Patent Application
20060226575
1. Field of the Invention
The invention generally relates to systems and methods of micro-fabricating medical devices comprised of bio-degradable polymers.
2. Related Art
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
a-1d illustrate various stages of fabricating a 2-dimensional generally planar bio-degradable polymer device according to the invention.
a-2b illustrate a non-patterned 2-dimensional planar polymer device fabricated according to the invention.
a-3d illustrate various views of a 2-dimensional planar having sealed recesses according to the invention.
a-4f illustrate various stages of a 3-dimensional planar device fabricated according to the invention.
a-5d illustrate various stages of fabricating an active 2-dimensional planar device according to the invention.
a-6e illustrate various stages of fabricating an active 2-dimensional device having sealed recesses according to the invention.
a-7f illustrate various stages of fabricating an active 3-dimensional device having sealed recesses according to the invention.
a-9h illustrate various stages of fabricating a non-planar 3-dimensional device according to the invention.
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.
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.
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.
a-1d 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
As shown in
Once patterned, as shown in
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.
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
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
a & 3c illustrate another embodiment of a passive device according to the invention. As shown in
Alternatively, as shown in
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.
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.
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.
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.
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.
In those embodiments where the device is an active 2-dimensional device without recessed areas, as shown in
Alternatively, in those embodiments where the device is an active 2-dimensional planar device with sealed recesses, as in
Referring still to
a-7f illustrate another embodiment of an active device fabricated according to the invention. The active device fabricated as shown in
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.
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.
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.
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.
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.
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.
Although the various devices comprised of bio-degradable polymer and fabricated as shown in
a-9h illustrates a 3-dimensional non-planar device fabricated according to the systems and methods of the invention.
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
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.
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.
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.
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.
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.
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.
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.
