the housing  5302 . The pin  5308  may be in a second position (illustrated in  FIG. 53B ) relative to the slot  5310  in which the needle lockout sleeve  5306  allows the injection needle  5304  to protrude outside the housing  5302 . 
     In an exemplary embodiment, an early-removal retraction trigger  5312  that, then tripped, triggers a retraction mechanism that retracts the injection needle  5304  into the housing  5302 . The early-removal retraction trigger  5312  may be tripped when the wearable automatic injection device  5300  is removed from the injection site before the therapeutically effective dose of therapeutic agent is completely delivered. In an exemplary embodiment, the early-removal retraction trigger  5312  may include a latch  5314 , e.g., a flexible plastic hook, that is released upon removal of the wearable automatic injection device  5300  from the injection site.  FIG. 53A  shows the early-removal retraction trigger  5312  in which the latch  5314  is engaged to a portion of the lockout sleeve  5306  when the wearable injection device is coupled to the injection site.  FIG. 53B  shows the early-removal retraction trigger  5312  in which the latch  5314  is released from the portion of the lockout sleeve  5306  when the wearable injection device is removed from the injection device. Release of the latch  5314  from the portion of the lockout sleeve  5306  triggers the retraction mechanism. An exemplary retraction mechanism may be responsive to an end-of-dose retraction trigger and responsive to the early-removal retraction trigger  5310  to automatically retract the injection needle  5304  from the injection site. 
       FIG. 54  illustrates an exemplary needle protection system  5400  that maintains an injection needle held by an injection carrier  5402  in a retracted position within a housing  5404  of an automatic injection system. The injection needle is movable relative to the housing  5404  away from or toward the patient&#39;s skin. When the injection needle is in a position within the housing  5404  farther from the patient&#39;s skin, the needle is in a retracted position and does not protrude outside the housing  5404 . When the needle is in a position within the housing  5404  closer to the patient&#39;s skin, the needle is in an inserted or deployed position and protrudes fully or partly from the housing  5404 . The housing  5404  may be provided with an aperture through which the needle may protrude outside the housing  5404 . 
     The needle protection system  5400  includes a needle lock  5408  provided in the vicinity of or in contact with the needle carrier  5402 . In an exemplary embodiment, the needle lock  5408  may be a pivoting or rotating member that may pivot or rotate about a pivoting point or interface. A needle lock release mechanism  5410  may be provided in the vicinity of or in contact with the needle lock  5408 . The needle lock release mechanism  5410  may be in a first position when the injection needle is in a vertically lowered position and protrudes outside the housing  5404  (in an injection state), and in a second position when the injection needle is in a vertically raised or retracted position within the housing  5404  (in a pre-injection state or a post-injection state) 
     When the needle lock release mechanism  5410  is in the first position (that is, when the injection needle is in a vertically lowered injection position), the needle lock  5408  may be in an unlocked position in which it does not lock the injection needle in the vertically raised position in the housing  5404 . Alternatively, the needle lock  5408  may in a locked position in which it locks the injection needle  5408  in the vertically lowered position in the housing  5404 . In an exemplary embodiment (that is, when the injection needle is in a vertically lowered injection position), retraction of the injection needle and/or the needle carrier  5402  to the vertically raised position within the housing  5404  may trigger the needle lock release mechanism  5410 , i.e., move the release mechanism from the first position to the second position. When the needle lock release mechanism  5410  is moved to the second position, the needle lock  5408  may pivot or rotate, thereby locking the injection needle and/or the needle carrier  5402  in the vertically raised position in the housing  5404 . 
       FIG. 55  illustrates an exemplary needle protection system  5500  that maintains an injection needle held by an injection carrier  5502  in a retracted position within a housing  5504  of an automatic injection system. The injection needle is movable relative to the housing  5504  away from or toward the patient&#39;s skin. When the injection needle is in a position within the housing  5504  farther from the patient&#39;s skin, the needle is in a retracted position and does not protrude outside the housing  5504 . When the needle is in a position within the housing  5504  closer to the patient&#39;s skin, the needle is in an inserted or deployed position and protrudes fully or partly from the housing  5504 . The housing  5504  may be provided with an aperture through which the needle may protrude outside the housing  5504 . 
     The needle protection system  5500  includes a needle lock  5508  provided in the vicinity of or in contact with the needle carrier  5502 . In an exemplary embodiment, the needle lock  5508  may be a pivoting or rotating member that may pivot or rotate about a pivoting point or interface. The needle lock  5508  may include a biasing mechanism  5506  that applies a rotational spring force to the needle carrier  5502  about a longitudinal axis of the biasing mechanism. In an exemplary embodiment, the needle lock  5508  may be provided in a symmetrical manner about the needle carrier  5502  such that the rotational force is applied by the biasing mechanism  5506  substantially symmetrically about the needle carrier  5502 . 
     A needle lock release mechanism  5510  may be provided in the vicinity of or in contact with the needle lock  5508 . The needle lock release mechanism  5510  may be in a first position when the injection needle is in a vertically lowered position and protrudes outside the housing  5504  (in an injection state), and in a second position when the injection needle is in a vertically raised or retracted position within the housing  5504  (in a pre-injection state or a post-injection state) 
     When the needle lock release mechanism  5510  is in the first position (that is, when the injection needle is in a vertically lowered injection position), the biasing mechanism  5506  may apply a spring force to the needle carrier  5502  in the clockwise direction toward the patient&#39;s body such that the needle carrier  5502  is held in the vertically lowered position. When the needle lock release mechanism  5510  is in the second position (that is, when the injection needle is in a vertically raised pre or post-injection state), the biasing mechanism  5506  may apply a spring force to the needle carrier  5502  in the counter-clockwise direction away from the patient&#39;s body such that the needle carrier  5502  is raised to and held in the vertically raised position. 
     In an exemplary embodiment, retraction of the injection needle and/or the needle carrier  5502  to the vertically raised position within the housing  5504  may trigger the needle lock release mechanism  5510 , i.e., move the release mechanism from the first position to the second position. When the needle lock release mechanism  5510  is moved to the second position, the needle lock  5508  may pivot or rotate under the force of the biasing member  5506  in the counter-clockwise direction away from the patient&#39;s body, thereby locking the injection needle and/or the needle carrier  5502  in the vertically raised position in the housing  5504 . 
     VI. Therapeutic Agents for Use in Exemplary Automatic Injection Devices 
     Exemplary automatic injection devices may be used to administer essentially any substance or therapeutic agent that is suitable for administration by injection. Typically, the substance or therapeutic agent will be in a fluid, e.g., liquid form, although medications in other forms such as gels or semi-solids, slurries, particulate solutions, etc. also may suitable for use if the wearable automatic injection device is designed to permit the administration of such forms of the medication. 
     Preferred medications are biological agents, such as antibodies, cytokines, vaccines, fusion proteins and growth factors. Methods of making antibodies are described above. 
     Non-limiting examples of other biological agents that can be used as the medication in the automatic injection device include but are not limited to antibodies to or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF; antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L); TNFα converting enzyme (TACE) inhibitors; IL-1 inhibitors (Interleukin-1-converting enzyme inhibitors, IL-1RA etc.); Interleukin 11; IL-18 antagonists including IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding proteins; non-depleting anti-CD4 inhibitors; antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands; agents which interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g. IRAK, NIK, IKK , p38 or MAP kinase inhibitors); IL-1□ converting enzyme (ICE) inhibitors; T-cell signaling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel™ and p55TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF-beta); Rituximab; IL-1 TRAP; MRA; CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15; IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline; see e.g., Arthritis &amp; Rheumatism (1995) Vol. 38; S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen; see e.g., Arthritis &amp; Rheumatism (1993) Vol. 36; 1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra (Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein; see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement); 5284; Amer. J. Physiol.—Heart and Circulatory Physiology (1995) 268:37-42); R973401 (phosphodiesterase Type IV inhibitor; see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement); S282); MK-966 (COX-2 Inhibitor; see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement); S81); Iloprost (see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement); S82); zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 or lck); VEGF inhibitor and/or VEGF-R inhibitor (inhibitors of vascular endothelial cell growth factor or vascular endothelial cell growth factor receptor; inhibitors of angiogenesis); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement), S296); interleukin-13 (see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement), S308); interleukin -17 inhibitors (see e.g., Arthritis &amp; Rheumatism (1996) 39(9, supplement), S120); anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins; ICAM-1 antisense phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies. 
     VII. TNFα Inhibitors for Use in Exemplary Automatic Injection Devices 
     According to one embodiment of the invention, the illustrative automatic injection device may be used to deliver a dose of a TNF inhibitor used to treat arthritis and other diseases. In one embodiment, the solution contained in the syringe contains 40 or 80 milligrams of drug product (TNFα blocker or inhibitor)/1 mL, for example, 40 or 80 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dehydrate, 1.22 mg dibasic sodium phosphate dehydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 50 and water for injection, with USP sodium hydroxide added as necessary to adjust pH to be about 5.2. 
     The present invention can be used to administer a dose of a substance, such as a liquid drug, e.g., a TNFα inhibitor, to a patient. In one embodiment, the dose delivered by the automatic injection device of the invention comprises a human TNFα antibody, or antigen-binding portion thereof. 
     In one embodiment, the TNF inhibitor used in the methods and compositions of the invention includes isolated human antibodies, or antigen-binding portions thereof, that bind to human TNFα with high affinity and a low off rate, and have a high neutralizing capacity. Preferably, the human antibodies of the invention are recombinant, neutralizing human anti-hTNFα antibodies, such as, e.g., the recombinant, neutralizing antibody referred to as D2E7, also referred to as HUMIRA □  or adalimumab (Abbott Laboratories; the amino acid sequence of the D2E7 VL region is shown in SEQ ID NO: 1 of U.S. Pat. No. 6,090,382 the amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2 of U.S. Pat. No. 6,090,382). Properties of D2E7 have been described in Salfeld et al., U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015. Other examples of TNFα inhibitors include chimeric and humanized murine anti-hTNFα antibodies that have undergone clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott et al. (1994) Lancet 344:1125-1127; Elliot et al. (1994) Lancet 344:1105-1110; and Rankin et al. (1995) Br. J. Rheumatol. 34:334-342). 
     An anti-TNFα antibody (also referred to herein as a TNFα antibody), or an antigen-binding fragment thereof, includes chimeric, humanized, and human antibodies. Examples of TNFα antibodies that may be used in the invention include, but not limited to, infliximab (Remicade®, Johnson and Johnson; described in U.S. Pat. No. 5,656,272, incorporated by reference herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb (Peptech), and CNTO 148 (golimumab; Medarex and Centocor, see WO 02/12502). Additional TNF antibodies that may be used in the invention are described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380. 
     Other examples of TNFα inhibitors which may be used in the methods and compositions of the invention include etanercept (Enbrel, described in WO 91/03553 and WO 09/406476), soluble TNF receptor Type I, a pegylated soluble TNF receptor Type I (PEGs TNF-R1), p55TNFR1 gG (Lenercept), and recombinant TNF binding protein (r-TBP-I) (Serono). 
     In one embodiment, exemplary embodiments provide improved uses and compositions for treating a disorder in which TNFα is detrimental, e.g., rheumatoid arthritis, with a TNFα inhibitor, e.g., a human TNFα antibody, or an antigen-binding portion thereof, through a wearable automatic injection device. 
     A TNFα inhibitor includes any agent (or substance) that interferes with TNFα activity. In a preferred embodiment, the TNFα inhibitor can neutralize TNFα activity, particularly detrimental TNFα activity which is associated with disorders in which TNFα activity is detrimental, including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn&#39;s disease, psoriasis, and psoriatic arthritis. 
     VIII. Pharmaceutical Compositions for Use in Exemplary Automatic Injection Devices 
     Pharmaceutical compositions may be loaded into the automatic injection device of the invention for delivery to a patient. In one embodiment, antibodies, antibody-portions, as well as other TNFα inhibitors, can be incorporated into pharmaceutical compositions suitable for administration to a patient using the device of the invention. Typically, the pharmaceutical composition comprises an antibody, antibody portion, or other TNFα inhibitor, and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody, antibody portion, or other TNFα inhibitor. 
     The compositions for use in the methods and compositions of the invention may be in a variety of forms in accordance with administration via the device of the invention, including, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions. In a preferred embodiment, the antibody or other TNFα inhibitor is administered by subcutaneous injection using the device of the invention. In one embodiment, the patient administers the TNFα inhibitor, including, but not limited to, TNFα antibody, or antigen-binding portion thereof, to himself/herself using the device of the invention 
     Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody, antibody portion, or other TNFα inhibitor) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. 
     In one embodiment, exemplary embodiments provide a wearable automatic injection device, e.g., autoinjector pen, comprising an effective TNFα inhibitor and a pharmaceutically acceptable carrier. Thus, the invention provides a pre-fillable and/or pre-filled automatic injection device comprising a TNFα inhibitor. 
     In one embodiment, the antibody or antibody portion for use in the methods of the invention is incorporated into a pharmaceutical formulation as described in PCT/IB03/04502 and U.S. Patent Publication No. 2004/0033228. This formulation includes a concentration 50 mg/ml of the antibody D2E7 (adalimumab), wherein a wearable automatic injection device contains 40 mg of antibody for subcutaneous injection. In one embodiment, the automatic injection device of the invention (or more specifically the syringe of the device) comprises a formulation of adalimumab having the following formula: adalimumab, sodium chloride, monobasic sodium phosphate dihydrate, dibasic sodium phosphate dihydrate, sodium citrate, citric acid monohydrate, mannitol, polysorbate 80 and water, e.g., water for injection. In another embodiment, the automatic injection device comprises a volume of adalimumab including 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80 and water, e.g., water for injection. In one embodiment, sodium hydroxide is added as necessary to adjust pH. 
     The dose amount of TNFα inhibitor in the automatic injection device may vary according to the disorder for which the TNFα inhibitor is being used to treat. In one embodiment, the invention includes a wearable automatic injection device comprising a dose of adalimumab of about 20 mg of adalimumab; 40 mg of adalimumab; 80 mg of adalimumab; and 160 mg of adalimumab. It should be noted that for all ranges described herein, including the dose ranges, all numbers intermediary to the recited values are included in the invention, e.g., 36 mg of adalimumab, 48 mg of adalimumab, etc. In addition ranges recited using said numbers are also included, e.g. 40 to 80 mg of adalimumab. The numbers recited herein are not intended to limit the scope of the invention. 
     The TNFα antibodies and inhibitors used in the invention may also be administered in the form of protein crystal formulations that include a combination of protein crystals encapsulated within a polymeric carrier to form coated particles. The coated particles of the protein crystal formulation may have a spherical morphology and be microspheres of up to 500 micro meters in diameter or they may have some other morphology and be microparticulates. The enhanced concentration of protein crystals allows the antibody of the invention to be delivered subcutaneously. In one embodiment, the TNFα antibodies of the invention are delivered via a protein delivery system, wherein one or more of a protein crystal formulation or composition, is administered to a patient with a TNFα-related disorder. Compositions and methods of preparing stabilized formulations of whole antibody crystals or antibody fragment crystals are also described in WO 02/072636, which is incorporated by reference herein. In one embodiment, a formulation comprising the crystallized antibody fragments described in International Patent Application No. PCT/IB03/04502 and U.S. Patent Publication No. 2004/0033228 is used to treat rheumatoid arthritis using the methods of the invention. 
     Supplementary active compounds can also be incorporated into the compositions. In certain embodiments, an antibody or antibody portion for use in the methods of the invention is co-formulated with and/or co-administered with one or more additional therapeutic agents, including a rheumatoid arthritis inhibitor or antagonist. For example, an anti-hTNFα antibody or antibody portion may be co-formulated and/or co-administered with one or more additional antibodies that bind other targets associated with TNFα related disorders (e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNFα receptor (see e.g., PCT Publication No. WO 94/06476) and/or one or more chemical agents that inhibit hTNFα production or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751) or any combination thereof. Furthermore, one or more antibodies of the invention may be used in combination with two or more of the foregoing therapeutic agents. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible side effects, complications or low level of response by the patient associated with the various monotherapies. Additional agents that may be used in combination with a TNFα antibody or antibody portion are described in U.S. patent application Ser. No. 11/800531, which is expressly incorporated herein by reference in its entirety. 
     IX. Incorporation by Reference 
     The contents of all references, including patents and patent applications, cited throughout this application are hereby incorporated herein by reference in their entirety. The appropriate components and methods of those references may be selected for the invention and embodiments thereof. Still further, the components and methods identified in the Background section are integral to this disclosure and can be used in conjunction with or substituted for components and methods described elsewhere in the disclosure within the scope of the invention. 
     X. Equivalents 
     In describing exemplary embodiments, specific terminology is used for the sake of clarity. For purposes of description, each specific term is intended to at least include all technical and functional equivalents that operate in a similar manner to accomplish a similar purpose. Additionally, in some instances where a particular exemplary embodiment includes a plurality of system elements or method steps, those elements or steps may be replaced with a single element or step. Likewise, a single element or step may be replaced with a plurality of elements or steps that serve the same purpose. Further, where parameters for various properties are specified herein for exemplary embodiments, those parameters may be adjusted up or down by 1/20th, 1/10th, ⅕th, ⅓rd, ½, etc., or by rounded-off approximations thereof, unless otherwise specified. Moreover, while exemplary embodiments have been shown and described with references to particular embodiments thereof, those of ordinary skill in the art will understand that various substitutions and alterations in form and details may be made therein without departing from the scope of the invention. Further still, other aspects, functions and advantages are also within the scope of the invention. 
     Exemplary flowcharts are provided herein for illustrative purposes and are non-limiting examples of methods. One of ordinary skill in the art will recognize that exemplary methods may include more or fewer steps than those illustrated in the exemplary flowcharts, and that the steps in the exemplary flowcharts may be performed in a different order than shown.