Abstract:
Various methods of micro-fabricating 2-dimensional and 3-dimensional medical devices comprised of bio-degradable materials. The various methods use conventional photo-lithographic techniques commonly used in the semi-conductor or integrated circuit industry and translate those techniques to process bio-degradable medical devices. The devices may be active, passive or combination active-passive devices for controlling the release of drugs or other bio-active agents contained within the devices. Such devices may be used externally or internally for drug delivery, wound healing, tissue re-generation or the like.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     1. Field of the Invention  
         [0002]     The invention generally relates to systems and methods of micro-fabricating medical devices comprised of bio-degradable polymers.  
         [0003]     2. Related Art  
         [0004]     Micro-patterning is a technique that has long been used for patterning micro-chips, integrated circuits and the like in the computer and semiconductor industries. Methods such as ultraviolet (UV) photo-lithography, reactive ion etching, and electron beam evaporation have commonly been used as micro-patterning techniques in those industries.  
         [0005]     More recently, patterning of substrates for biological applications has been contemplated. Fabrication methods have been developed for biological micro-chips, for example, that control the rate and time of release of drugs. The rate and time of release of the drugs may be controlled based on the type or thickness of polymer that caps one or more reservoirs provided in a micro-chip as in U.S. Pat. No. 6,123,861.  
         [0006]     Medical devices comprised of bio-degradable polymers thus have increasing relevance with respect to drug delivery in the medical field. Devices comprised of bio-degradable polymers also have significant potential in various other fields of medicine, such as tissue engineering and in vivo sensing.  
         [0007]     Whereas known drug delivery microchips, such as disclosed in U.S. Pat. No. 6,123,861, have polymer caps integral with an underlying substrate to comprise the device, there exists a need for systems and methods that micro-fabricates medical devices comprised of bio-degradable polymers that are independent of the underlying substrate from which the devices are molded. A further need exists for forming such bio-degradable devices in a quicker and cost effective manner.  
       SUMMARY OF THE INVENTION  
       [0008]     The systems and methods of the invention provide medical devices comprised of bio-degradable polymers. More specifically, the systems and methods of the invention provide new processes for micro-fabricating low-cost medical devices comprised of bio-degradable polymers.  
         [0009]     According to the systems and methods of the invention, the bio-degradable polymers are formed into 2-dimensional or 3-dimensional medical devices using various techniques, such as photolithography, laser etching, mold casting or machining. Master molds used to shape the devices may be either sacrificial or permanent. The medical devices may be usable as external or implantable devices such as drug delivery, stent, orthopedic, wound healing, tissue regeneration and/or tissue scaffold devices, for example. The devices made by the systems and methods of the invention may be passive, active, or a combination of passive and active devices. Where the devices are active devices or at least partly active, the active component of the device can be either electrical, chemical, mechanical, or any combination thereof.  
         [0010]     According to one embodiment of the systems and methods of the invention, a master mold is formed from a glass, silicon, ceramic, metal, polymer, or other patternable material including a sacrificial material, using conventional photo-lithography. The master mold generally provides 2-dimensional or 3-dimensional devices. To form 3-dimensional devices from the 2-dimensional device subsequent layers are generally added thereto using similar photo-lithographic techniques.  
         [0011]     A bio-degradable polymer is deposited onto the 2-dimensional master mold, cured, planarized and removed therefrom to form the basic device according to the invention. Where the 2-dimensional master mold includes a pattern, such as recessed or raised areas, the bio-degradable polymer is then spun, cast or otherwise deposited onto the master mold to uniformly cover the pattern of the master mold.  
         [0012]     The pattern of the master mold is thus inversely imparted to the bio-degradable polymer that is spun, cast or otherwise deposited onto the master mold. The patterned polymer is then cured, planarized and removed from the master mold. In either case, once removed, the device comprised of the bio-degradable polymer is stored until desired.  
         [0013]     In some embodiments of the systems and methods of the invention, the device is a passive device in which the biodegradable polymer is impregnated with one or more drugs or bio-active agents that are released as the polymer degrades.  
         [0014]     The polymer may or may not be patterned in this case. In other embodiments, the device is a passive device in which one or more drugs or agents are separately filled into recesses and sealingly contained within the recesses provided in the patterned polymer, or in the recesses provided in a subsequently photo-lithographically applied layer. In either of these cases a bio-degradable material seals the recessed areas, wherein the seals are photo-lithographically applied. In these embodiments with the sealed recessed areas the one or more drugs or bio-active agents are released from the recessed areas as the seal degrades. In still other embodiments, the device is a passive device in which drugs are sealingly contained within recessed areas as above, and the polymer is impregnated with one or more drugs or other agents. In this latter case, the seal and the polymer may degrade at different rates to release the drugs or other agents respectively contained therein accordingly.  
         [0015]     In other embodiments of the systems and methods of the invention, the device is an active device wherein the polymer is impregnated with one or more drugs or other bio-active agents and is doped with conductive bio-degradable materials. In these active devices sensors are embedded within the polymer prior to curing thereof and electrodes are provided thereon after curing such that the drugs or agents contained within the polymer are released as the polymer degrades when the conductive materials are energized by the electrodes. In still other embodiments, the device is an active device in which the one or more drugs or agents are sealingly contained within sealed recesses provided in the patterned polymer or in a subsequent photo-lithographically applied layer, as before. In these latter embodiments, the seals may be partially comprised of conductive materials, sensors are embedded within the seals and electrodes are placed thereon, similar to as before. The one or more drugs or agents contained within the recesses are released as the seal degrades when the conductive materials are energized by the electrodes to degrade the seal. A combination of a conductively bio-degradable seal with a conductively bio-degradable polymer may also be used to release one or more drugs or agents upon degradation of the seal and the polymer. An electric voltage signal may be used to energize the conductive materials to degrade the polymer, the seal, or both.  
         [0016]     In yet other embodiments of the systems and methods of the invention, the device is a combination active and passive device, wherein the polymer is impregnated with the one or more drugs or other agents to form a passive component of the device, and a conductive bio-degradable seal is provided to contain one or more drugs or agents within the sealed recessed areas provided in the patterned polymer or in a subsequent photo-lithographically provided layer. As before, an electric voltage signal may be used to degrade the conductive materials of the seal to release the drugs or agents from the recessed areas, whereas the drugs or other agents in the impregnated polymer will degrade naturally according to the polymer type and thickness used.  
         [0017]     Still other embodiments use conventional photo-lithographic techniques to micro-fabricate 3-dimensional non-planar medical devices comprised of bio-degradable materials. As in the 2-dimensional planar devices, these 3-dimensional non-planar devices may be passive, active or combination passive and active devices.  
         [0018]     The various passive, active and combination passive and active devices described herein are either 2-dimensional planar devices fabricated from the bio-degradable polymer formed by the photo-lithographically patterned master mold, 3-dimensional planar devices formed by adding subsequent layers atop the 2-dimensional planar devices, or more directly formed 3-dimensional non-planar devices whereby conventional photo-lithographic techniques are used.  
         [0019]     The above and other features of the invention, including various novel details thereof, will now be more particularly described with reference to the accompanying drawings and claims. It will be understood that the various exemplary embodiments of the invention described herein are shown by way of illustration only and not as a limitation thereof. The principles and features of this invention may be employed in various alternative embodiments without departing from the scope of the invention.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0020]     These and other features, aspects, and advantages of the apparatus and methods of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings where:  
         [0021]      FIGS. 1   a - 1   d  illustrate various stages of fabricating a 2-dimensional generally planar bio-degradable polymer device according to the invention.  
         [0022]      FIGS. 2   a - 2   b  illustrate a non-patterned 2-dimensional planar polymer device fabricated according to the invention.  
         [0023]      FIGS. 3   a - 3   d  illustrate various views of a 2-dimensional planar having sealed recesses according to the invention.  
         [0024]      FIGS. 4   a - 4   f  illustrate various stages of a 3-dimensional planar device fabricated according to the invention.  
         [0025]      FIGS. 5   a - 5   d  illustrate various stages of fabricating an active 2-dimensional planar device according to the invention.  
         [0026]      FIGS. 6   a - 6   e  illustrate various stages of fabricating an active 2-dimensional device having sealed recesses according to the invention.  
         [0027]      FIGS. 7   a - 7   f  illustrate various stages of fabricating an active 3-dimensional device having sealed recesses according to the invention.  
         [0028]      FIG. 8  illustrates a combination active and passive device fabricated according to the invention.  
         [0029]      FIGS. 9   a - 9   h  illustrate various stages of fabricating a non-planar 3-dimensional device according to the invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0030]     For purposes of the systems and methods of the invention described herein, the terms bio-degradable, bio-degradable polymer or bio-degradable materials refers to materials that are bioresorbable and/or degrade and/or break down or erode into components that are metabolizable or excretable, over a period of time, upon interaction with a physiological environment. The period of time may range from minutes to years, preferably less than one year, while maintaining the requisite structural integrity of the device in which one or more drugs, agents or other systems are incorporated. The mechanical properties of the bio-degradable materials is understood to range from hydrogels to rigid materials. Exemplary bio-degradable materials may thus comprise, but are not limited to, polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, and polyhydroxybutyrate. The bio- degradable materials may be used exclusively or in combination with one another. Where used in combination, various properties of the bio-degradable materials can be manipulated to achieve desired functions, such as rates of degradation of the bio-degradable polymeric device, by blending the combined bio-degradable materials at different ratios.  
         [0031]     The deposition techniques of imparting the bio-degradable materials to form a medical device according to the systems and methods of the invention can range from spin coating or casting, as described in greater detail further below, although the artisan will appreciate that other techniques known in the art, such as, for example, vapor depositing, spray coating, screen printing, and inkjet deposition may also be used according to the systems and methods of the invention. The patterning of the bio-degradable polymers to form a medical device according to the systems and methods of the invention can be done by photolithography, as described in greater detail further below, or can be done by screen printing, stenciling, or inkjet deposition as the artisan should also readily appreciate.  
         [0032]     Further, for purposes of the systems and methods of the invention described herein, where possible the same or similar reference numerals are used in the various embodiments described herein.  
         [0033]      FIGS. 1   a - 1   d  illustrate a basic technique for processing a 2-dimensional planar substrate according to the invention, wherein passive, active and combination aspects of the invention will be discussed in greater detail below with respect to  FIGS. 2   a - 7   f .  FIG. 1   a , in particular illustrates a planar substrate  1 . The substrate may be glass, silicon, ceramic, metal, polymer, or other material, including a sacrificial material, that is able to be patterned by conventional photo-lithography. Once patterned, the substrate becomes the master mold  10  that will be used to shape a bio-degradable polymer into a medical device according to the invention. The master mold  10  can be made from a 2-dimensional substrate that is built into a 2-dimensional or 3-dimensional medical device according to the systems and methods of the invention. The master mold may instead be a 3-dimensional non-planar substrate from which a 3-dimensional medical device is directly constructed as discussed in greater detail further below. In any case, the master mold may be either sacrificial or permanent, and can be made using a variety of techniques such as, but not limited to, photolithography, laser etching, mold casting or machining.  
         [0034]     As shown in  FIG. 1   b , the master mold  10  may be patterned to have raised portions  11 , for example. The artisan should readily appreciate that other patterns, such as channels, bumps, recesses, or the like, may also or instead be photo-lithographically imparted upon the master mold  10 . The features patterned onto the master mold  10  can thus be in the plane of the substrate  1 , or out of the plane of the substrate, as by being etched into the substrate, for example, as desired.  
         [0035]     Once patterned, as shown in  FIG. 1   c , a bio-degradable polymer  20  is deposited onto the master mold  10 . The polymer  20  is preferably spun or cast onto the patterned master mold  10  so as to uniformly cover the pattern, shown as raised portions  11  in  FIGS. 1   b  &amp;  1   c , of the master mold  10 . Preferably, the polymer is spun or cast onto the patterned master mold  10  in a thickness ranging from 500 angstroms to 200 microns, and the overall thickness of the device may therefore range from angstroms to millimeters.  
         [0036]     The polymer  20  is then cured, planarized and removed from the mold master substrate  10 . Preferably the curing of the polymer occurs under vacuum for from 2 to 24 hours. Alternatively, curing can occur by freeze-drying the polymer in the master mold  10  prior to removal therefrom.  
         [0037]      FIG. 1   d  illustrates the bio-degradable polymer  20  after removal from the master mold substrate  10 . The removed polymer  20  is a substantially 2-dimensional planar patterned device that exhibits the inverse of the pattern provided on the master mold substrate  10 . As shown in  FIG. 1   d , recesses  21  are imparted to the polymer  20  as a result of the raised portions  11  of the master mold substrate  10  onto which the polymer  20  was spun or cast. The master mold substrate  10  thus determines the complexity and size of the bio-degradable polymeric device that is made.  
         [0038]     Of course, as the artisan will appreciate, the 2-dimensional planar device according to the invention could be comprised in its simplest form as a passive device as shown in  FIG. 2   a  &amp;  2   b , wherein the polymer is impregnated with one or more drugs or other bio-active agents as the polymer is spun or cast onto the master mold  10 . Thereafter, the polymer  20  is cured, planarized and removed ( FIG. 2   b ) from the master mold  10  and stored for future use. In use, the drugs or other agents are released as the bio-degradable polymer naturally degrades over time. Although the master mold substrate  10  is shown as patterned in  FIGS. 1   a - 1   d , the artisan will also appreciate that the master mold substrate  10  need not be patterned to form the polymeric device in its simplest form according to the invention.  
         [0039]      FIGS. 3   a  &amp;  3   c  illustrate another embodiment of a passive device according to the invention. As shown in  FIGS. 3   a  &amp;  3   b , the 2-dimensional polymer  3  formed by the patterned master mold  10  of  FIGS. 1   a - 1   d  and removed therefrom is represented in cross-sectional view along the line A-A of  FIG. 1   d . The recesses  21  formed in the polymer  20  as a result of the master mold  10  are readily evident in upright position in  FIG. 3   a . After removing the polymer  20  from the master mold substrate  10 , the upright recesses  21  may be separately filled with one or more drugs or other bio-active agents. Thereafter, as shown in  FIGS. 3   b  &amp;  3   c  the polymer  20  with separately filled recesses  21  is transferred to a second master mold  30  that overlies the upright polymer  20  and photo-lithographically patterns seals  31  over the filled recesses  21  of the polymer  20 . The drugs or agents may be injected into the recesses using a standard micro-injection syringe, for example, as is true of all embodiments having filled recesses described herein. The seals  31  can be of varying thicknesses, as shown in cross-section along the line A-A in  FIG. 3   d , and are preferably comprised of bio-degradable materials. The bio-degradable materials used to comprise each of the seals  31  can be the same as, or different than, the other seals  31 . In this manner, the release of the drugs or bio-active agents from the recesses  21  may be passively controlled according to the type or thickness of the materials comprising the seals  31  according to the invention.  
         [0040]     Alternatively, as shown in  FIGS. 4   a - 4   f , a passive device according to the invention is formed with recesses  41  provided in a layer  40  applied subsequent to the polymer  20 . In this embodiment, the master mold  10  ( FIG. 4   a ) need not be patterned, in which case the polymer  20  deposited thereon ( FIG. 4   b ) is accordingly not inversely patterned by the master mold  10 . Instead, the polymer  20  is deposited as an initial polymer layer on the master mold  10  and is cured and planarized while thereon. Thereafter, a metal layer  35 , for example, is deposited atop the planarized surface of the initial polymer layer  30 . The metal layer  35  is then cured and planarized. Thereafter, a photoresist layer  40  is then applied to the metal layer  35 .  
         [0041]     The photoresist layer  40  is then masked and exposed using conventional photo-lithography techniques to produce recessed areas  41  in the photoresist layer  40 . The recessed areas  41  are then filled with one or more drugs or other bio-active agents, as desired. A second polymer layer  50  is then spun or otherwise cast over the filled recessed areas  41  to provide a seal  51  for the recessed areas The second polymer  50  is then cured and planarized and the device removed from the second mold substrate  10  similar to as in earlier embodiments. Of course if the master mold  10  is patterned, then the polymer  20  deposited thereon would be inversely patterned as before.  
         [0042]     Photo-lithographically depositing the additional layers to the underlying 2-dimensional device in this manner is understood in the art as representing one version of a 3-dimensional device. In use, the one or more drugs or bio-active agents are thus released as the biodegradable polymer comprising the seals  51  degrade. Of course, the artisan will appreciate that the additional layers need not contain recessed areas, but could instead contain any variety of patterns as desired using the same or similar processing steps as outlined above.  
         [0043]     A still further embodiment of a passive device according to the invention comprises impregnating the polymer  20  with one or more drugs or bio-active agents prior to curing and combining the impregnated polymer  20  with sealed recesses  21  or  41  filled with one or more drugs or bio-active agents as described above. The one or more drugs or other agents are thus released from the passive device as the bio-degradable polymer  20  and the seals  31  or  51  degrade. By design, the polymer  20  and the seals  31  or  51  may degrade at different rates, in order to control the release of the drugs and agents appropriately.  
         [0044]     Although the passive devices described thus far have been represented as drug delivery devices, the artisan will appreciate that the devices can be designed to serve other, or additional, purposes. For example, the devices could as well be constructed as stents, tissue regeneration or scaffolding devices, wound healing or orthopedic devices. The passive devices likewise can include passive sensors incorporated into the bio-degradable polymer that cause the release of the one or more drugs or bio-active agents included within the device when a parameter in excess of a pre-set threshold is sensed. Such sensors can include hydrogel or foam based sensors or chemical based sensors, such as pH sensors.  
         [0045]      FIGS. 5   a - d  illustrate a technique for processing an active 2-dimensional planar device according to the invention. As in the earlier described passive device embodiments, the master mold substrate may be glass, silicon, ceramic, metal, polymer or other material, including a sacrificial material, that is able to be patterned by conventional photo-lithography to form the master mold  100 . The master mold may be either sacrificial or permanent, and can be made using any of the variety of techniques as outlined above. The master mold  100  is then used to shape a bio-degradable polymer into the desired medical device according to the invention. The master mold  100  can thus be patterned or non-patterned.  
         [0046]     In those embodiments where the device is an active 2-dimensional device without recessed areas, as shown in  FIGS. 5   a - 5   d , the bio-degradable polymer  200  may be impregnated with one or more drugs or other bio-active agents and doped with metal components  201  as electronic components in the polymer  200  prior to curing of the polymer  200 . The conductive metal components can be doped into the polymer, or can be sputtered, evaporated, screen printed or inkjet printed onto the polymer. The metal components  201  are preferably bio-degradable metals such as, but not limited to, gold, titanium, platinum and carbon. Sensors  202  are embedded into the polymer  200  prior to curing of the polymer as well. After the polymer  200  has been cured and planarized, electrodes  203  are added to the planarized surface of the polymer  200 . The electrodes  203  can be sputtered, evaporated, screen-printed, or inkjet deposited to the polymer  200 . The impregnated polymer  200  with the metal components  201 , sensors  202  and electrodes  203  is then removed from the master mold  100  and stored for future use as before. In use, the metal components  201  in the polymer  200  are conductively energized to degrade the polymer  200  and release the drugs or other agents contained therein based on an electronic signal provided to the device via the electrodes  203 . The rate of drug release or other activity can thus be controlled in accordance with physiological parameters sensed by the sensors  202  such that, for example, when a sensed parameter varies from a desired threshold the electrodes  203  will be activated by a voltage signal and the conductivity of the metal components  201  in the polymer  200  will cause the polymer  200  to degrade.  
         [0047]     Alternatively, in those embodiments where the device is an active 2-dimensional planar device with sealed recesses, as in  FIGS. 6   a - 6   e , the master mold  100  is photo-lithographically patterned with raised areas  101 . The bio-degradable polymer  200  is spun or cast onto the master mold  100  such that the inverse pattern of the master mold  100  is imparted to the bio-degradable polymer  200 , when the bio-degradable polymer  200  is removed from the master mold  100 . As in the passive devices ( FIGS. 3   a - 3   d ) having sealed recesses  210 , the inverse pattern imparted to the polymer  200  includes recesses  210 . After curing, the polymer  200  with recesses  210  is removed from the master mold  100  and placed in an upright position ( FIG. 6   c ). The patterned polymer  200  may have the upright recesses  210  filled with one or more drugs or other bio-active agents using a standard micro-injection syringe as before. Thereafter, the polymer  200  with filled recesses  210  has a second master mold  300  applied atop the polymer  200 . The second master mold  300  is lined with a conductive bio-degradable material that overlies and seals  310  the recesses  210  of the molded polymer  200  when the bio-degradable material is cured. Of course, alternatively or in addition thereto, the polymer could instead be impregnated with the one or more drugs or other agents as outlined above as well.  
         [0048]     Referring still to  FIGS. 6   a - 6   e , prior to curing the conductive bio-degradable sealing material  310 , sensors  320  are embedded therein. After curing of the bio-degradable sealing material  310  electrodes  325  are provided thereon. As before, after formation of the active device in this manner, the device is removed from the master mold  100  and stored until desired. In use, therefore, the drugs or other agents contained within the recesses  210  are released when the conductive materials in the seals  310  are activated via the electrodes  325  to degrade the seals  310 . The electrodes  325  are generally activated when a sufficient variation from a threshold level of a physiological parameter is sensed by one or more of the sensors  320 . Of course, where the polymer is impregnated with the one or more drugs or other agents, the same are released over time as before as well.  
         [0049]      FIGS. 7   a - 7   f  illustrate another embodiment of an active device fabricated according to the invention. The active device fabricated as shown in  FIGS. 7   a - 7   f  is an active 3-dimensional device having sealed recesses. In  FIGS. 7   a - 7   f  the master mold  100  is non-patterned. An initial bio-degradable polymer  200  is spun or cast onto the master mold  100 . The polymer  200  is cured and planarized while in the master mold  100 . Thereafter, a conductive metal layer  300 , for example, is deposited atop the planarized surface of the initial polymer layer  200 . The metal layer  300  is then cured and planarized. A photoresist layer  400  is then applied to the planarized metal layer  300 . The photoresist can be dip-coated, spray-coated, screen-printed, air-brushed or rotisseried onto the metal layer  300 . The photoresist layer  400  is then masked and exposed using conventional photo-lithography techniques to produce recesses  410  in the photoresist layer  400 . The recesses  410  are then filled with one or more drugs or other bio-active agents, as desired, using a standard micro-injection syringe, for example. A second polymer layer  500  is then spun or otherwise cast over the filled recessed areas  410  to provide a corresponding seal  510  for the recesses  410 . Prior to curing, the second polymer  500  is doped with conductive materials and sensors  520  are embedded therein. As before, the conductive materials are preferably bio-degradable materials such as, but not limited to, gold, platinum, titanium and carbon. In each case, the conductive materials may be doped into the polymer, or sputtered, evaporated, screen-printed, or inkjet printed onto the polymer as also outlined above. Electrodes  530  are then provided on the surface of the second polymer layer  510  after curing and planarization thereof. The electrodes  530  may be sputtered, evaporated, screen-printed or inkjet deposited onto the second polymer  510 . The device is then removed from the second master mold  100  and stored for future use, similar to as in earlier embodiments. In use, the drugs or other agents are released as the conductive materials of the seals  510  degrade by activation of the electrodes  530 , also similar to as in other active device embodiments. Of course if the master mold  100  were patterned, then the polymer  200  deposited thereon would be inversely patterned as before.  
         [0050]     Photo-lithographically depositing the additional layers to the underlying 2-dimensional device in this manner is understood in the art as representing one version of a 3-dimensional device. Of course, the artisan will appreciate that the additional layers need not contain recessed areas, but could instead contain any variety of patterns as desired using the same or similar processing steps as outlined above.  
         [0051]     In still other embodiments of the systems and methods of the invention, the device fabricated is a combination active and passive device using generally various of the techniques outlined above. In this case, the active component of the device comprises the conductive bio-degradable seals  310  or  510  fabricated as described above to contain the drugs or other agents within the respective recessed areas  210  or  410 , wherein the seals  210  or  510  are provided with the embedded sensors and topical electrodes as also described above. In addition, the bio-degradable polymer  20  or  200  is impregnated with the one or more drugs or other bio-active agents similar to as described above. In use therefore, the seals are actively degraded according to the signal provided to the electrodes to deliver a relatively large dose of the drug or agent from the recessed areas by the active component of the device.  
         [0052]     During and thereafter the delivery of the large dose via active degradation of the seals, the impregnated polymer continuously degrades to passively release the one or more drugs or agents contained therein. Ideally, the drugs that are passively release will be released over a longer period of time. Of course, the artisan will appreciate that the order of the active and passive delivery of drugs can be reverse that as described herein.  
         [0053]     In the various 2-dimensional and 3-dimensional planar embodiments of the systems and methods of the invention described herein, the master mold may be coated with a release agent prior to introduction of the polymer to the master mold.  
         [0054]     The release agent may be used to ease the subsequent release of the polymer from the master mold substrate after the curing and planarization steps have occurred.  
         [0055]     The release agent can be gold, parylene, or other known or later developed release agent so as to minimize damage to the master mold and/or to the device when the cured, planarized bio-degradable polymeric device is removed from the master mold.  
         [0056]     Although the various devices comprised of bio-degradable polymer and fabricated as shown in  FIGS. 1   a - 8  are generally fabricated as 2-dimensional planar devices or 3-dimensional planar devices comprised of additional subsequent layers imposed upon an underlying 2-dimensional planar device, the artisan will appreciate that 3-dimensional non-planar devices can also be fabricated directly according to the systems and methods of the invention described herein with respect to  FIGS. 9   a - 9   h . As in the 2-dimensional planar or 3-dimensional planar devices, the 3-dimensional non-planar devices may be fabricated as passive, active or combination active-passive devices.  
         [0057]      FIGS. 9   a - 9   h  illustrates a 3-dimensional non-planar device fabricated according to the systems and methods of the invention.  FIG. 9   a , for example, illustrates a sacrificial non-planar substrate  1000 . The sacrificial substrate  1000  is coated with a bio-degradable film  2000 . The bio-degradable film  2000  can be, but is not limited to, polymers or metals. The bio-degradable film  2000  is cured and then coated with a patternable sacrificial layer  3000 . The sacrificial layer  3000  can be, but is not limited to, photoresist. The photoresist can be applied by dip-coating, spray-coating, screen-printing, air-brushing or rotisserieing as discussed in earlier described embodiments. Thereafter, in  FIG. 9   d , the sacrificial layer  3000  is masked with a sleeved mask  4000  having the desired pattern  4001  the non-planar device is to have upon completion. The mask  4000  exposes only those portions of the underlying sacrificial layer  3000  that are to be developed into the intended pattern.  
         [0058]      FIG. 9   e  shows the mask  4000  in cross-sectional view. The mask  4000  includes a lengthwise slit  4002  intended to ease removal of the mask  4000  after the desired patterning of the sacrificial layer  3000  is achieved. The masked sacrificial layer is then developed in  FIG. 9   f  and etched in  FIG. 9   g , whereafter the mask  400  is removed resulting in a 3-dimensional non-planar device with the desired pattern in  FIG. 9   h.    
         [0059]     Where the non-planar device is intended to be a passive device, the polymer  2000  may be impregnated with one or more drugs or other bio-active agents prior to curing of the polymer  2000 . In use, the one or more drugs or other agents are released as the polymer naturally degrades.  
         [0060]     Where the non-planar device is intended to be an active device, the polymer  2000  may be impregnated, as before, and further doped with conductive bio-degradable materials prior to curing of the polymer  2000 . As before, the conductive bio-degradable materials may be, but are not limited to, gold, titanium, platinum and carbon. As also before, the conductive materials can be doped into the polymer, or sputtered, evaporated, screen-printed or inkjet printed onto the polymer. Additionally, prior to curing of the polymer  2000 , sensors may be embedded within the polymer  2000 . After curing, electrodes may be provided on the polymer  2000  by sputtering, evaporating, screen-printing or inkjet depositing the electrodes onto the polymer  2000 . In use, the one or more drugs or other agents are released as the conductive materials are energized by a voltage signal from the electrodes, for example, as when one or more of the sensors senses a physiological parameter that varies sufficiently from a designated threshold.  
         [0061]     Of course, the artisan will appreciate that other variations of the 3-dimensional non-planar device are also available, wherein additional layers are photo-lithographically imposed upon the non-planar device. The artisan will also appreciate that a combination active-passive non-planar device is readily available by impregnating the polymer  2000  with the one or more drugs or other agents in combination with doping the polymer with the conductive bio-degradable materials, embedded sensors and topical electrodes as described above. In this latter case, the one or more drugs would thus be actively released as the conductive materials are energized by the electrodes, and would be passively released as the polymer otherwise naturally degrades.  
         [0062]     In the embodiments wherein an active device is fabricated, it is anticipated that an external controller may be worn by the patient, for example, to wirelessly transmit a signal from the controller to the electrodes in order to degrade the sealing membranes or conductively doped polymer accordingly. Of course, the artisan will readily appreciate that the active devices described herein as comprised solely of electrical or conductive components, could alternatively be comprised solely of chemical or mechanical components, or could alternatively be comprised of combinations of electrical, chemical and mechanical components similarly deployed within the various structures of the device according to the systems and methods of the invention.  
         [0063]     The various exemplary embodiments of the invention as described hereinabove do not limit different embodiments of the present invention. The material described herein is not limited to the materials, designs, or shapes referenced herein for illustrative purposes only, and may comprise various other materials, designs or shapes suitable for the systems and procedures described herein as should be appreciated by one of ordinary skill in the art, wherein the overall thickness of the device ranges from angstroms to millimeters.  
         [0064]     Ideally, the processes described herein require minimal equipment as the mold substrates are generally reusable. The processes are highly reproducible therefore and can be readily applied to diverse applications in in vivo biology and medicine.  
         [0065]     While there has been shown and described what is considered to be preferred embodiments of the invention, it will, of course, be understood that various modifications and changes in form or detail could readily be made without departing from the spirit or scope of the invention. It is therefore intended that the invention be not limited to the exact forms described and illustrated herein, but should be construed to cover all modifications that may fall within the scope of the appended claims.