Patent Publication Number: US-2020289248-A1

Title: Substance delivery device

Description:
CROSS-REFERENCE TO OTHER APPLICATIONS 
     This application claims priority from U.S. Provisional Patent Application 61/682,317, filed Aug. 13, 2012, PCT Patent Application PCT/US2013/054633, filed Aug. 13, 2013, U.S. patent application Ser. No. 14/419,245, filed Feb. 3, 2015, and from U.S. patent application Ser. No. 16/404,895, filed May 7, 2019, which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to delivery devices for substances, such as but not limited to, drugs and pharmaceuticals. 
     BACKGROUND OF THE INVENTION 
     There are many kinds of drug delivery devices. Some well-known devices include infusion pumps and transdermal delivery devices. Ultrasound has been used to rupture microcapsules for effecting drug release therefrom. Biodegradable hydrogels and temperature sensitive hydrophilic polymer gels or hydrogels have been used as carriers for biologically active materials such as hormones, enzymes, and antibiotics. 
     SUMMARY OF THE INVENTION 
     The present invention seeks to provide improved delivery devices for substances, such as but not limited to, drugs, pharmaceuticals, scents and deodorizers, as described more in detail herein below. The terms “substance” and “drugs” are used interchangeably throughout and it is noted that these terms encompass more than just a drug, pharmaceutical, scent or deodorizer, but also any chemical used to effect a desired result. The delivery devices of the invention may be of any size and shape, such as but not limited to, in the range of millimeters up to centimeters. The delivery devices of the invention may be drug delivery pumps, such as but not limited to, insulin delivery pumps. 
     In accordance with a non-limiting embodiment of the present invention, the delivery device is flexible, bendable and encapsulated with a conformal coating that protects it from possible environmental or other kinds of damage, and also protects the user from adverse effects from internal components of the device. “Bendable” and “flexible” means capable of being bent or flexed by normal human movement, such as being bent or flexed by fingers or other body parts. The flexible device conforms to the patient&#39;s body and is pleasant to the touch. A membrane assembly, described below, is used to dispense the substance. A soft, pliant bag or any other suitable container or reservoir contains the substance to be delivered, such as but not limited to, insulin or flea control substances and many more. In the case of a pliant reservoir (e.g., bag), the reservoir collapses to a flat state upon emptying the substance from it. The device can be used to deliver multiple substances, at the same time or at time intervals, using dependent or independent dosing protocols that control quantities and timing. 
     It is noted that throughout the specification and claims, the term “membrane” encompasses any suitable partition that responds to a force or pressure applied on one side of the membrane to transfer a force or pressure to the other side of the membrane, such as but not limited to, a membrane, partition, bellows, diaphragm, Belleville washer, tube and the like. The membrane is preferably resilient or flexible, but in certain applications the membrane can be rigid or semi-rigid. 
     In accordance with a non-limiting embodiment of the present invention, the delivery device has an actuating chamber with an actuating substance, sealed by a chamber membrane. A dosing chamber contains the substance to be delivered, sealed by a substance-delivery membrane. A separation element is located between the chamber membrane and the substance-delivery membrane. Upon expansion of the actuating substance, the chamber membrane pushes the separation element against the substance-delivery membrane to deliver the substance. The separation element is sealed tight against the chamber membrane so as to prevent liquid or vapor from leaking past the chamber membrane to the substance. This prevents any possible leaking due permeability of the membrane material. The separation element thus provides not only physical insulation (separation), but also thermal insulation, so the substance to be delivered is not affected by heating or cooling of the actuating substance, and electrical insulation. 
     In accordance with a non-limiting embodiment of the present invention, the heating element of the delivery device is mounted directly on a printed circuit board (PCB) or is a portion of one or more layers of the PCB. Alternatively, the heating element of the delivery device may be a resistive element disposed in (and may be electrically insulated from) the actuating substance. 
     The more actuating substance in the actuating chamber, the more energy is needed to heat the actuating substance to expand it (e.g., to vaporize it). A well designed device will contain a sufficient amount of actuating substance (e.g., heating liquid) in the actuating chamber to allow sufficient pressure and pushing force, yet small enough to minimize the heating energy required. To optimize the energy efficiency of the device, yet another non-limiting embodiment of the present invention is presented. 
     In accordance with this other non-limiting embodiment of the present invention, the actuating chamber contains a sufficient, yet minimal amount of actuating substance (e.g., heating liquid), so that the required heating energy is minimal. A reservoir containing additional actuating substance (e.g., heating liquid) is next to the heating chamber. Means to replenish “lost” actuating substance in the actuating chamber are provided, thus allowing maintaining a sufficient level/amount of actuating substance within the chamber over long periods of time even if any actuating substance is lost over time. 
     As described below, one way of accomplishing this is with a reservoir with low positive pressure plus a directional valve allowing entrance of actuating liquid into the chamber. Another way is to use a reservoir with low positive pressure which is sealed by a membrane which is constrained to remain stationary. The membrane has low permeability to allow slow entrance of liquid over time, to replenish the “lost” liquid within the chamber. 
     There is provided in accordance with an embodiment of the present invention a delivery device including a drug delivery pump including a dosing chamber for delivering a substance therefrom, pushing apparatus, a thermal energy source arranged to cause a sufficient change in temperature in a portion of the pushing apparatus so that the pushing apparatus imparts a pushing force against the substance to cause the substance to be delivered from the dosing chamber, a controller for controlling delivery of the substance from the dosing chamber, and a thermal insulator that thermally insulates the substance in the dosing chamber from the thermal energy source. 
     There is provided in accordance with an embodiment of the present invention a delivery device including a drug delivery pump including a dosing chamber for delivering a substance therefrom, a reservoir in fluid communication with the dosing chamber, pushing apparatus, an actuator operatively linked to the pushing apparatus to cause the pushing apparatus to impart a pushing force against the substance to cause the substance to be delivered from the dosing chamber, a controller for controlling delivery of the substance from the dosing chamber, and a limiter that limits compression of the substance in the dosing chamber. 
     There is provided in accordance with an embodiment of the present invention a delivery device including a collar device for wearing on an animal, the collar device including a dosing chamber for delivering a substance therefrom, an actuator for causing the substance to be delivered from the dosing chamber, a controller for controlling delivery of the substance from the dosing chamber, and a probe protruding from the collar towards skin of the animal. 
     There is provided in accordance with an embodiment of the present invention a delivery device including a collar device for wearing on an animal, the collar device including a dosing chamber for delivering a substance therefrom, pushing apparatus, a controller for controlling delivery of the substance from the dosing chamber, and a thermal energy source arranged to cause a sufficient change in temperature in a portion of the pushing apparatus so that the pushing apparatus imparts a pushing force against the substance to cause the substance to be delivered from the dosing chamber. 
     There is provided in accordance with an embodiment of the present invention a delivery device including a dosing chamber for delivering a substance therefrom, an actuator for causing the substance to be delivered from the dosing chamber, a flexible and bendable external housing in which the dosing chamber and the actuator are housed, a cannula or needle protrudable from the housing to penetrate into skin, and a fluid conduit in fluid communication between the dosing chamber and the cannula or needle. 
     In accordance with an embodiment of the present invention a sensor is operative to sense a rate of delivering the substance from the dosing chamber. The sensor communicates with the controller, and the controller is operative to detect clogging or leaking in accordance with information sensed by the sensor. 
     In accordance with an embodiment of the present invention the dosing chamber includes a substance-delivery membrane, and the pushing apparatus includes a pusher element arranged to push against the substance-delivery membrane to cause the substance to be delivered from the dosing chamber, and the pushing apparatus also includes an actuating chamber containing an actuating substance capable of imparting a force on the pusher element upon a suitable change in temperature and volume of the actuating substance. 
     In accordance with an embodiment of the present invention the actuating substance includes a fluid and a chamber membrane separates the fluid from the pusher element. 
     In accordance with an embodiment of the present invention the pusher element thermally insulates the substance in the dosing chamber from the actuating substance. 
     In accordance with an embodiment of the present invention the actuating chamber is sealed so that the actuating substance is prevented from leaking into the substance in the dosing chamber. 
     In accordance with an embodiment of the present invention the actuating chamber includes a maintaining element arranged to maintain the actuating substance in conductive thermal contact with the thermal energy source in any gravitational orientation. 
     In accordance with an embodiment of the present invention a filling device is operatively connected to the actuating chamber for maintaining a necessary amount of the actuating substance in the actuating chamber. 
     In accordance with an embodiment of the present invention the pushing apparatus includes a piston arranged to push against the substance to be delivered from the dosing chamber, and the pushing apparatus also includes an actuating chamber containing an actuating substance capable of imparting a force on the piston upon a suitable change in temperature of the actuating substance. 
     In accordance with an embodiment of the present invention the pushing apparatus includes a Belleville washer. 
     In accordance with an embodiment of the present invention the delivery device further includes a plurality of dosing chambers. 
     In accordance with an embodiment of the present invention different substances are delivered from the dosing chamber. 
     In accordance with an embodiment of the present invention a displacement sensor is operative to sense displacement of the pushing apparatus. 
     In accordance with an embodiment of the present invention the delivery device is encapsulated in a protective coating. 
     In accordance with an embodiment of the present invention the delivery device is flexible and bendable. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which: 
         FIGS. 1A and 1B  are simplified exploded illustrations of a delivery device, constructed and operative in accordance with a non-limiting embodiment of the present invention; 
         FIG. 2  is a simplified side-view illustration of the delivery device of  FIGS. 1A-1B ; 
         FIGS. 3A, 3B and 3C  are simplified sectional illustrations of the delivery device, taken along lines A-A in  FIG. 2 , respectively, before, during and after moving a separation element against a membrane to dispense a substance from the delivery device in accordance with a non-limiting embodiment of the present invention; 
         FIG. 3D  is a simplified top-view illustration of the delivery device; 
         FIG. 3E  is a simplified sectional illustration of the delivery device, taken along lines D-D in  FIG. 3D ; 
         FIG. 4A  is a simplified exploded illustration of a delivery device, constructed and operative in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 4B and 4C  are simplified sectional illustrations of a delivery device that includes a plurality of dosing chambers, constructed and operative in accordance with a non-limiting embodiment of the present invention, wherein each individual dosing chamber may be constructed like the dosing chamber of  FIG. 4A , and wherein  FIGS. 4B and 4C  are taken along lines  4 B- 4 B and  4 C- 4 C, respectively, in  FIG. 4A ; 
         FIG. 4D  is a simplified sectional illustration of a multilayer membrane in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 5A and 5B  are simplified pictorial and exploded illustrations, respectively, of the delivery device, showing reusable and disposable portions, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 5C-5E  are simplified pictorial, side-view before bending and side-view after bending views, respectively, of a delivery device, which may or may not have bending portions filled (fully or partially) with a resilient material, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 5F-5H  are simplified pictorial, side-view before bending and side-view after bending views, respectively, of a delivery device with shallow bending lines, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 5I, 5J and 5K  are simplified pictorial illustrations of a reusable portion of the delivery device, which may be inserted in a user control unit, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 6A, 6B and 6C  are simplified external pictorial, internal pictorial and sectional illustrations, respectively, of a delivery device for use as a collar, constructed and operative in accordance with a non-limiting embodiment of the present invention; 
         FIG. 6D  is a simplified pictorial illustration of a delivery device which is a standalone, one-piece collar, in accordance with a non-limiting embodiment of the present invention; 
         FIG. 6E  is a simplified pictorial illustration of a delivery device with a socket for receiving a disposable dosing portion, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 6F and 6G  are simplified pictorial illustrations of delivery devices, in which a dosing portion of the delivery device may be a disposable part mounted above a collar frame ( FIG. 6F ) or below the collar frame ( FIG. 6G ); 
         FIGS. 6H-6J  are simplified sectional, top-view and side-view illustrations, respectively, of a dosing probe formed with a distal exit slit, in accordance with a non-limiting embodiment of the present invention; 
         FIG. 7A  is a simplified illustration of a filling device, constructed and operative in accordance with a non-limiting embodiment of the present invention; 
         FIG. 7B  is a simplified illustration of a filling device, constructed and operative in accordance with another non-limiting embodiment of the present invention; 
         FIG. 8  is a simplified illustration of a delivery device with multiple dosing chambers, constructed and operative in accordance with a non-limiting embodiment of the present invention; 
         FIG. 9  is a simplified graphical illustration of actuation pulses for the thermal energy source to heat the actuating substance, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 9A, 9B and 9C  are simplified block diagrams of non-limiting methods of using drug delivery devices of the invention; 
         FIGS. 9D-9F  are simplified graphical illustrations of different pulse trains for operating the delivery devices of the invention; 
         FIGS. 9G and 9H  are simplified graphical illustrations of PWM pulse trains for operating the delivery devices of the invention; 
         FIGS. 10A and 10B  are simplified illustrations of optical sensors that sense the position of the separation element, in accordance with a non-limiting embodiment of the present invention, respectively with the separation element at initial and final positions; 
         FIGS. 10C-10E  are simplified illustrations of use of the optical sensor, in accordance with a non-limiting embodiment of the present invention, wherein the light source is at first unobstructed by the separation element ( FIG. 10C ), then gradually obstructed as the separation element rises ( FIG. 10D ) and then fully obstructed when the separation element moves to its maximum level ( FIG. 10E ); 
         FIG. 11A  is a simplified illustration of a piston used as the pushing apparatus for dispensing a substance from dosing chamber (so-called “piston-piston arrangement”), in accordance with a non-limiting embodiment of the present invention; 
         FIG. 11B  is a simplified illustration of a variation of the embodiment of  FIG. 11A , in which the piston has first and second piston faces of different sizes and has greater separation between the actuating and dosing chambers; 
         FIG. 11C  is a simplified illustration of a piston that pushes against a sub stance-delivery membrane (so-called “piston-membrane arrangement”), in accordance with a non-limiting embodiment of the present invention; 
         FIG. 11D  is a simplified illustration of a piston that is pushed by a chamber membrane (so-called “membrane-piston arrangement”), in accordance with a non-limiting embodiment of the present invention; 
         FIG. 11E  is a simplified illustration of a piston that abuts against the folds of a membrane in accordance with a non-limiting embodiment of the present invention; 
         FIG. 11F  is a simplified illustration of a Belleville washer used as the pushing apparatus, in accordance with a non-limiting embodiment of the present invention; 
         FIGS. 12A-12D  are simplified illustrations of an actuating chamber, in accordance with a non-limiting embodiment of the present invention, wherein  FIG. 12A  shows the chamber is a closed cushion or pliant, resilient closure,  FIGS. 12B and 12C  illustrate the chamber respectively before and after the actuating substance is heated and expanded, and  FIG. 12D  shows the actuating chamber used to push a piston or separator; 
         FIGS. 13A-13D  are simplified illustrations of a dosing chamber in accordance with another non-limiting embodiment of the present invention, wherein the substance-delivery membrane is in the form of a flexible tube; 
         FIGS. 14A-14F  are simplified illustrations of another embodiment of the invention, wherein the delivery device has a cannula mounted on a flexible mounting member, in accordance with a non-limiting embodiment of the present invention, wherein  FIGS. 14A and 14B  are side views,  14 C and  14 D are top views, respectively in rest and strained positions, and  14 E and  14 F are top views, respectively in rest and strained positions; and 
         FIGS. 15A-15B  are simplified illustrations of a plurality of thermally conducting fibers used to maintain good thermal contact with the actuating substance in the actuating chamber, in accordance with a non-limiting embodiment of the present invention. 
     
    
    
     DESCRIPTION OF EMBODIMENTS OF THE INVENTION 
     Reference is now made to  FIGS. 1A-3A , which illustrate a delivery device  10 , constructed and operative in accordance with a non-limiting embodiment of the present invention. In the illustrated embodiment, delivery device  10  is a miniature device constructed of multiple layers, which makes for an easy and inexpensive manufacturing and assembly. However, the device is not limited to such a construction. 
     Delivery device  10  includes a base  11 , at least part of which is occupied by a PCB  12 , on which is mounted a thermal energy source  14 , such as but not limited to, one or more resistors or any other kind of resistive heating elements, or thermoelectric components. Non-limiting examples include a thermal resistor, or a layer of resistive material such as graphite or thin metal laid on the PCB as part of the PCB manufacturing processes, or a segment of electrical conductors on the PCB. Electrical current running through the thermal resistor/resistance-material heats it up, and heat is transferred to the actuating substance (described next) by thermal conduction, convection or radiation (or combinations thereof, depending on the material) PCB  12  may extend beyond what is shown in  FIGS. 1A-3A . PCB  12  may also include a battery, a controller (such as control logic circuitry or microprocessor and the like), sensors, wireless communications and other electronic components (not shown here), for powering and controlling delivery device  10 . 
     As seen in  FIG. 3A , device  10  includes an actuating chamber  16  containing an actuating substance  18 , such as but not limited to, a fluid, e.g., water, methanol, hexane or alcohol or others, which may undergo a phase change from liquid to gas or from gas to liquid, or a solid phase-change material with a high change in volume, e.g., inorganic salt hydrates. The actuating chamber  16  may be formed by a chamber membrane  20  which overlies base  11 , separated therefrom by a spacer  22 . The chamber membrane  20 , with or without the addition of the spacer  22 , seals the actuating substance  18  in actuating chamber  16 . 
     As seen best in  FIG. 3A , a separation element  24  rests against chamber membrane  20 . Separation element  24  may be made of any suitably medically safe material, such as plastic or metal (with a poor thermal conductivity); element  24  may be hollow (to increase thermal insulation). In the illustrated embodiment, separation element  24  is a partial sphere, but it can have other shapes as well. Separation element  24  sits in an aperture  25  formed in an intermediate member  26 . Separation element  24  is arranged to push against a substance-delivery membrane  28  (also referred to as pushing apparatus), which is sandwiched between intermediate member  26  and a dose base  29 , in which is formed a dosing chamber  30 . In the illustrated embodiment, separation element  24  is attached to chamber membrane  20  by means of a lug  40  protruding from membrane  20 . Likewise, separation element  24  is attached to substance-delivery membrane  28  by means of a lug  42  protruding from membrane  28 . The lugs sit snugly in suitable apertures formed in separation element  24 . 
     A substance  32 , such as but not limited to, drugs for human or animal use, is contained in dosing chamber  30 . The substance-delivery membrane  28  seals substance  32  in dosing chamber  30 . Dosing chamber  30  may also be sealed by one or more plugs  31 . The substance  32  can exit dosing chamber  30  (in a manner about to be described below, and in further embodiments described with reference to the series of  FIGS. 11 and 13 ) via a conduit  35  ( FIGS. 3A, 3B and 3D ), which is initially covered by a valve membrane  34 . The pressure of the flowing substance  32 , induced by the separation element  24 , pushes up and opens valve membrane  34 , and substance  32  flows out of one or more exit ports  36  formed in a cover  38 . 
     A soft, pliant bag or any other suitable container or reservoir  44  (shown in  FIG. 1A ) contains the substance  32  to be delivered. Container  44  preferably, but not necessarily, collapses to a flat state after substance  32  is evacuated therefrom. Substance  32  may be introduced from container  44  by negative pressure as follows. When substance-delivery membrane  28  moves downwards in the sense of  FIG. 3A  (returning from its position in  FIG. 3C ), it creates a negative pressure in dosing chamber  30 . This pressure causes the inlet valve membrane  34  to open and causes the substance  32  to be drawn (sucked) from container  44 ; the substance  32  flows through one or more inlet ports  48  via passages  49  to dosing chamber  30 . Any other suitable means of attaching container  44  to device  10  and drawing the substance  32  from container  44  may be implemented. 
     The layered assembly of device  10  may be secured by fasteners  50  ( FIGS. 1A-1B ), such as posts or other mechanical elements, or by bonding or other means of joining. 
     Chamber membrane  20  and/or substance-delivery membrane  28  may be a “bellows” type of membrane (like in  FIG. 11E ), i.e., including folds that stretch out and fold back upon expansion and contraction, respectively. Alternatively, the membranes ( 20  and/or  28 ) may be Belleville washers (like in  FIG. 11F ), which “snap” from one position to another. 
     In operation, thermal energy source  14  is energized (by a battery, not shown) and controlled (by a controller, not shown) to heat actuating substance  18  so that the temperature change is sufficient to cause a volumetric change (e.g., expansion) in actuating substance  18 . In one embodiment, the sufficient temperature change causes a phase change in actuating substance  18  (e.g., solid-liquid or liquid-gas); alternatively, no phase change occurs (e.g., heating a gas, such as air). As seen in  FIG. 3B , the expanding actuating substance  18  pushes against chamber membrane  20 , which in turn pushes against separation element  24 . Separation element  24  pushes against substance-delivery membrane  28 , which in turn pushes against substance  32 , thereby causing substance  32  to be delivered out of dosing chamber  30 . In  FIG. 3C , substance  32  has been completely delivered out of dosing chamber  30 . After the dosage, the actuating substance  18  cools and separation element  24  returns to the position of  FIG. 3A , thereby by sucking in another dosage of substance  32  into dosing chamber  30 . 
     It is noted that chamber membrane  20  separates the actuating substance  18  from separation element  24 . Separation element  24  thermally insulates substance  32  in dosing chamber  30  from actuating substance  18 . Actuating chamber  16  is sealed, preferably by separation element  24 , so that the actuating substance  18  is prevented from leaking into substance  32  in dosing chamber  30 . More specifically, chamber membrane  20  encloses actuating chamber  16 , and separation element  24 , which is attached to membrane  20  before and after operation, prevents leakage of actuating substance  18  through chamber membrane  20  due to potential membrane permeability. Dosing chamber  30  and substance  32  are isolated from actuation substance  18  by a combination of chamber membrane  20 , separation element  24  and substance-delivery membrane  28 , thereby enhancing isolation and medical safety. Aperture  25  may be optionally ventilated through some vent passage  27  ( FIG. 3A ) to avoid pressure changes in aperture  25  during movements of separation element  24 , and to drain any leakage of the actuation substance  18  or substance  32  if leaked through membrane  20  or  28  into aperture  25 . 
     Alternatively, the thermal energy source  14  may be a cooling device (e.g., thermoelectric device) that cools actuating substance  18 , which expands upon cooling. 
     Since delivery device  10  may be oriented in all kinds of orientations, including upside down, the actuating substance  18  may become distanced from thermal energy source  14 . Accordingly, in one embodiment, actuating chamber  16  includes a maintaining element  52  ( FIG. 3A ) arranged to maintain actuating substance  18  in conductive thermal contact with thermal energy source  14  in any gravitational orientation. The maintaining element  52  may be, without limitation, carbon fibers, carbon cloth, capillary wires, rods or other slender elements, sponge members, electric charge device, and others. 
     Reference is now made to  FIG. 4A , which illustrates a delivery device  300 , constructed and operative in accordance with a non-limiting embodiment of the present invention. 
     Similarly to delivery device  10 , delivery device  300  includes a base  302  on which is mounted a thermal energy source  304 , such as but not limited to, one or more resistors or any other kind of resistive heating elements, or thermoelectric components. A controller (such as control logic circuitry or microprocessor and the like), sensors, wireless communications and other electronic components (all not shown for simplicity), for powering and controlling delivery device  300 , may be mounted on base  302 , as in delivery device  10 . Contact posts  305  may be provided that are in electrical contact with thermal energy source  304  and which are in electrical contact with a power source for energizing the thermal energy source  304 . 
     An actuating chamber  306  is formed in base  302  and contains an actuating substance  308 , such as but not limited to, a fluid, e.g., water, alcohol, or a phase-change material with a high change in volume, e.g., inorganic salt hydrates, as before. It is noted, for example, that one of the electronic components in communication with the controller may be one or more temperature or pressure sensors  307 , which may be useful for controlling the device and preventing overheating or over-pressurizing of the actuating substance  308 . The actuating chamber  306  is covered by a chamber membrane  310  (which may be single layer or multi-layer) attached to base  302 . The chamber membrane  310  may have a preformed shaped, such as but not limited to, a dome, as seen in the illustrated embodiment, or bellow or Belleville washer. Plugs  309  may be provided for filling and sealing actuating substance  308  in actuating chamber  306 . 
     A separation element  312  rests against chamber membrane  310 . Separation element  312  may be of a one-piece construction, or may be made of more than one piece. Separation element  312  sits in an aperture  313  formed in an intermediate member  314 . Separation element  312  serves as the pushing apparatus that is arranged to push against a substance-delivery membrane  316  for pushing against and thereby dispensing a substance from a dosing chamber  320 . Separation element  312  may include guiding members  317  to guide its travel in aperture  313 , which are slidingly received in grooves  319  formed in member  314 . Substance-delivery membrane  316  fluidly communicates with an inlet valve  316 A and an exit valve  316 B. Substance-delivery membrane  316 , inlet valve  316 A and exit valve  316 B are all part of the same membrane layer. As before, dosing chamber  320  may have more than one compartment that contain substances for delivery (different or same substances). 
     As will be described further below with reference to  FIGS. 10A-10B , optical sensors may be provided, which sense the position of the separation element  312 . In the illustrated embodiment, the optical sensors include two light sources  322  (e.g., LEDs) which emit light beams that are detected by two light receivers  324 . The light beams are positioned at two different places in the travel of separation element  312 . In this manner, the optical sensors can easily detect the initial and final positions of separation element  312  (for example, to indicate that the drug has been properly dispensed). 
     Reference is now made to  FIGS. 4B and 4C , which illustrate another delivery device  800  that includes a plurality of dosing chambers  802 . Each individual dosing chamber  802  may be constructed like the dosing chambers of  FIG. 4A ;  FIGS. 4B and 4C  are taken along lines  4 B- 4 B and  4 C- 4 C, respectively, in  FIG. 4A . As seen in  FIGS. 4B and 4C , the dosing chambers  802  may be of different sizes, but of course may alternatively be identical in size. 
     Each dosing chamber  802  has its own dedicated separation element  804  and actuation chamber  806  with thermal energy source  808 . However, all the dosing chambers  802  share a common chamber membrane  810  and a common substance-delivery membrane  812 . Membrane  812  also serves as the outlet and inlet valves  814  and  816 , respectively, for each dosing chamber  802 . It is noted that the membranes  810  and  812  each may have rims that are received in grooves in the device, which help achieve desired engineering properties of the membranes and valves, such as permissible stretching and positioning. 
     Reference is now made to  FIG. 4D . The membranes  20  and  28  of the embodiment of  FIG. 1A  may be replaced by single multilayer membrane  23 , including without limitation, a top layer  23 A, intermediate layer  23 B (which may serve as a thermal insulation layer) and a bottom layer  23 C. This simplifies the construction as it eliminates the need for elements  20 ,  24 ,  25 ,  26 ,  27  and  28 . The top layer  23 A serves as the substance-delivery membrane (sealing the to-be-delivered substance in the dosing chamber), the intermediate layer  23 B serves as the separator (mechanical and thermal isolation), and the bottom layer  23 C serves as the chamber membrane  20  (overlying the actuating chamber containing the actuating substance), as in the previous embodiments. The top layer  23 A and/or the bottom layer  23 C may be a metal or metallized layer (such as by metal deposition of aluminum or silver metals or alloys) which achieves reduced or negligible permeability of the layer, and may also provide improved thermal insulation and other mechanical properties, such as reduced or negligible wrinkling or sagging. 
     Of course, the membranes of the embodiments of  FIGS. 1A and 4A , or any of the other embodiments of the invention, may be constructed as a variety of multilayer membranes. 
     Reference is now made to  FIGS. 5A and 5B , which illustrate that the entire device, including the dosing chamber, actuator and electronic components, may be encapsulated in a flexible, external housing  100 . The device may be a patch (e.g., patch pump for drug delivery, such as but not limited to, insulin patch pump), which is attached to the skin of the user with adhesive or other suitable means. The device may be a disposable one piece product. Alternatively, in the illustrated embodiment, the device includes reusable  120  and disposable portions  122 . For example, the dosing cell and/or battery may be on the reusable portion  120  or the disposable portion  122 . As another example, the actuation part of the dosing cell may be reusable portion  120 , whereas the dosing cell may be on the disposable portion  122 , and the separation element placed between the two portions. The battery may be rechargeable or non-rechargeable. 
     The reusable portion  120  may be mounted on a user control unit (e.g., personal diabetes manager that may include a blood glucose meter)  123 , for example, simply for storing and ensuring that reusable portion  120  does not get lost, or for recharging the battery, or for data communication (e.g., uploading and downloading instructions and operational data). After operation and depletion of the battery, reusable portion  120  may be detached from the disposable portion  122  and attached to user control unit  123  for recharging for later reuse. Meanwhile another reusable portion  120  can be attached to a new disposable portion  122  and put into operation on the user&#39;s skin. As seen in  FIGS. 5A and 5B , the components of the device are separated by bending lines  127 . The position of the bending lines  127  and/or the components of the device can be designed to achieve different bending modes (e.g., allowing easier bending in certain directions but different—for example, more difficult—bending in other directions). Additionally or alternatively, different bending modes and properties can be achieved by using a combination of different materials with different hardnesses or other mechanical properties. One example is shown in  FIGS. 5C-5E , which has bending portions  129  filled (fully or partially) with a resilient material which may be different than the rest of the device or the same material but made with a different hardness. As seen in  FIG. 5E , the bending portion may stretch so that it “vees” outwards more than when not stretched ( FIG. 5D ). Alternatively, there may be no bending portions  129  and the encapsulated device bends in accordance with the placement of the components C, which determine the different bending possibilities of the device. The components C may be flexible, semi-rigid or rigid, e.g., drug reservoir, battery, dosing device and others. Another example is shown in  FIGS. 5F-5H , in which the components of the device are separated by shallow bending lines  121 . In the embodiments of  FIGS. 5C-5H , a cannula  119  protrudes from the device for drug delivery (as explained elsewhere a needle may first puncture the user&#39;s skin and then be retracted, leaving the cannula in place for drug delivery). 
     A further example of the possible combinations of reusable and disposable portions of a device  100 A is shown in  FIGS. 5I-5J . The reusable portion  120  may be inserted in a socket  123 A formed in user control unit  123  (such as, without limitation, a smart phone), for example, simply for storing and ensuring that reusable portion  120  does not get lost, or for recharging the battery or for data communication. 
     A further example of the possible combinations of reusable and disposable portions of the device is shown in  FIG. 5K . The reusable portion  120  may be inserted in a socket  401  formed in a protective cover  402  (which may be made of a flexible elastic material) of a smart phone or personal diabetes manager  403  which serves as the user control unit. Socket  401  has pins, tabs or other connectors for connecting to corresponding connections in the reusable electronic module (i.e., reusable portion)  120 . The connectors of socket  401  may in wired communication with a port  404 . A smart-phone charging/communication cable  405  may connect to port  404 , either directly or via an intermediate adaptor (not shown). Port  404  thus serves as a communication and charging connector, for example, for recharging the battery of reusable portion  120  or for communicating with reusable portion  120 . Port  404  may be molded or otherwise assembled together with protective cover  402 . 
     Reference is now made to  FIGS. 6A-6C , which illustrate a delivery device  130  for use as a collar, constructed and operative in accordance with a non-limiting embodiment of the present invention. This is particularly useful for pets, such as dogs or cats. Alternatively, the device can be in the form of a harness or neck strap, for use with farm animals, such as horse, cattle, sheep, goats, etc. Alternatively, the device can be used for humans. The term “collar device” encompasses a standalone collar and a collar accessory which is attached to a collar. 
     As seen in  FIG. 6C , delivery device  130  includes one or more delivery devices  10 , which are used to deliver a substance through a dosing probe  132 , which extends to the skin of the animal. The entire delivery device  130 , which includes any of the actuators and controllers of any of the other embodiments, may be encapsulated in a flexible, external housing (such as by over-casting or molding in a suitable polymeric material. This achieves a flexible feel, robust mechanical properties and can be made with a simple, low-cost production. 
     Dosing probe  132  is preferably flexible and bendable. A seal or valve  133  is positioned at or near the tip of probe  132  to avoid congelation/drying of the substance to be administered. A skin contact sensor  134  is provided for sensing that the collar is properly positioned on the animal so that the substance is administered only when the collar is on the animal. “Properly positioned” means the collar is touching the fur or skin of the animal and probe  132  is directed towards the fur or skin of the animal. Sensor  134  may be a temperature sensor (e.g., thermistor) that senses contact with the skin by means of sensing the skin temperature. This also provides a safety feature, by discriminately sensing normally higher animal temperatures (which are typically higher than normal human body temperature). Alternatively, the sensor can be a proximity sensor, such as a capacitance sensor. A battery  136  is provided in the collar. As seen in  FIG. 6B , the collar may include flexible, jointed portions  137  that protect the device  10  from external force/pressure, yet can be flexed and bent to best suit the collar shape and the animal&#39;s neck. 
     The device may be attached to an existing collar (as in  FIGS. 6A-6C ), or alternatively may be provided as an integral part of the collar, that is, a standalone, one-piece collar, as seen in  FIG. 6D . Optional dosing probes and/or sensors  161  and  163  can sense proximity or attachment of the collar  165  to the animal, or can sense if the collar is open to ensure safe operation and avoid drug delivery once the collar is removed from the animal. The device can be used, for example, to deliver multiple drugs (see embodiments of  FIG. 8 ) for combating multiple parasites (e.g., fleas, ticks, heartworms, etc.). 
     As seen in  FIG. 6E , instead of a one-piece construction, a socket  167  can be formed in the collar  165  for receiving a disposable dosing portion  120 , which may be made like any of the disposable units described throughout the specification, such as disposable unit  120 , and which may contain the drug capsule, dosing cell, battery or any other components, and which may have a dosing probe  132 . 
     As seen in  FIGS. 6F and 6G , the collar can have the dosing portion of the delivery device  130  as a disposable part  130 A mounted on the collar frame  165  (above the collar frame as in  FIG. 6F  or below as in  FIG. 6G ). Alternatively, part  130 A is not separate from device  130 ; rather they are one unit which is either disposable or reusable. 
     As seen in  FIGS. 6H-6J , the dosing probe  132  may be formed with a distal exit slit  169  (e.g., like a duck bill). The flexible dosing probe  132  with its exit slit  169  can prevent clogging of dosing probe  132 , because they prevent ingress of outside air, and if a clog forms, the dosing probe  132  and slit  169  extend/expand to eject the clogged particle. The dosing probe  132  can bend upon pressing against the fur or skin of the animal, and this also helps to release any clogs. 
     In order to maintain a necessary amount of actuating substance  18  in actuating chamber  16 , the delivery device  10  may further include a filling device  54  operatively connected to actuating chamber  16 . In one embodiment, shown in  FIG. 7A , filling device  54  includes a reservoir  56  at least partially filled with actuating substance  18 , and pressurized at low pressure. Actuating substance  18  in reservoir  56  is nominally separated from actuating chamber  16  by a membrane  58 . However, membrane  58  is somewhat permeable to actuation substance  18  so that an osmotic pressure difference (higher pressure on the reservoir side of membrane  58 ) will causes a very slow passage of actuation substance  18  through membrane  58  over a long period of time. Thus, if actuating substance  18  leaks out of actuating chamber  16  for any reason, this causes a drop in pressure in actuating chamber  16 . Since reservoir  56  is partially pressurized, the difference in pressure will cause a slow passage of actuation substance  18  from reservoir  56  through membrane  58  and via a conduit  59  into chamber  16 , thereby replenishing actuating chamber  16  with actuating substance  18 . Reservoir membrane  58  thus serves as one-way valve at a very slow rate and over long period of time. 
     In another embodiment, shown in  FIG. 7B , the actuating substance  18  in reservoir  56  flows to actuating chamber  16  via conduit  59  and a directional valve  60  (e.g., one-way valve). 
     Reference is now made to  FIG. 8 . In this embodiment, the delivery device includes a plurality of dosing chambers, for example, dosing chambers  81 ,  82  and  83  (any number is within the scope of the invention). In the illustrated embodiment, a reservoir  84  of a first substance (such as, but not limited to, insulin) is connected to dosing chambers  81  and  82  via one-way valves  85  and  86 , respectively. A reservoir  87  of a second substance (such as, but not limited to, GLP-1 [glucagon-like peptide-1] analogs) is connected to dosing chamber  83  via a one-way valve  88 . In other embodiments, each of the dosing chambers may contain a different substance to be delivered. In the illustrated embodiment, dosing chambers  81 ,  82  and  83  are of different sizes ( 81  being the smallest and  82  the largest. For example, without limitation, chamber  81  may be used for a basal dosage of insulin (such as 0.5 μl), whereas chamber  82  may be used for a bolus dosage (such as 10 μl). 
     In the illustrated embodiment, each dosing chamber has its own dedicated separation element and/or actuation chamber, collectively labeled  91 ,  92  and  93 . In another embodiment, there is a common separation element and/or actuation chamber for all of the dosing chambers. A controller  90  controls operation of the actuation chambers. 
     It is noted that in any of the embodiments of the invention, communication with the controller may be wireless or through the Internet or with any kind of suitable communication means. 
     In the illustrated embodiment, there is a common outlet  94  for all of the dosing chambers via one-way valves  95 ,  96  and  97 , respectively. Alternatively, separate outlets may be provided. Alternatively, a common inlet may be used for all of the dosing chambers. 
     Controller  90  may be used to provide a variety of dosage plans, depending on the patient (human or animal) and the substances being administered. In one non-limiting example, dosing chamber  81  may be used to administer a basal amount of insulin, at any rate of dosage amount per time (e.g., discrete small dosages of insulin at set time intervals; the amount, time interval and length of time the dosages are given can be modified). Before meals, dosing chamber  82  may be used to administer a bolus of insulin, such as two boluses of 10 μl of insulin plus a few dosages of 0.5 μl from chamber  81 . Reservoir  87  and dosing cell  83  may be used for providing boluses of GLP-1 before meals. Alternatively, they may be used for dosing glucagon in emergency cases of hypoglycemia. Reference is now made to  FIG. 9 , which illustrates an example of actuation pulses for thermal energy source  14  to heat actuating substance  18 , as controlled by controller  90  ( FIG. 8 ). The number of actuation pulses may be determined by the size and number of the dosing chambers. Initially, a relatively large amount of energy is required to heat the actuating substance to vapor, as indicated by initial pulse A from time t0 (membrane at initial, unexpanded state; full chamber) to time t1 (membrane at fully expanded state; empty chamber). The device may include sensors (examples described below) that sense the full or empty state of the dosing chamber, or the position of the chamber membrane and/or the separation element. This may help save on the energy and time needed to heat the actuating substance for the next dosage, because the controller knows when the actuating substance has cooled enough so that the chamber membrane has gone back to its initial state (e.g., near the bottom of the actuating chamber) and can start reheating the actuating substance, which is near its vapor temperature, before the actuating substance has cooled down unnecessarily. Thus, the subsequent energy pulses B may be significantly shorter and of less magnitude than the initial pulse A. The heating times may be in the range of milliseconds to several seconds, for example. 
     Reference is now made to  FIGS. 9A .  9 B and  9 C, which illustrate non-limiting methods of using drug delivery devices of the invention.  FIG. 9A  illustrates using the collar device of the invention for animals (or humans), such as that of  FIGS. 6A-6C . The collar device may be configured as a reusable device with one or more disposable drug capsules, which include the dosing cell  901  and drug reservoir(s)  902 . Alternatively the device may be a fully disposable one-piece device. The device may be provided as a standalone collar or an accessory attached to the pet&#39;s collar. The device has a control module which includes a controller  903  and battery  904 . The controller provides dosing actuation and verification. The device can operate via wireless communication with a smartphone, Wi-Fi or any other suitable communication device. Various sensors may be provided, such as without limitation, body temperature sensors, probe or other animal sensors, etc. 
       FIG. 9B  illustrates using an insulin device of the invention, such as that of  FIG. 8 . The device may be configured as a disposable patch, which includes the dosing cell  901  and drug capsule(s)  902  (e.g., insulin, GLP-1, glucagon) and infusion set  905  (including a needle which may be removed after infusion, and a cannula  906 ). The device has a control module which includes a controller  903  and battery  904 . The controller provides dosing actuation and verification. The device can operate via wireless communication with a personal diabetes manager, smartphone, WiFi or any other suitable communication device. Various sensors may be provided, such as without limitation, body temperature sensors or other body sensors, etc. 
       FIG. 9C  illustrates a dosing control system, which may operate in a closed or open control loop, and which may be used in any of the embodiments of the invention. The control system may include, without limitation, a control module  181 , one or more temperature sensors  182 , one or more pressure sensors  183 , and one or more position sensors  184 . The control module  181  can control electrical power to various components of the delivery device, such as but not limited to, the thermal energy source  185  (e.g., heating element), actuators and others. The control module  181  may control operation in accordance with a physical behavior model  186  of the dispensing device or any operational portion of the device controlled by the dosing control system. The physical behavior includes, without limitation, thermodynamic, mechanical, and/or chemical behavior and other behaviors. Accordingly, in one embodiment, by processing all the sensed and/or stored information, the control module  181  controls the dosage provided to the user in a closed control loop with feedback. In another embodiment, the control module  181  controls the dosage provided to the user in an open control loop, without taking into account sensed information for feedback. For example, the control module  181  can provide a series of operating electrical pulses with a predetermined time duration and magnitude. 
     Examples are shown in  FIGS. 9D-9F . The amount of substance administered by the dosing device is related to the number of pulses in a pulse train that heat the actuating substance to cause the dosing mechanism to administer the substance from the dosing cell. The magnitude and duration of the pulse train, as well as the gaps between the pulses (i.e., the duration of no energy between the pulses), determines the dosage and energy efficiency characteristics. The graphs show the displacement of the dosing mechanism (e.g., any of the membranes and/or separator) vs. time and the pulses vs. time. It is noted that the dosing mechanism travels between two limits, e.g., a starting position and finishing position. 
     In  FIG. 9D , pulses are provided at a predetermined time duration with gaps of no energy between them (open loop). Thus, the pulses are provided at predetermined time periods and the pulse duration is also predetermined. 
     In  FIG. 9E , position sensor data for the finishing position is used in a feedback loop to control the pulses. When the dosing mechanism has reached its finishing position, the pulse is stopped. Thus, the pulses are provided at predetermined time periods, but the pulse duration is not predetermined, rather it ends when the dosing mechanism has reached its finishing position. This conserves energy as opposed to  FIG. 9D , because the pulses last shorter. It also saves overheating and over-pressurizing of the device. 
     In  FIG. 9F , position sensor data for the starting and finishing positions is used in a feedback loop to control the pulses. When the dosing mechanism has reached its finishing position, the pulse is stopped. When the dosing mechanism has returned to its starting position, the next pulse starts. Thus, the pulses are not provided at predetermined time periods, rather the pulse ends when the dosing mechanism has reached its finishing position and the next pulse starts upon the dosing mechanism returning to its starting position. This conserves energy even more energy as opposed to  FIG. 9E , because the substance has not fully cooled between pulses, but just cooled enough to reach the starting position. 
     Other examples of controlling the pulses for operation of the device are shown in  FIGS. 9G and 9H . In these examples, pulse-width modulation or pulse-duration modulation (PWM) is used to determine the width or duration of the pulse based on modulation signals. The PWM duty cycle is equal to (time on)/(time on+time off). 
     In the systems of  FIGS. 9D-9F , each pulse is a step function which is basically immediately input at a constant magnitude to cause displacement of the dosing mechanism. By using PWM, each individual pulse of  FIGS. 9D-9F  is divided into shorter pulses and the frequency of these pulses can be controlled so that the input to the dosing mechanism is not a step function but rather a gradual increase, as seen in  FIGS. 9G and 9H , or other mathematical functions. By combining PWM with feedback sensors, the control system can provide very controlled displacement of the dosing mechanism to suit any dosing rate and quantity according to desired dosing protocols. 
     The control system can immediately sense different dosing problems. For example, if some clog has formed (such as in the cannula, needle or dosing cell) the control system will detect that the finishing position of the pushing apparatus or substance-delivery membrane has not been reached within the defined time. The control system recognizes this delay, i.e., longer dosing time, as the presence of a clog or other kind of obstruction. Conversely, if there is some leak, the control system will detect that the finishing position of the pushing apparatus or substance-delivery membrane has been reached before the defined time due to a reduced or lack of resistance to the movement. The control system recognizes this shorter dosing time as the presence of a leak. 
     The control system can combine the above with temperature and/or pressure sensors to improve the accurate assessment of dosing time and behavior to improve the sensitivity of sensing clogs and leaks. The displacement, temperature and pressure sensors are examples of sensors that sense a rate of delivering the substance from the dosing chamber, and other suitable sensors can also be used. The control system can provide alarms of clogging or leaking or other abnormal dosing behavior. 
     Reference is now made to  FIGS. 10A-10B , which illustrate optical sensors that sense the position of the separation element  24 . In the illustrated embodiment, in  FIG. 10A , separation element  24  is at the initial position, wherein chamber membrane  20  has not yet expanded and substance-delivery membrane  28  has not yet been forced against the substance  32  in chamber  30 . A first light source  101  (e.g., LED) emits a first light beam  102  through a passage  103  formed in separation element  24 . The first light beam  102  is detected afterwards by a first light receiver  104 . Similarly, a second light source  111  emits a second light beam  112 . In the position of  FIG. 10A , second light beam  112  is reflected off separation element  24 . After separation element  24  has moved to the final position, shown in  FIG. 10B  (in this position, all of the substance  32  has been delivered from chamber  30 ), the second light beam  112  now can pass through passage  103  and is detected by a second light receiver  114 . In the final position, the first light beam  102  is reflected off chamber membrane  20 . In this manner, the optical sensors can easily detect the initial and final positions of separation element  24  (for example, to indicate that the drug has been properly dispensed). 
     The sensors can be implemented in other ways as well, such as but not limited to, only one light receiver, or only one LED in a variety of operational logics. For example, one light receiver may have a larger viewing port or window and serve as an analog sensor, that is, it views the rising and setting of the separation element or other moving portion of the assembly. An example of such an arrangement is shown in  FIGS. 10C-10E , which shows the light source  322  of the embodiment of  FIG. 4A . Light source  322  is at first unobstructed by the separation element  312  ( FIG. 10C ), then gradually obstructed as the separation element  312  rises ( FIG. 10D ) and then fully obstructed when the separation element  312  rises to its maximum level ( FIG. 10E ). This arrangement allows various precise dosing rates profiles in a closed loop control as previously explained. 
     Other types of sensors, such as but not limited to, electrical contacts or capacitance proximity sensors, may be used instead of the optical sensors. 
     Reference is now made to  FIG. 11A . In this embodiment, instead of a substance-delivery membrane as the pushing apparatus, a piston  200  is the pushing apparatus arranged to push against substance  32  to be delivered from dosing chamber  30 . The opposite face of piston  200  is pushed directly by expansion of actuating substance  18  in actuating chamber  16 , instead of using a chamber membrane. Actuating substance  18  may be heated by thermal energy source  14 , as before. One or more seals  201 , such as O-rings, may be used to slidingly seal piston  200  in its travel in a cylinder  202  between actuating chamber  16  and dosing chamber  30 . 
       FIG. 11B  shows a variation of the embodiment of  FIG. 11A . In this embodiment, a piston  204  has a first piston face  205  sealed by one or more seals  206 , and a second piston face  207  sealed by one or more seals  208 . In the illustrated embodiment, first piston face  205  is larger in diameter than second piston face  207 , but the opposite can also be used. In this manner, greater separation is achieved and the shaft  209  of the piston serves as the separator between the two chambers. Ventilation ports  210  may be provided for venting gas or other fluid during the piston travel in its cylinder. 
     Reference is now made to  FIG. 11C . In this embodiment, a piston  212  is pushed directly by expansion of actuating substance  18  in actuating chamber  16 , as in the embodiment of  FIG. 11A . The opposite face of piston  212  pushes against substance-delivery membrane  213 , which serves as the pushing apparatus to push against and deliver substance  32  from dosing chamber  30 . 
     Reference is now made to  FIG. 11D . In this embodiment, a piston  214  is the pushing apparatus arranged to push against substance  32  to be delivered from dosing chamber  30 . The opposite face of piston  200  is pushed by a chamber membrane  215 , which is moved by expansion of actuating substance  18  in actuating chamber  16 , as described in previous embodiments. 
     Reference is now made to  FIG. 11E . In this embodiment, a piston  216  is mounted in or abuts against the folds (like bellows) of a membrane  217 . This arrangement enables a large range of movement with minimal resistance (elastic) force. The membrane  217  may either be the substance-delivery membrane or the chamber membrane or both, and can be used with the separator of previous embodiments instead of piston  216 . 
     In all the embodiments of the invention described herein, the membranes may be elastic or may have sufficient stiffness for applying forces in the direction of either chamber. 
     Reference is now made to  FIG. 11F . In this embodiment, the pushing apparatus is a Belleville washer  218 , which can serve as the substance-delivery membrane or the chamber membrane or both. Belleville washer  218  may have different sizes and shapes and may be made of different materials to suit any engineering need. 
     Reference is now made to  FIGS. 12A-12D , which illustrate another actuating chamber  220  useful in the present invention. In this embodiment, actuating chamber  220  is constructed as a closed cushion or pliant, resilient closure, made of any suitable resilient or flexible material, such as but not limited to, multilayer foil (such as that described above), polyurethane, polyethylene, cloth from synthetic or natural fibers, and many others. The actuating chamber  220  may be made of two parts sealed around their periphery, such as by adhesive bonding, thermal bonding, welding, and other methods of joining. The actuating substance  18  is disposed in actuating chamber  220  and heated by thermal energy source  14 , as before.  FIGS. 12B and 12C  illustrate actuating chamber  220  respectively before and after actuating substance  18  is heated by thermal energy source  14 .  FIG. 12D  illustrates actuating chamber  220  in its expanded, pressurized state used to push a piston or separator  221 . 
     Reference is now made to  FIGS. 13A-13D , which illustrate another dosing chamber  230  useful in the present invention. In this embodiment, the substance  32  is expelled from dosing chamber  230  using a separator (piston)  231  and chamber membrane  232  which is actuated by actuating substance  18  heated by thermal energy source  14  in actuating chamber  16 , as before. Dosing chamber  230  includes a resilient, flexible tube with a substance inlet  233  and substance outlet  234  (the walls of tube  230  serve as the substance-delivery membrane). The tube  230  is mounted in a housing  235 . As seen in  FIG. 13C , tube  230  is substantially round (circular) before being pressed by separator  231 . As seen in  FIG. 13D , tube  230  becomes flattened when pressed by separator  231 . For certain substances it may be important to ensure that tube  230  does not get pressed to the point of being completely flattened, e.g., so as not to damage large molecules which may become altered or whose properties may become adversely affected upon excessive pressing forces. To ensure that tube  230  does not get over-pressed, housing  235  may have an abutment (limiter)  236 , such as a shoulder, which serves as a stopper against separator  231 . 
     Reference is now made to  FIGS. 14A-14F , which illustrate an embodiment for use with devices of the invention that have a needle and cannula, e.g., the embodiments of  FIGS. 5C-5H . A needle first punctures the user&#39;s skin. The needle runs through a cannula (or the cannula is introduced over the needle). After puncturing, the needle is retracted and the cannula remains as the conduit for drug delivery. 
     In the embodiment of  FIGS. 14A and 14B , the cannula  119  is mounted on a flexible mounting member  170 , which may be an elastomeric member with a plurality of folds  172 . In  FIGS. 14C-14D , flexible mounting member  170  is shown to be generally circular, whereas in  FIGS. 14E-14F , flexible mounting member  170  is shown to be generally rectangular with rounded corners. Of course, the invention is not limited to any shape or size. The purpose of flexible mounting member  170  and folds  172  is to compensate for any sideways forces (from bending, stretching and other movements of the skin surface, for example) which may be applied to cannula  119 , which would have caused strain to the cannula  119  and discomfort to the user, and may have even forced the cannula out of the skin. The flexible mounting member  170  and folds  172  urge the cannula  119  downwards into the skin. 
     In  FIGS. 14C-14F , flexible mounting member  170  is mounted on a patch  174 . Alternatively, flexible mounting member  170  may be part of the flexible patch of  FIGS. 5A-5H . In one embodiment, patch  174  is fully flexible and stretchable, which also compensates for skin tension and movement. In an alternative embodiment, patch  174  is rigid or semi-rigid, in which case, flexible mounting member  170  is the sole compensator. 
     As mentioned above, since the delivery device may be oriented in all kinds of orientations, including upside down, a maintaining element may be included to maintain the actuating substance in conductive thermal contact with the thermal energy source in any gravitational orientation. Reference is now made to  FIGS. 15A-15B , which illustrate a further example of such a maintaining element. In this embodiment, the thermal energy source is a plurality of thermally conducting fibers  180  (for example, carbon fibers or carbon cloth), which are disposed in actuating chamber  16 . The fibers  180  may be in the form of a pad of any shape (e.g., circular), which is a woven pad or felt pad and the like, with the fibers arranged in any manner, such as weave, felt and the like. As seen in  FIG. 15A , the fiber pad periphery may be in electrical contact with electrical contacts  182 , for electrical resistance heating of the fibers  180 . A clamping ring  184  may fix the fiber pad periphery and ensure good electrical contact with electrical contacts  182 . In this manner, the fibers  180  are in excellent thermal contact with actuating substance  18  disposed in actuating chamber  16 , so that actuating substance  18  is quickly and efficiently heated by electrical resistance heating of fibers  180 . The capillary action of the fibers  180  maintains contact with actuating substance  18  no matter what the orientation of the device. A seal  186  may be provided to fluidly seal actuating substance  18  disposed in actuating chamber  16  and press the fibers onto contacts  182 . Accordingly, the thermal energy source is also the maintaining element. The thermal energy source is in intimate contact with the actuating substance with substantially enhance contact area and thermal conductivity.