Patent Publication Number: US-9833562-B2

Title: Self-injection device

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to a substance delivery device having improved patient convenience and ease of use, and improved pressurization and activation mechanisms. The present invention also relates generally to a patch-like, self-contained substance infusion or self-injection device that can be used to deliver a variety of substances or medications to a patient. More specifically, the present invention relates to an infusion or self-injection device in which the force required to activate the device is reduced. 
     BACKGROUND OF THE INVENTION 
     A large number of people, such as those suffering from conditions such as diabetes, use some form of infusion therapy, such as daily insulin infusions, to maintain close control of their glucose levels. Currently, in the insulin infusion treatment example, there are two principal modes of daily insulin therapy. The first mode includes syringes and insulin pens. These devices are simple to use and are relatively low in cost, but they require a needle stick at each injection typically three to four times per day. The second mode includes infusion pump therapy, which entails the purchase of an expensive pump that lasts for about three years. The high cost (roughly 8 to 10 times the daily cost of syringe therapy) and limited lifetime of the pump are high barriers to this type of therapy. Insulin pumps also represent relatively old technology and are cumbersome to use. From a lifestyle standpoint, moreover, the tubing (known as the “infusion set”) that links the pump with the delivery site on the patient&#39;s abdomen is very inconvenient and the pumps are relatively heavy, making carrying the pump a burden. From a patient perspective, however, the overwhelming majority of patients who have used pumps prefer to remain with pumps for the rest of their lives. This is because infusion pumps, although more complex than syringes and pens, offer the advantages of continuous infusion of insulin, precision dosing and programmable delivery schedules. This results in closer glucose control and an improved feeling of wellness. 
     Interest in better therapy is on the rise, accounting for the observed growth in pump therapy and increased number of daily injections. In this and similar infusion examples, what is needed to fully meet this increased interest is a form of insulin delivery or infusion that combines the best features of daily injection therapy (low cost and ease of use) with those of the insulin pump (continuous infusion and precision dosing) and that also avoids the disadvantages of each. 
     Several attempts have been made to provide ambulatory or “wearable” drug infusion devices that are low in cost and convenient to use. Some of these devices are intended to be partially or entirely disposable. In theory, devices of this type can provide many of the advantages of an infusion pump without the attendant cost and inconvenience. Unfortunately, however, many of these devices suffer from disadvantages including patient discomfort (due to the gauge and/or length of injection needle used), compatibility and interaction between the substance being delivered and the materials used in the construction of the infusion device, and possible malfunctioning if not properly activated by the patient (for example, “wet” injections resulting from premature activation of the device). Difficulties in manufacturing and in controlling needle penetration depth have also been encountered, particularly when short and/or fine-gauge injection needles are used. The possibility of needle-stick injuries to those who come into contact with the used device has also been problematic. 
     Accordingly, a need exists for an alternative to current infusion devices, such as infusion pumps for insulin, that further provides simplicity in manufacture and use improvements for insulin and non-insulin applications. 
     SUMMARY OF THE INVENTION 
     An aspect of the present invention is to provide a patch-like infusion or self-injection device that can be conveniently worn against the skin while providing infusion of a desired substance, and providing minimal discomfort by using one or more microneedles. An additional aspect of the present invention is to provide such an infusion or self-injection device in which the force required by a patient to activate the device is reduced. 
     The foregoing and/or other aspects of the present invention are achieved by providing a drug delivery device, including a body having a top enclosure and a bottom enclosure, a reservoir disposed within the body for containing a medicament, and an injection needle to penetrate the skin of a patient, the needle providing a path for the medicament between the reservoir and the patient. The device also includes a retention plate disposed between the top enclosure and the bottom enclosure, a plunger movable within the main body for causing the medicament to be expelled from the reservoir, and a spring disposed between the retention plate and the plunger and biasing the plunger. First guide means are provided on one of the retention plate and the plunger. The first guide means have a portion with a predetermined size and shape. Second guide means are disposed on the other one of the retention plate and the plunger and has a size and shape complementary to the size and shape of the first guide means. The first guide means and the second guide means maintain the plunger in a first position with respect to the reservoir. Upon activation of the device, one of the retention plate and the plunger rotates with respect to a non-rotating one of the retention plate and the plunger such that the first guide means aligns with the second guide means causing the plunger to be released from the first position and allowing the plunger to move under the force of the spring to pressurize the reservoir. 
     The foregoing and/or other aspects of the present invention are also achieved by providing a drug delivery device, including a body including a top enclosure and a bottom enclosure, one of the top enclosure and the bottom enclosure having a cylindrical housing, a reservoir disposed within the body for containing a medicament, and an injection needle to penetrate the skin of a patient, the needle providing a path for the medicament between the reservoir and the patient. The device also includes a retention plate disposed between the top enclosure and the bottom enclosure, a plunger rotatable between a pre-activated position and an aligned position and translatable within the cylindrical housing between the aligned position and an activated position for causing the medicament to be expelled from the reservoir, a spring disposed on the retention plate, biasing the plunger, and compressed by the plunger when the plunger is in the pre-activated position, and first guide means substantially at a center of the cylindrical housing on one of the retention plate and the plunger. The first guide means has a portion with a predetermined size and shape. Second guide means are disposed on the other one of the retention plate and the plunger. The second guide means has a size and shape complementary to the size and shape of the first guide means, the first guide means and the second guide means maintaining the plunger in a first position with respect to the reservoir. Upon activation of the device, the plunger rotates to the aligned position, aligning the first guide means with the second guide means, releasing the plunger to translate to the activated position due to the force of the spring, to pressurize the reservoir. 
     The foregoing and/or other aspects of the present invention are also achieved by providing a drug delivery device, including a body having a reservoir disposed therein for containing a medicament, a retention plate disposed within the body, a plunger movable within the body for causing the medicament to be expelled from the reservoir, and a spring disposed between the retention plate and the plunger and biasing the plunger. The device also includes first guide means provided on one of the retention plate and the plunger, the first guide means having a portion with a predetermined size and shape. The device further includes second guide means provided on the other one of the retention plate and the plunger and having a size and shape complementary to the size and shape of the first guide means, the first guide means and the second guide means maintaining the plunger in a first position with respect to the reservoir. Upon activation of the device, one of the retention plate and the plunger rotates with respect to a non-rotating one of the retention plate and the plunger such that the first guide means aligns with the second guide means causing the plunger to be released from the first position and allowing the plunger to move under the force of the spring to pressurize the reservoir for delivery of the medicament to a patient 
     Additional and/or other aspects and advantages of the present invention will be set forth in part in the description that follows and, in part, will be apparent from the description, or may be learned by practice of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above and/or other aspects and advantages of embodiments of the invention will be more readily appreciated from the following detailed description, taken in conjunction with the accompanying drawings, of which: 
         FIG. 1  illustrates a perspective view of an embodiment of a patch-like infusion device in a pre-activated state prior to activation; 
         FIG. 2  illustrates a partially exploded view of the infusion device of  FIG. 1  in the pre-activated state; 
         FIG. 3  illustrates a partially exploded view of the infusion device of  FIG. 1  in the pre-activated state with an activator button rotated away to reveal more detail; 
         FIG. 4  illustrates a more fully exploded view of the infusion device of  FIG. 1  in the pre-activated state; 
         FIG. 5  illustrates a cross-sectional view of the infusion device of  FIG. 1  in the pre-activated state; 
         FIG. 6  illustrates a cross-sectional view of the infusion device of  FIG. 1  in the pre-activated state with the activator button rotated away; 
         FIG. 7  illustrates a partially exploded view of the infusion device of  FIG. 1  during installation of a safety mechanism; 
         FIG. 8  illustrates a partially exploded view of the infusion device of  FIG. 1  subsequent to activation; 
         FIG. 9  illustrates a more fully exploded view of the infusion device of  FIG. 1  subsequent to activation; 
         FIG. 10  illustrates a cross-sectional view of the infusion device of  FIG. 1  subsequent to activation; 
         FIG. 11  illustrates a partially exploded view of the infusion device of  FIG. 1  subsequent to deployment of the safety mechanism; 
         FIG. 12  illustrates a cross-sectional view of the infusion device of  FIG. 1  subsequent to deployment of the safety mechanism; 
         FIG. 13  illustrates a bottom surface of the safety mechanism; 
         FIG. 14  further illustrates the structure of the safety mechanism; 
         FIGS. 15A-15D  illustrate an end-of-dose indicator and the operation thereof in the infusion device of  FIG. 1 ; 
         FIG. 16  illustrates an embodiment of an infusion device with an injection port; 
         FIG. 17  illustrates an exploded view of an embodiment of a retention assembly to reduce a force required to activate the infusion device of  FIG. 1 ; 
         FIGS. 18A and 18B  respectively illustrate plan views of a sprocket and a corresponding sprocket opening in the assembly of  FIG. 17 ; 
         FIG. 19  illustrates a cross-sectional view of the assembly of  FIG. 17  in a pre-activated position; 
         FIGS. 20A and 20B  respectively illustrate free body diagrams of embodiments of retention assemblies; 
         FIGS. 21 and 22  illustrate another embodiment of a retention assembly to reduce a force required to activate the infusion device of  FIG. 1 ; 
         FIGS. 23A and 23B  illustrate a tool for loading a plunger of  FIG. 4  to the pre-activated state; and 
         FIG. 24  illustrates a tool for loading a plunger of  FIG. 17  to the pre-activated state. 
     
    
    
     DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS 
     Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the like elements throughout. The embodiments described exemplify the present invention by referring to the drawings. 
     The embodiments of the present invention described below can be used as a convenient, patch-like infusion or self-injection device  100  to deliver a pre-measured dose of a substance, such as a liquid drug or medication, to a patient over a period of time or all at once. The device is preferably provided to the end user in a pre-filled condition, that is, with the drug or medication already contained in the device reservoir. Though the patch-like infusion or self-injection device  100  (shown, for example, in  FIG. 1 ) described herein can be employed by a patient and/or a caregiver, for convenience, a user of the device is hereinafter referred to as a “patient.” Additionally, for convenience, terms such as “vertical” and “horizontal” and “top” and “bottom” are employed to represent relative directions with respect to an infusion device  100  disposed on a horizontal surface. It will be understood, however, that the infusion device  100  is not limited to such an orientation, and that the infusion device  100  may be employed in any orientation. Further, the alternative use of the terms “infusion device” and “self-injection device” to describe devices embodying the present invention is not intended in a limiting sense. Infusion devices that do not have a self-injection capability are within the scope of the present invention, as are self-injection devices that do not carry out continuous infusion. For convenience, but not by way of limitation, the term “infusion device” is used in the description that follows. 
     The patch-like infusion device  100  of  FIG. 1  is self-contained and is attached to the skin surface of the patient by adhesive disposed on a bottom surface of the infusion device  100  (as will be described in greater detail below). Once properly positioned and activated by the patient, the pressure of a released spring on a flexible reservoir within the device can be used to empty the contents of the reservoir through one or more patient needles (for example, microneedles) via a needle manifold. The substance within the reservoir is then delivered through the skin of the patient by the microneedles, which are driven into the skin. It will be understood that other embodiments are possible in which the spring is replaced with a different type of stored energy device, which may be mechanical, electrical and/or chemical in nature. 
     As will be appreciated by one skilled in the art, there are numerous ways of constructing and using the patch-like infusion device  100  disclosed herein. Although reference will be made to the embodiments depicted in the drawings and the following descriptions, the embodiments disclosed herein are not meant to be exhaustive of the various alternative designs and embodiments that are encompassed by the disclosed invention. In each disclosed embodiment, the device is referred to as an infusion device, but the device may also inject substances at a much faster (bolus) rate than is commonly accomplished by typical infusion devices. For example, the contents can be delivered in a period as short as several seconds or as long as several days. 
     In an embodiment of the device shown in  FIGS. 1 through 12 , a push-button design of the patch-like infusion device  100  is shown wherein the activation and energizing of the device is accomplished in a single multi-function/step process.  FIG. 1  illustrates an assembled embodiment of the infusion device  100  in a pre-activated state.  FIGS. 2-6  illustrate partially exploded and cross-sectional views of the infusion device  100  in the pre-activated state,  FIG. 7  illustrates a partially exploded view of the infusion device  100  during installation of a safety mechanism,  FIGS. 8-10  illustrate exploded and cross-sectional views of the infusion device  100  subsequent to activation, and  FIGS. 11 and 12  illustrate exploded and cross-sectional views of the infusion device  100  subsequent to deployment of the safety mechanism. The infusion device  100  is configured to operate between the pre-activated state (shown, for example, in  FIGS. 1, 2, and 5 ), an activated or fired state (shown, for example, in  FIGS. 8-10 ), and a retracted or safe state (shown, for example, in  FIGS. 11 and 12 ). 
     As shown in  FIG. 1 , an embodiment of the patch-like infusion device  100  includes a bottom enclosure  104 , a safety mechanism  108 , a flexible needle cover  112 , a top enclosure  116 , a reservoir subassembly  120 , an end-of-dose indicator (EDI)  124 , and an activator button  128 , which includes a patient interface surface  132 . Additionally, as shown in  FIGS. 2-6 , the infusion device  100  also includes a rotor or activation ring  136 , a pressurization spring  140 , a dome-like metal plunger  144 , and a drive spring  148 . 
     The flexible needle cover  112  provides patient and device safety by protecting at least one needle  152  (described in greater detail below) and providing a sterile barrier. The needle cover  112 , protects the needle  152  during device manufacture, protects the patient prior to use, and provides a sterility barrier at any point prior to removal. According to one embodiment, the needle cover  112  is attached via a press fit with a needle manifold in which the at least one needle  152  is disposed. Additionally, according to one embodiment, a needle opening  156  (described in greater detail below) of the safety mechanism  108  is shaped to closely correspond to a perimeter of the needle cover  112 . 
     As shown, for example, in  FIGS. 2, 3, 5, 6, 8, 10, and 12 , the reservoir subassembly  120  includes a reservoir dome seal  164 , a valve  168 , at least one needle  152 , and at least one channel  172  (see, for example,  FIG. 8 ) disposed between the valve  168  and the needle  152  and creating a flow path therebetween, and a dome  176 . Additionally, the reservoir subassembly  120  includes the removable needle cover  112  to selectively cover the at least one needle  152 . According to one embodiment, the reservoir subassembly  120  also includes a reservoir arm seal  180 , covering the channel  172 . Preferably, the needle  152  includes a needle manifold and a plurality of microneedles  152 . 
     The reservoir dome seal (flexible film)  164  of the reservoir subassembly  120 , as shown, for example, in  FIG. 5 , is disposed between the plunger  144  and the dome  176 . Reservoir contents (for example, medicinal material) for the infusion device  100  are disposed in the space between the reservoir dome seal  164  and the dome  176 . The combination of the reservoir dome seal  164 , the dome  176 , and the space therebetween defines a reservoir  160 . The dome  176  is preferably transparent to permit viewing of the reservoir contents. The reservoir dome seal  164  can be made of non-distensible materials or laminates, such as metal-coated films or other similar substances. For example, one possible flexible laminate film that can be used in the reservoir dome seal  164  includes a first polyethylene layer, a second chemical layer as known to those skilled in the art to provide an attachment mechanism for a third metal layer which is chosen based upon barrier characteristics, and a fourth layer that includes polyester and/or nylon. By utilizing a metal-coated or metallized film in conjunction with a rigid portion (for example, dome  176 ), the barrier properties of the reservoir  160  are improved, thereby increasing or improving the shelf life of the contents contained within. For example, where a reservoir content includes insulin, the primary materials of contact in the reservoir  160  include linear, low-density polyethylene (LLDPE), low-density polyethylene (LDPE), cyclic olefin copolymer (COC) and Teflon. As described in greater detail below, the primary materials of contact in the remaining flow path of the reservoir contents may also include COC and LLDPE, as well as polyethylene (PE) thermoplastic elastomer (TPE), medical grade acrylic, and stainless steel, and a needle adhesive (e.g. a UV cured adhesive). Such materials that remain in extended contact with the contents of the reservoir  160  preferably pass ISO 10-993 and other applicable biocompatibility testing. 
     The reservoir subassembly  120  is further preferably able to be stored for the prescribed shelf life of the reservoir contents in applicable controlled environments without adverse effect to the contents, and is capable of applications in a variety of environmental conditions. Additionally, the barrier provided by the components of the reservoir subassembly  120  do not permit the transport of gas, liquid, and/or solid materials into or out of the contents at a rate greater than that allowable to meet the desired shelf life. In the embodiments shown above, the reservoir materials are capable of being stored and operated in a temperature range of approximately 34 to 120 degrees Fahrenheit and can have a shelf life of two or more years. 
     In addition to satisfying stability requirements, the reservoir subassembly  120  can further ensure operation by successfully passing any number of leak tests, such as holding a 30 psi sample for 20 minutes without leaking. Additional filling, storage and delivery benefits resulting from the configuration of the reservoir include minimized headspace and adaptability as described in greater detail below. 
     In one embodiment, the reservoir  160  is evacuated prior to filling. By evacuating the reservoir  160  prior to filling and having only a slight depression in the dome  176 , headspace and excess waste within the reservoir  160  can be minimized. In addition, as discussed in greater detail below, the shape of the reservoir can be configured to adapt to the type of energizing mechanism or pressurizing system (for example, pressurization spring  140  and plunger  144 ) used. Additionally, using an evacuated flexible reservoir  160  during filling can minimize any air or bubbles within the filled reservoir  160 . It will be understood, however, that some embodiments of the present invention may not employ an evacuated reservoir. The use of a flexible reservoir  160  is also very beneficial when the infusion device  100  is subjected to external pressure or temperature variations, which can lead to increased internal reservoir pressures. In such case, the flexible reservoir  160  expands and contracts with the reservoir contents, thereby preventing possible leaks due to expansion and contraction forces. 
     Yet another feature of the reservoir  160  includes the ability to permit automated particulate inspection at the time of filling or by a patient at the time of use. One or more reservoir barriers, such as the dome  176 , can be molded of a transparent, clear plastic material, which allows inspection of the substance contained within the reservoir. The transparent, clear plastic material is preferably a cyclic olefin copolymer that is characterized by high transparency and clarity, low extractables, and biocompatibility with the substance contained in the reservoir  160 . A suitable material is available from Zeon Chemicals, L.P., of Louisville, Ky. under the designation “BD CCP Resin,” and is listed by the U.S. Food and Drug Administration and DMF No. 16368. In such applications, the reservoir  160  includes minimal features that could possibly obstruct inspection (i.e. rotation during inspection is permitted). 
     Channel arm  172  is provided in the form of at least one flexible arcuate arm extending from the valve  168  to the needle manifold or microneedles  152 . The arcuate arm has a groove  174  (see, for example,  FIG. 2 ) formed therein. To provide a fluid path between valve  168  and the needle manifold or microneedles  152 , the reservoir arm seal  180  covers the groove  174 . The fluid path (disposed in channel arm  172 —shown, for example, in  FIG. 8 ) between the reservoir  160  and the microneedles  152  is constructed of materials similar or identical to those described above for the reservoir  160 . For example, channel arm  172  may be constructed of the same material as the dome  160  and the reservoir arm seal  180  may constructed of the same material as the reservoir dome seal  164 . According to one embodiment, both channel arms  172  are employed as fluid paths between the valve  168  and the needle manifold or microneedles  152 . According to another embodiment, only one of the channel arms  172  is employed as a fluid path, and the remaining channel arm  172  provides structural support. In such an embodiment, the groove  174  extends fully from the valve  168  to the needle manifold or microneedles  152  only in the channel arm  174  that will be employed as the fluid path. 
     The channel arm  172  must be sufficiently flexible to withstand the force of activation. Contrasting the position of the channel arm  172  in  FIGS. 2 and 8 , the channel arm  172  (covered by reservoir arm seal  180  in  FIG. 2 , which is removed in  FIG. 8  for clarity) elastically deforms when the microneedles  152  are driven into the patient&#39;s skin (described in greater detail below). During such deformation, the channel arm  172  must maintain the integrity of the fluid path between the valve  168  and the needle manifold or microneedles  152 . Additionally, the materials for the channel arm  172  satisfy numerous biocompatibility and storage tests. For example, as shown in Table 1 below, where an infusion device content includes insulin, the primary materials of contact in the reservoir  160  include linear, low-density polyethylene, cyclic olefin copolymer, and Teflon, and can also include a transparent, clear plastic. The primary materials of contact in the remaining flow path (channel  62 ) between the reservoir  160  and the microneedles  152  of the needle manifold include COC and/or, medical grade acrylic, LLDPE, TPE, and and/or stainless steel, as well as the needle adhesive. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Path Component 
                 Material 
               
               
                   
                   
               
             
            
               
                   
                 Reservoir 
                 Polyethylene, cyclic olefin copolymer, 
               
               
                   
                   
                 and/or Teflon 
               
               
                   
                 Reservoir Dome Seal 
                 Metal-coated film, such as 
               
               
                   
                   
                 polyethylene, aluminum, polyester, 
               
               
                   
                   
                 and/or nylon with a chemical tie layer 
               
               
                   
                 Valve 
                 TPE 
               
               
                   
                 Needle Manifold 
                 COC and/or medical grade acrylic 
               
               
                   
                 Needle adhesive 
                 UV-cured adhesive 
               
               
                   
                 Microneedle 
                 Stainless steel 
               
               
                   
                   
               
            
           
         
       
     
     More specifically, the microneedles  152  can be constructed of stainless steel, and the needle manifold can be constructed of polyethylene and/or medical grade acrylic. Such materials, when in extended contact with the contents of the reservoir, preferably pass ISO 10-993 biocompatibility testing. 
     The valve  168 , disposed between the reservoir  160  and the channel  172 , selectively permits and restricts fluid flow between the reservoir  160  and the channel  172 . The valve  168  moves between a pre-activated position (shown, for example, in  FIGS. 2, 3 , and  6 ) and an activated position (shown, for example, in  FIGS. 8-10 ). When in the activated position, the valve permits fluid flow between the reservoir  160  and the channel  172 , and therefore to the needle manifold and microneedles  152 . 
     In use, the valve  168  will eventually be pushed into the activated position by the movement of the activator button  128 , best illustrated by the movement of the valve  168  between  FIGS. 5 and 10 . As shown in  FIG. 10 , the movement of the valve  168  advances the enlarged distal end of the valve  168 , thereby permitting the drug to flow from the reservoir  160  into the channel  172  and down the fluid path to the needle manifold. 
     The embodiment described above includes at least one needle  152 , or microneedle  152 , but may contain several, such as the two illustrated microneedles  152 . Each microneedle  152  is preferably at least 31 gauge or smaller, such as 34 gauge, and is anchored within a patient needle manifold that can be placed in fluid communication with the reservoir  160 . The microneedles  152 , when more than one is included in the infusion device  100 , can also be of differing lengths, or gauges, or a combination of both differing lengths and gauges, and can contain one or more ports along a body length, preferably located near the tip of the microneedle  152  or near the tip bevel if any of the microneedles  152  has one. 
     According to one embodiment, the gauge of the microneedles  152  governs the delivery rate of reservoir contents of the infusion device  100 . The use of multiple 34 gauge microneedles  152  to deliver the reservoir contents is practical when the infusion occurs over a longer period than typically associated with an immediate syringe injection requiring a much larger cannula, or needle. In the disclosed embodiments, any microneedles  152  that target either an intradermal or subcutaneous space can be used, but the illustrated embodiments include intradermal microneedles  152  of between 1 and 7 mm in length (i.e., 4 mm). The arrangement of the microneedles  152  can be in a linear or nonlinear array, and can include any number of microneedles  152  as required by the specific application. 
     As noted above, the microneedles  152  are positioned in a needle manifold. In the needle manifold, at least one fluid communication path, or channel  172 , is provided to each microneedle  152 . The manifold may simply have a single path to one or more microneedles  152 , or may provide multiple fluid paths or channels routing the reservoir contents to each microneedle  152  separately. These paths or channels may further comprise a tortuous path for the contents to travel, thereby affecting fluid pressures and rates of delivery, and acting as a flow restrictor. The channels or paths within the needle manifold can range in width, depth and configuration depending upon application, where channel widths are typically between about 0.015 and 0.04 inch, preferably 0.02 inch, and are constructed to minimize dead space within the manifold. 
     According to one embodiment, the reservoir subassembly  120  has a pair of holes  184  and  188  to aid registration of the reservoir subassembly  120  with respect to the bottom enclosure  104 . First and second posts  192  and  196  (described in greater detail below) of the bottom enclosure  104  are inserted through the respective holes  184  and  188 . 
     In exploded views with the reservoir subassembly  120  removed,  FIGS. 4, 7, and 9  illustrate that bottom enclosure  104  includes a substantially cylindrical housing  200  in which pressurization spring  140  and plunger  144  are disposed. According to one embodiment, cylindrical housing  200  includes a plurality of recessed channels  204  to guide a respective plurality of legs  208  and feet  212  of the plunger  144  as the plunger translates within the housing  200 . Collectively, a leg  208  and a foot  212  constitute a plunger tab  214 . As shown in  FIGS. 4, 7 , and  9 , for example, the recessed channels  204  extend only part of the way down the cylindrical housing  200  from a top thereof. Below the recessed channels  204 , there are openings  216  through which the feet  212  of plunger  144  can extend outside of the cylindrical housing  200 . The openings  216  are substantially L-shaped with horizontal portions at the base of the cylindrical housing  200 , and a vertical portion substantially aligned with the recessed channels  204 . The plunger tab  214  and the housing  200 , including the channels  204 , illustrate an exemplary embodiment of a means for selectively maintaining the plunger in the pre-activated position with respect to the reservoir and, upon releasing the plunger from the pre-activated position, for guiding the plunger. 
     When the infusion device  100  is in the pre-activated state, the pressurization spring  140  is compressed by the plunger  144  (as shown, for example, in  FIGS. 4-6 ), and the feet  212  of the plunger  144  are substantially disposed in the horizontal portions of the openings  216 . The force of the pressurization spring  140  biases the feet  212  of the plunger  144  against a top of the horizontal portions of the openings  216  (i.e., a ledge of the cylindrical housing  200 ). Together, as described in greater detail below, the pressurization spring  140  and the plunger  144  form a pressurization system to pressurize the reservoir  160  when the infusion device  100  is activated. 
     As described in greater detail below, the rotor  136  rotates around the base of the cylindrical housing  200  between a pre-activated position (illustrated, for example, in  FIGS. 2-4 ) and an activated position (illustrated, for example, in  FIGS. 8-10 ). When the rotor  136  rotates from the pre-activated position to the activated position, at least one rotor foot engaging surface  217  (shown, for example, in  FIG. 4 ) of the rotor  136  engages at least one of the feet  212  of the plunger  144  and rotates the plunger  144  so that the feet  212  align with the vertical portions of the openings  216  and the recessed channels  204 . At this point, the pressurization spring  140  moves the plunger  144  upward with the feet  212  being guided by the raised channels  204 . 
     The pressurization spring  140  is included in the infusion device  100  to apply an essentially even force to the reservoir  160 , to force the contents from the reservoir  160 . The pressurization spring  140  is used to store energy that, when released, pressurizes the reservoir  160  at the time of use. The pressurization spring  140  is held in a compressed state by engagement between feet  212  of the plunger  144  and the cylindrical housing  200 . This engagement prevents the pressurization spring  140  from putting stress on a film (to be described later) of the reservoir  160  or any remaining device components (other than the bottom enclosure  104  and the plunger  144 ) during storage. The plunger  144  is sufficiently rigid to resist spring tension and deformation, and should not fail under normal load. 
     As noted above, when the rotor  136  rotates from the pre-activated position to the activated position, the rotor  136  engages at least one of the feet  212  of the plunger  144  and rotates the plunger  144  to align the feet  212  with the vertical portions of the openings  216  and the recessed channels  204 . The compressed pressurization spring  140 , then moves the plunger  144  upward, and in doing so, exerts a force on the film of the reservoir  160 . The pressurization spring  140  can be configured to preferably create a pressure within the reservoir  116  of from about 1 to 50 psi, and more preferably from about 2 to about 25 psi for intradermal delivery of the reservoir contents. For sub-cutaneous injection or infusion, a range of about 2 to 5 psi may be sufficient. 
     To load the plunger  144  and pressurization spring  140  into the pre-activated position, a tool  219  (see, for example,  FIGS. 23A and 23B ) having, for example, a square protrusion  220  protruding from an end thereof is inserted so that the protrusion  220  passes through a tool opening  222  (see, for example,  FIGS. 4 and 27 ) of the plunger  144 . The tool  219  is then used to compress the pressurization spring  140  through downward pressure on the plunger  144 . The tool  219  continues the downward motion of the plunger  144  and compression of the pressurization spring  140  until the foot  212  is vertically below a height of a foot engaging surface  218  of the cylindrical housing within the recessed channel  204 . Subsequently, the tool  219  rotates to rotate the plunger  144  so that the foot  212  is disposed beneath the foot engaging surface  218 . At this point, the tool  219  can be removed, thereby engaging the foot  212  with the foot engaging surface  218  of the cylindrical housing  200 , and maintaining compression of the pressurization spring  140 . 
     According to one embodiment, the activator button  128  includes the patient interface surface  132  that the patient presses to activate the infusion device  100 . The activator button  128  also includes a hinge arm  224  and an activation arm  228  (both shown, for example, in  FIG. 3 ). The hinge arm  224  of the activator button  128  includes a cylindrical portion with an opening. The activation arm  228  includes a tab  230  (see for example,  FIG. 3 ). According to one embodiment, the tab  230  includes a bearing surface  232  and a locking surface  234  disposed adjacent to the cantilevered end of the bearing surface  232 . According to one embodiment, the tab  230  forms an acute angle with a main portion of the activation arm  228 . 
     The first post  192 , disposed on the bottom enclosure  104 , extends upwardly therefrom. According to one embodiment (as shown, for example, in  FIGS. 4 and 7 ), a base of the first post  192  includes a pair of flat sides  236  and a pair of rounded sides  240 . Additionally, as shown, for example, in  FIGS. 4 and 7 , the second post  196  and first and second drive spring bases  244  and  248  extend upwardly from the bottom enclosure  104 . As will be described in greater detail below, the first and second drive spring bases  244  and  248  anchor respective ends of drive spring  148 . The first drive spring base  244  is disposed adjacent to the second post  196  with a space therebetween. 
     According to one embodiment,  FIGS. 3 and 6  illustrate the positioning of the activator button  128  with respect to the bottom enclosure  104 , for assembly of the activator button  128 . In this position, the opening of the cylindrical portion of the hinge arm  224  allows the activator button  128  to slide horizontally (passing the flat sides  236 ) and engage the first post  192 . The hinge arm  224  (and therefore the activator button  128 ) can then rotate about the first post  192 . As the activation arm  228  passes into the space between the second post  196  and the first drive spring base  244 , at least one of the tab  230  and the activation arm  228  elastically deforms until a cantilevered end of the bearing surface  232  of tab  230  passes a retaining face  252  of the second post  196 . The passage of the cantilevered end of the bearing surface  232  of tab  230  past the retaining face  252  (see, for example,  FIG. 4 ) of the second post  196  and the engagement of the locking surface  234  of tab  230  with the retaining face  252  provides an audible click and tactile feedback conveying that the activator button  128  is in the pre-activated position. 
     Referring back to  FIGS. 2-4, and 7-9 , rotor  136  additionally includes an activation projection  256  and a drive spring holder  260 . The activation arm  228  of the activator button  128  engages the activation projection  256  when a patient depresses the activator button  128 , thereby rotating the rotor  136  from the pre-activated position to the activated position. 
     The drive spring holder  260  maintains the drive spring  148  in a pre-activated position when the rotor  136  is in the pre-activated position. As noted previously, the first and second drive spring bases  244  and  248  anchor opposing ends of the drive spring  148 . At approximately a midpoint of the drive spring  148 , there is a substantially U-shaped projection as shown, for example, in  FIGS. 2 and 3 , for engagement with the drive spring holder  260  of the rotor  136 . Accordingly, when the rotor  136  is in the pre-activated position and the drive spring  148  engages the drive spring holder  260 , the drive spring  148  is maintained in a tensile state. And when the drive spring holder  260  releases the drive spring  148  (i.e., when the rotor rotates from the pre-activated position to the activated position as illustrated, for example, in  FIGS. 8-10 ), the drive spring  148  drives the microneedles  152  to extend outside of the infusion device  100  through an opening  300  in the bottom enclosure  104  (and through an opening in the safety mechanism  108  described in greater detail below). 
     Thus, as will be described in greater detail below, the activation and energizing of the infusion device  100  that is accomplished in a single multi-function/step process includes depression of the activator button  128  by a patient, and rotation of the rotor  136  due to engagement between the activation arm  228  of the activator button  128  and the activation projection  256  of the rotor  136 . As described above, the rotation of the rotor  136  rotates and releases the plunger  144  to pressurize the fluid within the reservoir  160 . Additionally, the rotation of the rotor  136  releases the drive spring  148  from the drive spring holder  260 , thereby driving the microneedles  152  to extend outside of the infusion device  100 . The single multi-function/step process also includes movement of the valve  168  from the pre-activated position to the activated position due to the activator button  128  engaging and moving the valve  168  when the activator button  128  is depressed, thereby commencing fluid flow between the reservoir and the microneedles  152  via the channel  172 . 
     As noted above, the patch-like infusion device  100  also includes a safety mechanism  108 . To prevent inadvertent or accidental needle stick injuries, prevent intentional re-use of the device, and to shield exposed needles, the locking needle safety mechanism  108  is provided. The safety mechanism  108  automatically activates immediately upon removal of the infusion device  100  from the skin surface of the patient. According to one embodiment described in greater detail below, a flexible adhesive pad  264  adheres to a bottom portion of the bottom enclosure  104  and a bottom portion of the safety mechanism  108 . The adhesive pad  264  contacts with the patient&#39;s skin and holds the infusion device  100  in position on the skin surface during use. As shown, for example, in  FIGS. 11 and 12 , upon removal of the infusion device  100  from the skin surface, the safety mechanism  108  extends to a position shielding the microneedles  152 . When fully extended, safety mechanism  108  locks into place and prevents accidental injury or exposure to the patient needles  152 . 
     In general, a passive safety system is most desirable. This allows the device to be self-protecting in case of accidental removal or if the patient forgets that there is a safety step. Because one typical use for this infusion device  100  is to provide human growth hormone, which is usually given in the evening, it can be expected that patients that wear the device (such as children) may actually wear them overnight, even though the delivery may be expected to take less than 10 minutes. Without a passive system, if the infusion device  100  falls off, the microneedles  152  could re-stick the patient or a caregiver. The solution is to either limit the activities during use, or include a passive safety system. 
     With respect to safety systems, there are typically three options. A first option is to retract the needles  152  into the device. A second option is to shield the needles  152  to remove access, and a third option is to destroy the needles  152  in a way that prevents needle stick injuries. Other systems, such as active systems, utilize manual shielding and/or destruction, or manual release of safety features with an additional button push or similar action. A detailed description of passive safety embodiments of the present invention is provided below. 
     One safety embodiment of the present invention is a passive, fully enclosed pull-out design embodiment, such as safety mechanism  108 .  FIGS. 5, 10, and 12  are perspective cutaway views of the infusion device  100  that illustrate the safety mechanism  108  prior to activation, subsequent to activation, and subsequent to deployment of the safety mechanism  108 , respectively. 
     When the infusion device  100  is removed from the skin, the flexible adhesive pad  264  (attached to both the bottom surface of the bottom enclosure  104  and the bottom surface of the safety mechanism  108 ) will pull the safety mechanism  108  out and lock it into place before the adhesive pad  264  releases the skin surface. In other words, the force required to remove the adhesive pad from the skin surface is greater than that required to deploy the safety mechanism  108 . According to one embodiment, the safety mechanism  108 , as shown, for example, in  FIG. 13 , includes a flat surface portion  268  that is in contact with the patient&#39;s skin. The flat surface  268  is where a portion of adhesive pad  264  (shown as a dotted line in  FIG. 13 ) is affixed to safety mechanism  108  such that when the infusion device  100  is removed by the patient from the skin, the adhesive pad  264  will act to deploy the safety mechanism  108  from the infusion device  100 , thereby shielding the microneedles  152 , which otherwise would be exposed upon removal of the infusion device  100  from the patient. When the safety mechanism  108  is fully extended, the safety mechanism  108  locks into place and prevents accidental injury or exposure to the microneedles  152 . 
     According to one embodiment, the adhesive pad  264  is provided in substantially two parts, one on the bulk of the bottom surface of the bottom enclosure  104 , and one on the bottom surface of the safety mechanism  108 . When the infusion device  100  is removed, the two patches move independently and the safety mechanism  108  is rotatable with respect to the bottom enclosure  104 . According to another embodiment, the two parts are formed as a unitary, flexible adhesive pad  264  with one part being disposed on the on the bulk of the bottom surface of the bottom enclosure  104 , and one part disposed on the bottom surface of the safety mechanism  108 . 
     According to one embodiment, the safety mechanism  108  is a stamped metal part. According to another embodiment, the safety mechanism  108  is made of substantially the same material as the bottom enclosure  104 . As shown in  FIG. 14 , the safety mechanism  108  includes a front shield  272 , a pair of insertion tabs  276  disposed at a rear portion of the safety mechanism  108 , a pair of pivot tabs  280  disposed, respectively, at upper rear ends of a rim portion  284  of the safety mechanism  108 , a guide post  288  extending upwardly from a substantially flat bottom inner surface of the safety mechanism  108 , and locking posts  292  also extending upwardly from the bottom inner surface of the safety mechanism  108 . Front shield  272  extends above the rim portion  284  to shield the patient from the microneedles  152  when the safety mechanism  108  is deployed. The guide post  288  includes a cutout therein to engage a safety retaining projection  296  of the rotor  136  (shown, for example, in  FIGS. 7 and 9 ) when the rotor  136  is in the pre-activated position, to prevent the safety mechanism  108  from deploying prior to activation of the infusion device  100 . 
     Additionally, as noted above, the safety mechanism  108  includes the needle opening  156 . Prior to deployment of the safety mechanism  108 , the needle opening  156  at least partially overlaps the opening  300  in bottom enclosure  104  to provide space for movement of the microneedles  152 . The locking posts  292  are respectively disposed adjacent to front side edges of the needle opening  156 . The bottom enclosure  104  includes a guidepost opening  304  (shown, for example, in  FIGS. 7 and 9 ), a pair of insertion tab openings  308  (one of which is shown, for example, in  FIG. 4 ) disposed adjacent to opposing side edges of the bottom enclosure  104 , and a pair of pivot rests  312  disposed on opposing sides of the bottom enclosure  104  (shown, for example, in  FIGS. 7 and 9 ). 
     Referring again to  FIG. 14 , insertion tabs  276  each include a connecting portion  316  and an extending portion  320 . According to one embodiment, the connecting portions  316  extend from the bottom inner surface of the safety mechanism  108  toward a rear of the infusion device  100  at a non-perpendicular angle with respect to the bottom inner surface of the safety mechanism  108 . Extending portions  320  each extend substantially perpendicularly from the extending portions  320  toward respective outer sides of the safety mechanism  108 . To assemble the safety mechanism  108  to the bottom enclosure  104 , safety mechanism  108  is held at an approximately 45° angle with respect to the bottom enclosure  104  and the insertion tabs  276  are inserted through the insertion tab openings  308 . The safety mechanism  108  is then rotated to a position such that the guidepost  288  is inserted through the guidepost opening  304  and the bottom inner surface of the safety mechanism  108  is substantially parallel and in contact with the bottom surface of the bottom enclosure  104 . 
     Referring again to  FIGS. 7 and 9 , although these views illustrate the rotor  136  in the activated position, the exploded nature of  FIGS. 7 and 9  is convenient to illustrate this stage of the assembly of the safety mechanism  108  to the bottom enclosure  104 . It will be understood, however, that the safety mechanism  108  should be assembled to the bottom enclosure prior to activation. Subsequent to the upward rotation of the safety mechanism  108 , as shown in  FIG. 4 , safety mechanism  108  translates rearwardly with respect to the bottom enclosure  104  such that pivot tabs  280  clear respective front edges of the pivot rests  312  and are disposed above the pivot rests  312 , the locking posts  292  are disposed adjacent to side edges of the opening  300  of the bottom enclosure  104 , and the safety retaining projection  296  of the rotor  136  engages the guide post  288 . 
     Returning to  FIG. 14 , each of the locking posts  292  includes a post extending portion  324  extending substantially perpendicular from the flat bottom inner surface of the safety mechanism  108 , and a wedge portion  328  disposed at an end of the post extending portion  324 . As a height of the wedge portion  328  increases with respect to the bottom inner surface of the safety mechanism  108 , a width of the wedge portion  328  increases. 
     As the safety mechanism  108  deploys and rotates downward with respect to the bottom enclosure  104 , the wedge portions  328  act against respective side edges of the openings  180  of the bottom enclosure  104 , causing the locking posts  192  to deform elastically toward one another. As the safety mechanism  108  is fully deployed, the tabs  280  become seated in pivot rests  312 . Additionally, top edges of the wedge portions  328  pass bottom edges of the opening  300  and the locking posts  292  snap back to their substantially un-deformed states, providing an audible click and tactile feedback communicating that the safety mechanism  108  is fully deployed, and therefore, that the microneedles  152  are covered. Returning to  FIGS. 11 and 12 , once the safety mechanism  108  is fully deployed and the locking posts  292  have snapped back to their substantially un-deformed states, the top edges of the wedge portions  328  engage the bottom surface of the bottom enclosure  104  adjacent to the opening  300 , thereby preventing the safety mechanism  108  from rotating upward with respect to the bottom enclosure  104  and exposing the microneedles  152 . Additionally, as noted above, front shield  272  shields the patient from the microneedles  152 . 
     Accordingly, the safety mechanism  108  is a passive safety embodiment provided as a single part and provides a good lock that will not crush under human loads. With this passive safety mechanism, no additional forces are applied to the skin during injection, and the microneedles  152  are safely held within the infusion device  100  after use. 
     After use of the infusion device  100 , the patient can once again inspect the device to ensure the entire dose was delivered. In this regard, as shown in  FIGS. 15A-D , the infusion device  100  includes the end-of-dose indicator (EDI)  124 . The EDI  124  includes a main body  332  and first and second arms  336  and  340  extending substantially horizontally with respect to a top of the main body  332 . 
     The EDI  124  also includes a spring arm  344  that curves upwardly from the top of the main body  332 . According to one embodiment, the spring arm  344  pushes against a bottom side of the reservoir subassembly  120 , elastically biasing the EDI  124  toward the bottom enclosure  104 , to ensure that the EDI  124  does not move freely out of the infusion device  100 , for example, during shipping and handling of the infusion device  100 . 
     Returning to  FIG. 4 , the main body  332  is disposed in an EDI channel  348  and translates substantially vertically therein. The EDI channel adjacent to one of the recessed channels  204  that guides legs  208  and feet  212  of plunger  144 . The first arm  336  extends across a top of this recessed channel  204 . 
     Returning to  FIG. 15A , a vertical extrusion  352  extends upwardly from an end of the second arm  340 . When the reservoir contents have been delivered, the vertical extrusion extends through an EDI opening  356  (see, for example,  FIG. 15C ) in the top enclosure  116  to communicate that the end of the dose has been reached. According to one embodiment, the EDI  124  is formed as a one-piece construction. 
     As shown in  FIG. 15B , as the plunger  144  travels upwardly in the cylindrical housing  200  due to the pressurization spring  140  subsequent to activation, one of the feet  212  of the plunger  144  contacts the first arm of the EDI  124 . The foot  212  lifts the EDI  124  upward, overcoming the bias of the spring arm  344 , and causing the vertical extrusion  352  to increasingly extend through the EDI opening  356  during delivery of the reservoir contents. Referring back to  FIG. 10 , vertical extrusion  352  partially extends from the infusion device  100 . Once the delivery of the reservoir contents is complete and the plunger has achieved its full stroke, the vertical extrusion  352  is fully extended, as shown in  FIG. 15D . Thus, the EDI  124  employs the linear movement of the plunger  144  to generate linear movement of the EDI  124  that is visible outside of the infusion device  100  thereby communicating the delivery of the reservoir contents. 
       FIG. 16  illustrates an embodiment of an infusion device  400  with an injection port  404 . The injection port provides access to an evacuated or partially-filled reservoir  408 , so that the patient can inject a substance or combination of substances into the reservoir prior to activation. Alternatively, a pharmaceutical manufacturer or pharmacist could employ the injection port  404  to fill the infusion device  400  with a substance or combination of substances prior to sale. In substantially all other respects, the infusion device  400  is similar to the previously-described infusion device  100 . 
     Operation of the infusion device  100  will now be described. The embodiments of the present invention described above preferably include a push-button (activator button  128 ) design wherein the infusion device  100  can be positioned and affixed to a skin surface, and energized and/or activated by pressing the activator button  128 . More specifically, in a first step, the patient removes the device from a sterile packaging (not shown), removes a cover (not shown) of the adhesive pad  264 . The patient also removes the needle cover  112 . Upon removal of the infusion device  100  from the package and prior to use (see, for example,  FIGS. 1, 2, 4, and 5 ), the infusion device  100  in the pre-activated state allows the patient to inspect both the device and the contents therein, including inspection for missing or damaged components, expiration dates(s), hazy or color-shifted drugs, and so forth. 
     The next step is the positioning and application of the infusion device  100  to the patient&#39;s skin surface. Like a medicinal patch, the patient firmly presses the infusion device  100  onto the skin. One side of the adhesive pad  264  adheres to a bottom surface of the bottom enclosure  104  and a bottom surface of the safety mechanism  108 , and the opposing side of the adhesive pad  264  secures the infusion device  100  to the skin of the patient. These bottom surfaces (of the bottom enclosure  104  and the safety mechanism  108 ) can be flat, contoured, or shaped in any suitable fashion and the adhesive pad  264  is secured thereon. According to one embodiment, prior to shipping, the cover of the adhesive pad  264 , such as a film, is applied to the patient-side of the adhesive pad  264  to preserve the adhesive during shipping. As noted above, prior to use, the patient peels back the adhesive cover, thereby exposing the adhesive pad  264  for placement against the skin. 
     After removing the adhesive cover, the patient is able to place the infusion device  100  against the skin and press to ensure proper adhesion. As noted above, once properly positioned, the device is activated by depressing the activator button  128 . This activation step releases plunger  144  and the pressurization spring  140 , allowing a plunger  144  to press against the flexible film (reservoir dome seal  164 ) of the reservoir  160 , thereby pressurizing the reservoir. This activation step also serves to release the drive spring  148  from the drive spring holder  260  of the rotor  136 , thereby driving the microneedles  152  to extend outside the infusion device  100  (through the opening  300  in the bottom enclosure  104  and the needle opening  156  of the safety mechanism  108 ) and seat the microneedles  152  within the patient. Further, the activation step opens the valve  168 , establishing a fluid communication path between the reservoir  160  and the microneedles  152 , via the channel  172  (see, for example,  FIGS. 8-10 ). A significant benefit derives from the ability to achieve each of these actions in a single push-button operation. Additionally, another significant benefit includes the use of a continuous fluid communication path comprised entirely within the reservoir subassembly  120 . 
     Once activated, the patient typically leaves the infusion device  100  in position, or wears the device, for some period of time (such as ten minutes to seventy-two hours) for complete delivery of the reservoir contents. The patient then removes and discards the device with no damage to the underlying skin or tissue. Upon intentional or accidental removal, one or more safety features deploy to shield the exposed microneedles  152 . More specifically, when the infusion device  100  is removed by the patient from the skin, the adhesive pad  264  acts to deploy the safety mechanism  108  from the infusion device  100 , thereby shielding the microneedles  152 , which otherwise would be exposed upon removal of the infusion device  100  from the patient. When the safety mechanism  108  is fully extended, the safety mechanism  108  locks into place and prevents accidental injury or exposure to the microneedles  152 . The safety features, however, can be configured to not deploy if the activator button  128  has not been depressed and the microneedles  152  have not been extended, thereby preventing pre-use safety mechanism deployment. After use, the patient can once again inspect the device to ensure the entire dose was delivered. For example, the patient can view the reservoir interior through the transparent dome  176  and/or inspect the EDI  124 . 
     In the above-described embodiments, in which metal plunger tabs  214  bear upwardly against foot engaging surfaces  218  of plastic cylindrical housing  200  to maintain compression of pressurizing spring  140  in the pre-activated position, high stresses may be imparted to the plastic bottom enclosure  104  and creep may be induced therein. 
       FIG. 17  illustrates an exploded view of an embodiment of a retention assembly  500  to reduce a force required to activate an infusion device (for example,  100 ). Though, the retention assembly  500  is illustrated with respect to the infusion device  100 , it will be understood that the retention assembly  500  is not limited to employment with the infusion device  100 , and may be employed with infusion device  400  or another infusion or self-injection device. As shown in  FIG. 17 , the retention assembly  500  includes a retention plate  504 , pressurization spring  140 , and a plunger  508 . The pressurization spring  140  is disposed on the retention plate  504  between the retention plate  504  and the plunger  508 . Retention plate  504  is disposed within the cylindrical housing  200 , in a recess of the top surface of the bottom enclosure  104 . According to one embodiment, the retention plate  504  is disposed substantially at the center of the cylindrical enclosure  200 . According to one embodiment, the retention plate  504  includes stabilization tabs  512  to prevent rotation of the retention plate  504  within the cylindrical housing  200 . The stabilization tabs  512  engage corresponding recesses in the top surface of the bottom enclosure  104 . The retention plate  504  and the plunger  508  illustrate an exemplary embodiment of a means for selectively maintaining the plunger in the pre-activated position with respect to the reservoir and, upon releasing the plunger from the pre-activated position, for guiding the plunger. 
     As shown in  FIG. 17 , retention plate  504  includes a post  516  and a sprocket  520  disposed at a distal end of the post  516 . According to one embodiment, the post  516  is disposed substantially at the center of the retention plate  504 . According to one embodiment, the post  516  and the sprocket  520  are integrally formed as a unitary metal structure. Additionally, according to one embodiment, the post  516  is attached to the retention plate  504  by spot welding. According to another embodiment, the post  516  is screwed to the retention plate  504 . According to yet another embodiment, the post  516  is attached to the retention plate  504  by a friction fit. According to yet another embodiment, the post  516  has a flange and a threaded end, and the threaded end is inserted through an opening in the retention plate  504  and attached to the retention plate  504  with a nut, tightened until the flange is secured against the retention plate  504 . According to an alternative embodiment, the post  516  and the retention plate  504  are integrally formed as a unitary metal structure. 
     According to one embodiment, the retention plate  504  is made of steel, such as, for example, plated steel or  302  stainless steel. Such a choice of materials generally provides superior creep characteristics and a higher modulus of rigidity with respect to a plastic (for example, that used for the cylindrical housing  200  of the bottom enclosure  104 ). Additionally, such a choice of materials provides the ability to employ a stronger pressurization spring  140 . For example, according to one embodiment, a 50 pound pressurization spring  140  can be employed in the retention assembly  500 . 
     Plunger  508  includes a sprocket opening  524  with a shape corresponding to the sprocket  520 . As described in greater detail below, plunger  508  also includes at least one tool opening  528  for assembling the retention assembly  500  into a pre-activated position. Put another way, the plunger  508  has the sprocket opening  524  punched substantially in the center thereof, and the post  516  has a sprocket  520  with a corresponding toothed profile disposed at the distal end thereof. 
     As shown in greater detail in  FIGS. 18A and 18B , sprocket  520  includes a plurality of sprocket teeth  532 , and the sprocket opening  524  includes a plurality of slots  536  interposed between a plurality of fingers  540  of the plunger  508 . According to one embodiment, the plurality of slots  536  and the plurality of fingers  540  correspond, respectively, to the plurality of sprocket teeth  532 . 
     When the retention assembly  500  is in the pre-activated position, as shown in  FIG. 19 , the sprocket teeth  532  align with and engage the fingers  540  of the plunger  508  to maintain compression of the pressurization spring  140 . Additionally, in contrast to the above-described embodiments, when the retention assembly  500  is in the pre-activated position, the plunger tabs do not bear on the foot engaging surface  218  of the cylindrical housing  200 . Instead, the force of maintaining the pressurization spring  140  in the compressed, pre-activated position is borne by the engagement between the sprocket teeth  532  and the fingers  540  of the plunger  508 . In such an embodiment, however, the foot engaging surface  218  of the cylindrical housing  200  may still perform a useful function by preventing excessive rocking of the plunger  508 . 
     Upon activation of the infusion device  100 , plunger  508  is rotated (for example, by the rotor  136 , which is rotated around the cylindrical housing  200  by the movement of the activator button  128 , as described above) such that the sprocket teeth  532  align with the slots  536  of the sprocket opening  524  (and the plunger tabs align with the recessed channels  204  of the cylindrical housing  200 ), to release the plunger  508  to translate upwardly within the cylindrical housing  200  under the force of the pressurization spring  140 , to pressurize the reservoir  160 . 
     To assemble the retention assembly  500  into the pre-activated position, a tool  544  (see, for example,  FIG. 24 ) having, for example, a pair of protrusions  548  protruding from an end thereof is inserted so that the protrusions  548  pass through tool openings  528  (see, for example,  FIG. 17 ) of the plunger  508 . The tool  544  is then used to compress the pressurization spring  140  through downward pressure on the plunger  508 . The tool  544  continues the downward motion of the plunger  508  and compression of the pressurization spring  140  until the sprocket  520  passes through the sprocket opening  524 . For the sprocket  520  to pass through the sprocket opening  524 , the sprocket teeth  532 , must be aligned with the slots  536  of the sprocket opening  524 . If the slots  536  of the sprocket opening  524  align with the sprocket teeth  532 , the tool  544  may be rotated to rotate the plunger  508  into the desired alignment. Subsequent to the sprocket  520  passing through the sprocket opening  524 , the tool  544  rotates so that the tool protrusions  548  engage the sides of the tool openings  528  to rotate the plunger  508 , so that the sprocket teeth  532  align with fingers  540  of the plunger  508 . At this point, the tool  544  can be removed, thereby engaging the sprocket teeth  532  with the fingers  540  of the plunger  508 , and maintaining compression of the pressurization spring  140 . The sprocket  520  and the sprocket opening  524  of the plunger  508 , in either order, illustrate exemplary embodiments of first and second guide means. 
       FIG. 20A  illustrates a free body diagram of an embodiment of a retention assembly employing plunger  144 .  FIG. 20B  illustrates free body diagram of the retention assembly  500 . In  FIG. 20A , μ T  represents the coefficient of friction between the plunger tab  214  in the foot engaging surface  218  of the cylindrical housing  200 , and μ T F T  represents the frictional force induced by engagement between the plunger tab  214  and the foot engaging surface  218  of the cylindrical housing  200  due to pressurization spring  140  pressing upward. Additionally, with respect to the rotation of the plunger  144  at activation of the infusion device  100 , the force μ T F T  acts over the distance (radius) L T  resulting in the frictional moment μ T F T L T . 
     In contrast, as shown in  FIG. 20B , μ K F K  represents the frictional force induced by engagement between the sprocket teeth  532  and the fingers  540  of the plunger  508  due to pressurization spring  140  pressing upward. Because the same pressurization spring  140  is employed in both embodiments, the force μ T F T  is substantially equal to the force μ K F K . But the distance (radius) L K  over which μ K F K  acts (resulting in the frictional moment μ K F K L K ) is substantially smaller than the distance L T . Thus, the frictional moment μ K F K L K  is substantially smaller than the frictional moment μ T F T L T . Accordingly, the force from the activator button  128  required to overcome the frictional moment μ K F K L K  (by employing retention assembly  500 ) is substantially smaller than the force from the activator button  128  required to overcome the frictional moment μ T F T L T  (in the embodiments employing plunger  144  described above). In other words, the frictional moment due to holding the pressurization spring  140  in the pre-activated position is substantially reduced due to the reduction in the moment where the load is applied. Therefore, in comparison to an infusion device employing plunger  144 , an embodiment employing retention assembly  500  requires a reduced force applied by the patient to activate the infusion device  100 . 
     Is to be noted, however, that in an embodiment employing retention assembly  500 , pressurization spring  140  bears against steel retention plate  504 , whereas in an embodiment employing plunger  144 , as described above, pressurization spring  140  bears against the plastic bottom enclosure  104 . But while the coefficient of friction of steel on steel is somewhat higher than the coefficient of friction of steel and plastic, the reduced distance (L K  v. L T ) more than makes up for the higher coefficient of friction. For example, in experiments with embodiments employing plunger  144 , an average of more than 4 lb f  was required to activate infusion device. In contrast, in experiments with embodiments employing retention assembly  500 , an average of about 1.5 lb f  was required to activate the infusion device. 
     Because the sprocket  520  sits above a top surface of the plunger  508  in the pre-activated position (as shown, for example, in  FIG. 19 ), one option to reduce a total height of the infusion device  100  is to create a pocket within the plunger, such that in the pre-activated position, the sprocket  520  would be flush with a top of the plunger  508 . Such an embodiment, however, may increase a dead or unusable volume of the reservoir  160 . Upon activation of an embodiment without such a pocket, however, the plunger  508  travels a greater distance within the cylindrical housing  200  prior to impacting the reservoir dome seal  164 . Thus, there is a larger kinetic energy prior to such impact. This impact between the plunger  508  and the reservoir dome seal may result in a loud sound. One way to reduce this kinetic energy would be to inject a very viscous damping gel in the area where the sprocket teeth  532  and the fingers  540  of the plunger  508  engage. 
     Another way to address such issues is to employ an alternative embodiment of a retention assembly  560  as illustrated in  FIGS. 21 and 22 .  FIG. 21  illustrates a plunger  564  with a post  568  disposed thereon. A sprocket  572  is disposed at a distal end of the post  568  and the sprocket includes a plurality of sprocket teeth  576 . According to one embodiment, the post  568  is disposed substantially at the center of the plunger  564 . Thus, the post  568  extends from the plunger  564  in an umbrella-like fashion with the sprocket  572  pointing away from the reservoir dome seal  164  to prevent inadvertent contact therebetween. 
     Additionally, according to one embodiment, the post  568  has a reduced diameter portion  578  to facilitate engagement with a retention plate  580  (described in greater detail below). Further, according to one embodiment, the post  568  and the sprocket  572  are integrally formed as a unitary metal structure. Additionally, according to one embodiment, the post  568  is attached to the plunger  564  by spot welding. According to another embodiment, the post  568  is screwed to the plunger  564 . According to yet another embodiment, the post  568  is attached to the plunger  564  by a friction fit. According to yet another embodiment, the post  586  has a flange and a threaded end, and the threaded end is inserted through an opening in the plunger  564  and attached to the plunger  564  with a nut, tightened until the flange is secured against the plunger  564 . According to an alternative embodiment, the post  568  and the plunger  564  are integrally formed as a unitary metal structure. Further, as described in greater detail below, plunger  564  also includes at least one tool opening  580  for assembling the retention assembly  560  into a pre-activated position. 
     Correspondingly, as shown in  FIG. 22  in the cross-sectional view of the retention assembly  560  in a pre-activated position, a retention plate  582  includes a sprocket opening  584  with a shape corresponding to the sprocket  572 . Put another way, the retention plate  582  has the sprocket opening  584  punched substantially in the center thereof, and the post  568  has a sprocket  572  with a corresponding toothed profile disposed at the distal end thereof. According to one embodiment, similar to the retention plate  504  described above, retention plate  582  is stationary with respect to bottom enclosure  104 , and is indexed with respect thereto. Thus, the retention plate  582  does not rotate when the plunger  564  rotates upon activation. The sprocket  572  and the sprocket opening  584  of the retention plate  582 , in either order, illustrate exemplary embodiments of first and second guide means. 
     Similar to  FIG. 18B , sprocket the sprocket opening  584  includes a plurality of slots  588  interposed between a plurality of fingers  592  of the retention plate  582 . According to one embodiment, each of the plurality of slots  588  and the plurality of fingers  592  correspond, respectively, to the plurality of sprocket teeth  576 . 
     When the retention assembly  560  is in the pre-activated position, as shown in  FIG. 22 , the sprocket teeth  576  align with and engage the fingers  592  of the retention plate  582  to maintain compression of the pressurization spring  140 . Additionally, as with the retention assembly  500 , when the retention assembly  560  is in the pre-activated position, the plunger tabs of plunger  564  do not bear on the foot engaging surface  218  of the cylindrical housing  200 . Instead, the force of maintaining the pressurization spring  140  in the compressed, pre-activated position is borne by the engagement between the sprocket teeth  576  and the fingers  592  of the retention plate  582 . In such an embodiment, however, the foot engaging surface  218  of the cylindrical housing  200  may still prevent excessive rocking of the plunger  564 . 
     Upon activation of the infusion device  100 , plunger  564  is rotated (for example, by the rotor  136 , which is rotated around the cylindrical housing  200  by the movement of the activator button  128 , as described above) such that the sprocket teeth  576  align with the slots  588  of the sprocket opening  584  (and the plunger tabs align with the recessed channels  204  of the cylindrical housing  200 ), to release the plunger  564  to translate within the cylindrical housing  200  under the force of the pressurization spring  140 , to pressurize the reservoir  160 . 
     To assemble the retention assembly  560  into the pre-activated position, a tool (not shown) having, for example, a pair of protrusions protruding from an end thereof is inserted so that the protrusions pass through the tool openings  580  (see, for example,  FIG. 21 ) of the plunger  564 . The tool is then used to compress the pressurization spring  140  through downward pressure on the plunger  564 . The tool continues the downward motion of the plunger  564  and compression of the pressurization spring  140  until the sprocket  572  passes through the sprocket opening  584 . Of course, for the sprocket  572  to pass through the sprocket opening  584 , the sprocket teeth  576 , must be aligned with the slots  588  of the sprocket opening  584 . Subsequent to the sprocket  572  passing through the sprocket opening  584 , the tool rotates so that the tool protrusions engage the sides of the tool openings  580  to rotate the plunger  564 , so that the sprocket teeth  576  align with fingers  592  of the retention plate  582 . At this point, the tool can be removed, thereby engaging the sprocket teeth  576  with the fingers  592  of the retention plate  582 , and maintaining compression of the pressurization spring  140 . During compression of the pressurization spring  140 , if the slots  588  of the sprocket opening  584  align with the sprocket teeth  576 , the tool may be rotated to rotate the plunger  564  into the desired alignment. 
     The described embodiment of the retention assembly  560  eliminates an opening in the plunger, and therefore reduces or eliminates the problem of dead volume of the reservoir  160 . And the sprocket  572  is retained by the bottom of the retention plate  582  and resides within the thickness of the bottom enclosure in a pre-activated state, thus, the height of the sprocket  572  does not increase the overall height of the infusion device  100 . 
     According to another embodiment, rather than being stationary, the retention plate  582  is rotatably disposed with respect to the bottom enclosure  104  and the plunger  564  does not rotate upon activation. In other words, in this embodiment, at least with respect to the retention assembly  560 , the retention plate replaces the rotor  136 . Put another way, in this embodiment, the retention plate  582  has an engagement tab that is engaged by the activator button  128  when the activator button  128  is depressed, thereby rotating the retention plate  582  with respect to the bottom enclosure  104 . This rotation aligns the slots  588  with the sprocket teeth  576 , thereby releasing the plunger  564  to translate within the cylindrical enclosure  200  due to the force of the pressurization spring  140 . 
     The described embodiments are suitable for use in administering various substances, including medications and pharmaceutical agents, to a patient, and particularly to a human patient. As used herein, a pharmaceutical agent includes a substance having biological activity that can be delivered through the body membranes and surfaces, and particularly the skin. Examples, listed in greater detail below, include antibiotics, antiviral agents, analgesics, anesthetics, anorexics, antiarthritics, antidepressants, antihistamines, anti-inflammatory agents, antineoplastic agents, vaccines, including DNA vaccines, and the like. Other substances that can be delivered intradermally or subcutaneously to a patient include human growth hormone, insulin, proteins, peptides and fragments thereof. The proteins and peptides can be naturally occurring, synthesized or recombinantly produced. Additionally, the device can be used in cell therapy, as during intradermal infusion of dendritic cells. Still other substances which can be delivered in accordance with the method of the present invention can be selected from the group consisting of drugs, vaccines and the like used in the prevention, diagnosis, alleviation, treatment, or cure of disease, with the drugs including Alpha-1 anti-trypsin, Anti-Angiogenesis agents, Antisense, butorphanol, Calcitonin and analogs, Ceredase, COX-II inhibitors, dermatological agents, dihydroergotamine, Dopamine agonists and antagonists, Enkephalins and other opioid peptides, Epidermal growth factors, Erythropoietin and analogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs (including growth hormone releasing hormone), Growth hormone antagonists, Hirudin and Hirudin analogs such as hirulog, IgE suppressors, Insulin, insulinotropin and analogs, Insulin-like growth factors, Interferons, Interleukins, Leutenizing hormone, Leutenizing hormone releasing hormone and analogs, Low molecular weight heparin, M-CSF, metoclopramide, Midazolam, Monoclonal antibodies, Narcotic analgesics, nicotine, Non-steroid anti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroid hormone and analogs, Parathyroid hormone antagonists, Prostaglandin antagonists, Prostaglandins, Recombinant soluble receptors, scopolamine, Serotonin agonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen activators, TNF-, and TNF-antagonist, the vaccines, with or without carriers/adjuvants, including prophylactics and therapeutic antigens (including but not limited to subunit protein, peptide and polysaccharide, polysaccharide conjugates, toxoids, genetic based vaccines, live attenuated, reassortant, inactivated, whole cells, viral and bacterial vectors) in connection with, addiction, arthritis, cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps, rubella, varicella, yellow fever, Respiratory syncytial virus, tick borne japanese encephalitis, pneumococcus, streptococcus, typhoid, influenza, hepatitis, including hepatitis A, B, C and E, otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia, non-typeable haemophilus, moraxella catarrhalis, human papilloma virus, tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosis malaria,  E - coli , Alzheimers,  H. Pylori, salmonella , diabetes, cancer, herpes simplex, human papilloma and the like other substances including all of the major therapeutics such as agents for the common cold, Anti-addiction, anti-allergy, anti-emetics, anti-obesity, antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants, antidiabetic agents, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, anticholinergics, benzodiazepine antagonists, vasodilators, including general, coronary, peripheral and cerebral, bone stimulating agents, central nervous system stimulants, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetrics, prostaglandins, proteins, peptides, polypeptides and other macromolecules, psychostimulants, sedatives, sexual hypofunction and tranquilizers and major diagnostics such as tuberculin and other hypersensitivity agents as described in U.S. Pat. No. 6,569,143, entitled “Method of Intradermally Injecting Substances,” the entire content of which is expressly incorporated herein by reference. 
     Vaccine formulations which can be delivered in accordance with the system and method of the present invention can be selected from the group consisting of an antigen or antigenic composition capable of eliciting an immune response against a human pathogen, which antigen or antigenic composition is derived from HIV-1, (such as tat, nef, gp120 or gp160), human herpes viruses (HSV), such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV1 or HSV2, cytomegalovirus (CMV (esp Human) (such as gB or derivatives thereof), Rotavirus (including live-attenuated viruses), Epstein Barr virus (such as gp350 or derivatives thereof), Varicella Zoster Virus (VZV, such as gp1, II and IE63) or from a hepatitis virus such as hepatitis B virus (for example Hepatitis B Surface antigen or a derivative thereof), hepatitis A virus (HAV), hepatitis C virus and hepatitis E virus, or from other viral pathogens, such as paramyxoviruses: Respiratory Syncytial virus (RSV, such as F and G proteins or derivatives thereof), parainfluenza virus, measles virus, mumps virus, human papilloma viruses (HPV for example HPV6, 11, 16, 18), flaviviruses (e.g. Yellow Fever Virus, Dengue Virus, Tick-borne encephalitis virus, Japanese Encephalitis Virus) or Influenza virus (whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or whole flu virosomes or purified or recombinant proteins thereof, such as HA, NP, NA, or M proteins, or combinations thereof), or derived from bacterial pathogens such as  Neisseria  spp, including  N. gonorrhea  and  N. meningitidis  (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins);  S. pyogenes  (for example M proteins or fragments thereof, C5A protease, lipoteichoic acids),  S. agalactiae, S. mutans; H. ducreyi; Moraxella  spp, including  M catarrhalis , also known as  Branhamella catarrhalis  (for example high and low molecular weight adhesins and invasins);  Bordetella  spp, including  B. pertussis  (for example pertactin, pertussis toxin or derivatives thereof, filamenteous hemagglutinin, adenylate cyclase, fimbriae),  B. parapertussis  and  B. bronchiseptica; Mycobacterium  spp., including  M. tuberculosis  (for example ESAT6, Antigen 85A, -B or -C),  M. bovis, M. leprae, M. avium, M. paratuberculosis M. smegmatis; Legionella  spp, including  L. pneumophila; Escherichia  spp, including enterotoxic  E. coli  (for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorragic  E. coli , enteropathogenic  E. coli  (for example shiga toxin-like toxin or derivatives thereof);  Vibrio  spp, including  V. cholera  (for example cholera toxin or derivatives thereof);  Shigella  spp, including  S. sonnei, S. dysenteriae, S. flexnerii; Yersinia  spp, including  Y. enterocolitica  (for example a Yop protein),  Y. pestis, Y. pseudotuberculosis; Campylobacter  spp, including  C. jejuni  (for example toxins, adhesins and invasins) and  C. coli; Salmonella  spp, including  S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria  spp., including  L. monocytogenes; Helicobacter  spp, including  H. pylori  (for example urease, catalase, vacuolating toxin);  Pseudomonas  spp, including  P. aeruginosa; Staphylococcus  spp., including  S. aureus, S. Epidermidis; Enterococcus  spp., including  E. faecalis, E. faecium; Clostridium  spp., including  C. tetani  (for example tetanus toxin and derivative thereof),  C. botulinum  (for example  Botulinum  toxin and derivative thereof),  C. difficile  (for example clostridium toxins A or B and derivatives thereof);  Bacillus  spp., including  B. anthracis  (for example  botulinum  toxin and derivatives thereof);  Corynebacterium  spp., including  C. diphtheriae  (for example diphtheria toxin and derivatives thereof);  Borrelia  spp., including  B. Burgdorferi  (for example OspA, OspC, DbpA, DbpB),  B. garinii  (for example OspA, OspC, DbpA, DbpB),  B. afzelii  (for example OspA, OspC, DbpA, DbpB),  B. andersonii  (for example OspA, OspC, DbpA, DbpB),  B. Hermsii; Ehrlichia  spp., including  E. equi  and the agent of the Human Granulocytic Ehrlichiosis;  Rickettsia  spp, including  R. rickettsii; Chlamydia  spp., including  C. Trachomatis  (for example MOMP, heparin-binding proteins),  C. pneumoniae  (for example MOMP, heparin-binding proteins),  C. psittaci; Leptospira  spp., including  L. interrogans; Treponema  spp., including  T. pallidum  (for example the rare outer membrane proteins),  T. denticola, T. hyodysenteriae ; or derived from parasites such as  Plasmodium  spp., including  P. Falciparum; Toxoplasma  spp., including  T. gondii  (for example SAG2, SAG3, Tg34);  Entamoeba  spp., including  E. histolytica; Babesia  spp., including  B. microti; Trypanosoma  spp., including  T. cruzi; Giardia  spp., including  G. lamblia; Leshmania  spp., including  L. major; Pneumocystis  spp., including  P. Carinii; Trichomonas  spp., including  T. vaginalis; Schisostoma  spp., including  S. mansoni , or derived from yeast such as  Candida  spp., including  C. albicans; Cryptococcus  spp., including  C. neoformans , as described in PCT Patent Publication No. WO 02/083214, entitled “Vaccine Delivery System”, the entire content of which is expressly incorporated herein by reference. 
     These also include other preferred specific antigens for  M. tuberculosis , for example Tb Ra12, Tb H9, Tb Ra35, Tb38-1, Erd 14, DPV, MTI, MSL, mTTC2 and hTCC1. Proteins for  M. tuberculosis  also include fusion proteins and variants thereof where at least two, preferably three polypeptides of  M. tuberculosis  are fused into a larger protein. Preferred fusions include Ra12-TbH9-Ra35, Erd14-DPV-MTI, DPV-MTI-MSL, Erd14-DPV-MTI-MSL-mTCC2, Erd14-DPV-MTI-MSL, DPV-MTI-MSL-mTCC2, TbH9-DPV-MTI. Most preferred antigens for  Chlamydia  include for example the High Molecular Weight Protein (HWMP), ORF3, and putative membrane proteins (Pmps). Preferred bacterial vaccines comprise antigens derived from  Streptococcus  spp, including  S. pneumoniae  (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, streptolysin, choline-binding proteins) and the protein antigen  Pneumolysin  (Biochem Biophys Acta, 1989, 67, 1007; Rubins et al., Microbial Pathogenesis, 25, 337-342), and mutant detoxified derivatives thereof. Other preferred bacterial vaccines comprise antigens derived from  Haemophilus  spp., including  H. influenzae  type B (“Hib”, for example PRP and conjugates thereof), non typeable  H. influenzae , for example OMP26, high molecular weight adhesins, P5, P6, protein D and lipoprotein D, and fimbrin and fimbrin derived peptides or multiple copy variants or fusion proteins thereof. Derivatives of Hepatitis B Surface antigen are well known in the art and include, inter alia, PreS1, PreS2 S antigens. In one preferred aspect the vaccine formulation of the invention comprises the HIV-1 antigen, gp120, especially when expressed in CHO cells. In a further embodiment, the vaccine formulation of the invention comprises gD2t as hereinabove defined. 
     In addition to the delivery of substances listed above, the infusion device  100  can also be used for withdrawing a substance from a patient, or monitoring a level of a substance in the patient. Examples of substances that can be monitored or withdrawn include blood, interstitial fluid or plasma. The withdrawn substances can then be analyzed for analytes, glucose, drugs, and the like. 
     Although only a few exemplary embodiments of the present invention have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of the appended claims and equivalents thereof.