U.S. patent application number 09/520735 was filed with the patent office on 2002-01-03 for biodegradable implant precursor.
Invention is credited to Cox, Charles P., Dunn, Richard L., Lowe, Bryan K., Norton, Richard L., Peterson, Kenneth S., Polson, Alan M., Swanbom, Deryl D..
Application Number | 20020001608 09/520735 |
Document ID | / |
Family ID | 22431142 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020001608 |
Kind Code |
A1 |
Polson, Alan M. ; et
al. |
January 3, 2002 |
Biodegradable implant precursor
Abstract
The invention is directed to a biodegradable implant precursor
having a two-part structure made of an outer sac and a liquid
content. The implant precursor is composed of a biodegradable,
water-coagulable thermoplastic polymer and a water-miscible organic
solvent. When administered to an implant site in an animal, the
implant precursor will solidify in situ to a solid, microporous
matrix by dissipation of the organic solvent to surrounding tissue
fluids and coagulation of the polymer. The invention also includes
methods of making the implant precursor, an apparatus for forming
the precursor, and a kit containing the apparatus. Also provided
are methods of using the implant precursor for treating a tissue
defect in an animal, for example, for enhancing cell growth and
tissue regeneration, wound and organ repair, nerve regeneration,
soft and hard tissue regeneration, and the like, for delivery of
biologically-active substances to tissue or organs, and other like
therapies.
Inventors: |
Polson, Alan M.; (Fort
Collins, CO) ; Swanbom, Deryl D.; (Fort Collins,
CO) ; Dunn, Richard L.; (Fort Collins, CO) ;
Cox, Charles P.; (Fort Collins, CO) ; Norton, Richard
L.; (Fort Collins, CO) ; Lowe, Bryan K.; (Fort
Collins, CO) ; Peterson, Kenneth S.; (Fort Collins,
CO) |
Correspondence
Address: |
SCHWEGMAN, LUNDBERG, WOESSNER & KLUTH, P.A.
P. O. BOX 2938
MINNEAPOLIS
MN
55402
US
|
Family ID: |
22431142 |
Appl. No.: |
09/520735 |
Filed: |
March 8, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09520735 |
Mar 8, 2000 |
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08883260 |
Jun 26, 1997 |
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6071530 |
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08883260 |
Jun 26, 1997 |
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08294754 |
Aug 23, 1994 |
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5660849 |
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08883260 |
Jun 26, 1997 |
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07783512 |
Oct 28, 1991 |
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5324519 |
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07783512 |
Oct 28, 1991 |
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07384416 |
Jul 24, 1989 |
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5077049 |
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Current U.S.
Class: |
424/426 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61K 9/1647 20130101; B29C 41/08 20130101; A61L 27/16 20130101;
A61L 2300/43 20130101; A61K 9/0024 20130101; A61L 27/56 20130101;
A61L 27/54 20130101; B29C 41/12 20130101; B29K 2995/0056 20130101;
A61K 9/0063 20130101; A61K 33/42 20130101; A61L 31/148 20130101;
A61L 27/58 20130101; A61L 2300/404 20130101; A61K 31/74 20130101;
A61L 27/50 20130101; A61L 2300/406 20130101; A61L 27/18 20130101;
B29K 2995/006 20130101; A61K 47/34 20130101; A61L 2300/602
20130101; A61L 2300/414 20130101; B29C 67/06 20130101; A61L 31/14
20130101; A61L 2300/41 20130101; A61L 27/18 20130101; C08L 67/04
20130101 |
Class at
Publication: |
424/426 |
International
Class: |
A61F 002/00 |
Claims
What is claimed is:
1. An implant precursor for implantation in a tissue defect in an
animal, comprising: a two-part structure composed of an outer sac
and a liquid content; the implant precursor comprising a mixture of
a biocompatible, biodegradable, water-coagulable thermoplastic
polymer, and a pharmaceutically-acceptable, water-soluble organic
solvent.
2. The implant precursor according to claim 1, wherein the liquid
content of the implant precursor has a consistency ranging from
watery to viscous, and the outer sac has a consistency ranging from
gelatinous to waxen-like.
3. The implant precursor according to claim 1, wherein the implant
precursor is capable of reverting to an all-liquid form after about
30-90 minutes within being formed, and without subsequent contact
with an aqueous medium.
4. The implant precursor according to claim 1, wherein the
thermoplastic polymer is selected from the group consisting of
polylactides, polyglycolides, polycaprolactones, polyanhydrides,
polyamides, polyurethanes, polyesteramides, polyorthoesters,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,
polyhydroxyvalerates, polyalkylene oxalates, polyalkylene
succinates, polymalic acid, polyamino acids, polymethyl vinyl
ether, chitin, chitosan, and copolymers, terpolymers, and any
combination thereof.
5. The implant precursor according to claim 1, wherein the solvent
is selected from the group consisting of N-methyl-2-pyrrolidone,
2-pyrrolidone, ethanol, propylene glycol, propylene carbonate,
acetone, acetic acid, ethyl acetate, ethyl lactate, methyl acetate,
methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide,
dimethyl sulfone, tetrahydrofuran, caprolactam,
decylmethylsulfoxide, oleic acid, N,N-diethyl-m-toluamide, and
1-dodecylazacycloheptan-2-one, and any combination thereof.
6. The implant precursor according to claim 1, further comprising a
pore-forming agent selected from the group consisting essentially
of a sugar, a salt, a water-soluble polymer, and a water-insoluble
substance that rapidly degrades to a water soluble substance.
7. The implant precursor according to claim 1, further comprising a
biologically-active agent selected from the group consisting of an
antibacterial agent, an antifungal agent, and an antiviral
agent.
8. The implant precursor according to claim 1, further comprising a
biologically-active agent selected from the group consisting of an
anti-inflammatory agent, an antiparasitic agent, anti-neoplastic
agent, an analgesic agent, an anaesthetic agent, a vaccine, a
central nervous system agent, a growth factor, a hormone, an
antihistamine, an osteoinductive agent, a cardiovascular agent, an
anti-ulcer agent, a bronchodilating agent, a vasodilating agent, a
birth control agent, and a fertility-enhancing agent.
9. The implant precursor according to claim 1, further comprising a
release rate modification agent for controlling the rate of release
of a bioactive agent in vivo from the implant matrix.
10. The implant precursor according to claim 9 wherein the release
rate modification agent is selected from the group consisting of an
ester of a monocarboxylic acid, an ester of a dicarboxylic acid, an
ester of a tricarboxylic acid, a polyhydroxy alcohol, a fatty acid,
a triester of glycerol, a sterol, an alcohol, and any combination
thereof.
11. The implant precursor according to claim 10, wherein the
release rate modification agent is selected from the group
consisting of 2-ethoxyethyl acetate, methyl acetate, ethyl acetate,
diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl
adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,
triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate,
glycerol triacetate, di(n-butyl) sebecate, propylene glycol,
polyethylene glycol, glycerin, sorbitol, triglyceride, epoxidized
soybean oil, cholesterol, a C.sub.6-C.sub.12 alkanol,
2-ethoxyethanol, or any combination thereof.
12. The implant precursor according to claim 10, wherein the
release rate modification agent is selected from the group
consisting of dimethyl citrate, triethyl citrate, ethyl heptanoate,
glycerin, hexanediol, and any combination thereof.
13. A method of making an implant precursor, comprising: (a)
applying an effective amount of an aqueous medium to a surface of a
solid support substrate to form an aqueous layer; (b) dispensing an
effective amount of a liquid polymer solution onto the aqueous
layer; the polymer solution comprising a water-coagulable,
biocompatible, biodegradable thermoplastic polymer and a
water-miscible, pharmaceutically-acceptable organic solvent; (c)
applying an effective amount of an aqueous medium onto the surface
of the polymer solution; and (d) allowing the polymer adjacent the
aqueous medium to coagulate to form the implant precursor
comprising a two-part structure composed of an outer sac and a
liquid content; the amount of aqueous medium applied in steps (a)
and (c) being effective to cause surface coagulation of the polymer
to form the outer sac of the implant precursor.
14. The method according to claim 13, further comprising step (e)
of maintaining the implant precursor at a thickness of about
400-1500 .mu.m.
15. The method according to claim 13, wherein the thickness of the
implant precursor is maintained by compressing the coagulating
polymer solution during step (d).
16. The method according to claim 13, wherein the implant precursor
is formed ex vivo.
17. The method according to claim 13, wherein the support substrate
comprises glass, porous plastic, sintered stainless steel,
porcelain, bone material, bone, oxidized cellulose foam,
biocompatible polymer foam, particles of biocompatible polymer,
tricalcium phosphate and blood materials.
18. The method according to claim 13, wherein the implant precursor
is formed in vivo.
19. The method according to claim 13, wherein the support substrate
is a hard tissue.
20. The method according to claim 19, wherein the substrate is a
bone tissue.
21. The method according to claim 13, further comprising prior to
step (a), the steps of: (i) applying a minor but effective amount
of an aqueous medium as a layer on the surface of the support
substrate; (ii) dispensing an effective amount of a polymer
solution onto the aqueous layer to form a line defining an area
thereon; the polymer solution comprising a biocompatible,
biodegradable, water-coagulable thermoplastic polymer, and a
pharmaceutically-acceptable, water-soluble organic solvent; (iii)
applying an effective amount of an aqueous medium to the surface of
the line; and (iv) allowing the polymer to coagulate-to form a
boundary line comprising a two-part structure composed of an outer
sac with a liquid content; wherein the implant precursor is formed
on the support substrate within the area confined by the boundary
line.
22. The method according to claim 13, further comprising prior to
step (a), the step of applying a support layer to the surface of
the tissue defect, the support layer comprising a bioabsorbable or
bioerodible material; wherein the implant precursor is formed on
the surface of the support layer.
23. The method according to claim 22, wherein the support layer
comprises a polymer solution coated onto the surface of the tissue
defect; the polymer solution comprising a biocompatible,
biodegradable, water-coagulable thermoplastic polymer, and a
pharmaceutically-acceptable- , water-miscible organic solvent.
24. The method according to claim 23, further comprising
incorporating a gas-forming agent into a polymer solution, and
forming the support layer as a porous, foam-like structure.
25. The method according to claim 22, wherein the support layer
comprises a natural body substance.
26. The method according to claim 22, wherein the support layer
comprises clotted blood.
27. The method according to claim 22, wherein the support layer
comprises an oxidized cellulose or gelatin.
28. The method according to claim 22, wherein the support layer
comprises a water-soluble polymer.
29. The method according to claim 22, wherein the support layer
comprises tricalcium phosphate, calcium sulfate or
hydroxyapatite.
30. The method according to claim 28, wherein the support layer
consisting of polylactides, polyglycolides, polycaprolactones,
polyanhydrides, polyamides, polyurethanes, polyesteramides,
polyorthoesters, polydioxanones, polyacetals, polyketals,
polycarbonates, polyorthocarbonates, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, polymalic acid, polyethylene glycol,
hydroxypropyl cellulose, polyvinyl pyrrolidone, polyamino acids,
polymethyl vinyl ether, chitin, chitosan, and copolymers,
terpolymers, and any combination thereof.
31. A method for treating a tissue defect in a mammal, comprising:
(a) administering to the tissue defect, an implant precursor
comprising a two-part structure composed of an outer sac and a
liquid content; the implant precursor comprising a mixture of a
biocompatible, biodegradable, water-coagulable thermoplastic
polymer, and a pharmaceutically-acceptable- , water-miscible
organic solvent; and (b) allowing the implant precursor to
coagulate in situ to an implant comprising a solid, microporous
matrix; the implant being effective for treating the tissue
defect.
32. The method according to claim 31, wherein the implant precursor
further comprises a biologically active agent selected from the
group consisting of an antibacterial agent, an antifungal agent,
and an antiviral agent.
33. The method according to claim 32, wherein the implant precursor
further comprises a biologically-active agent selected from the
group consisting of an anti-inflammatory agent, an antiparasitic
agent, anti-neoplastic agent, an analgesic agent, an anaesthetic
agent, a vaccine, a central nervous system agent, a growth factor,
a hormone, an antihistamine, an osteoinductive agent, a
cardiovascular agent, an anti-ulcer agent, a bronchodilating agent,
a vasodilating agent, a birth control agent, and a
fertility-enhancing agent.
34. The method according to claim 32, wherein the implant precursor
further comprises a release rate modification agent for controlling
the rate of release of a bioactive agent in vivo from the implant
matrix.
35. An apparatus for forming an implant precursor, comprising: (a)
support means for maintaining a polymer solution thereon during
formation of an implant precursor; (b) means for compressing the
polymer solution during formation of the implant precursor; and (c)
means for hinging the support means to the compressing means; the
hinging means being positioned along one edge of the support means
and the compressing means; wherein the compressing means may be
pivoted and placed onto the polymer solution on the support
means.
36. A kit comprising, in combination: (a) an apparatus for forming
an implant precursor ex vivo, comprising: (i) support means for
maintaining a polymer solution thereon during formation of an
implant precursor; (ii) means for compressing the polymer solution
during formation of the implant precursor; and (iii) means for
hinging the support means to the compressing means; the hinging
means being positioned along one edge of the support means and the
compressing means; wherein the compressing means may be pivoted and
placed onto the polymer solution on the support means; (b) at least
one spacer means for maintaining a gap between the support means
and compressing means of the apparatus when the compressing mean is
pivoted and placed on the support means; (c) a vial containing a
polymer mixture comprising a biocompatible, biodegradable,
water-coagulable thermoplastic polymer, and a
pharmaceutically-acceptable- , water-miscible organic solvent; and
(d) a vial containing a source of an aqueous medium.
37. The kit according to claim 36, further comprising one or more
items (e)-(i): (e) means for lifting and holding the formed implant
precursor; (f) means for measuring the dimensions of the tissue
defect or the implant precursor; (g) a gridded means for measuring
the -dimensions of the implant precursor; (h) means for cutting the
implant precursor; or (i) means for removing the aqueous medium
from the surface of the implant precursor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation-in-part of U.S.
patent application Ser. No. 07/783,512, filed Oct. 29, 1991, which
is a continuation-in-part of U.S. patent application Ser. No.
07/384,416, filed Jul. 24, 1989 (now U.S. Pat. No. 5,077,049).
BACKGROUND OF THE INVENTION
[0002] In the course of periodontal disease, infection of gingival
tissue by plaque bacteria causes the ligaments attaching the gum
and teeth to recede, decalcifies the bony structure holding the
teeth roots to the bone, and forms periodontal pockets in the
gingival tissue adjacent the teeth. Successful periodontal
restoration is known to occur if periodontal ligament cells are
allowed to colonize root surfaces preferentially over gingival
epithelial cells, gingival fibroblasts or osteoblasts. Surgery
alone, however, does not result in restoration of lost
periodontium.
[0003] In an attempt to promote and achieve periodontal
restoration, implant techniques have been developed. For example,
microporous membranes, such as the Millipore.RTM. filter and
GORE-TEX.RTM. membranes, have been developed for use in periodontal
tissue regeneration. Typically, the periodontal flap is cut, and
the microporous membrane is surgically inserted to cover the
surface of the tooth root and to physically occlude epithelial
cells from apically migrating along the root surface.
[0004] These membranes have several drawbacks. Besides providing
variable results, a second surgical entry is needed to remove the
membrane after tissue regeneration has been achieved because the
membranes are not biodegradable. There is also a higher incidence
of infection in connection with their use.
[0005] To preclude surgical removal of an implant, membranes made
of bioabsorbable material, such as microfibrillar collagen,
polylactic acid, and polygalactin (Vicryl.RTM.) mesh have been
used. Fitting and positioning these membranes to the implant site
is cumbersome and time-consuming, and the therapeutic effect of
these membranes has been unpredictable. In addition, the
degradation time of membranes composed of collagen has been
variable, and the risk of adverse immunological reaction to this
foreign protein material in the body presents a major concern.
[0006] A liquid system containing a biodegradable polymer has been
developed wherein the solution is injected into an implant site,
and solidifies in situ to form a biodegradable implant having a
solid microporous matrix. Advantageously, the implant does not
require surgical removal. However, controlled delivery and
containment of a liquid system within a particular area within the
implant site is difficult, and the liquid may spread to areas other
than the implant site.
[0007] Therefore, there is a need for an article which will
facilitate the controlled placement in an implant site of a liquid
polymer solution for forming an implant. A further need is to
develop a precursor to a solid implant which is neither all-liquid
nor all-solid but will solidify in situ to form a solid microporous
implant. There is also a need for a precursor to a solid implant
that can be applied to a tissue defect in an animal and shaped or
molded in situ to conform to the defect. Yet another need is to
develop in vivo and ex vivo methods of making an implant precursor
having such characteristics.
SUMMARY OF THE INVENTION
[0008] These and other goals are achieved by the present invention
which is directed to an implant precursor for implantation in an
animal, such as a human or other mammal, which will eventually
harden in situ to a solid implant having a microporous matrix. The
invention also provides a method of making and using the implant
precursor. An apparatus is also provided for forming an implant
precursor ex vivo, and a kit containing the apparatus.
[0009] The implant precursor is a two-part structure composed of an
outer sac with a liquid content. The implant precursor is composed
of a biocompatible, biodegradable and/or bioerodible,
water-coagulable thermoplastic polymer or copolymer which is
substantially insoluble in an aqueous media, and a
pharmaceutically-acceptable, water-soluble organic solvent. The
two-part structure of the implant precursor is formed by contacting
a portion of a water-coagulable polymer solution with water or
other aqueous medium, whereupon the solvent dissipates into the
aqueous medium. This causes the polymer on the surface of the
portion of polymer solution adjacent the aqueous medium to
coagulate to form an outer sac having a firm consistency ranging
from gelatinous to waxen-like, while the solution inside the sac
(i.e., sac contents) remains a liquid. The sac contents of the
implant precursor may range in consistency from watery to slightly
viscous.
[0010] The implant precursor may-be applied to an implant site in
an animal, such as a void, a defect, surgical incision, and the
like, in or on a hard or soft tissue. Once placed in the implant
site, the implant precursor eventually forms a solid microporous
implant by the dissipation of the organic solvent into surrounding
tissue fluids and the further coagulation of the polymer.
Preferably, the matrix of the resulting implant has a two-layered
pore structure with a highly porous inner core portion and a
comparatively less porous outer surface layer or skin. Pores are
formed in the solid matrix of the implant by dissipation of the
solvent out of the composition into surrounding tissue fluids.
Optionally, the implant precursor may include a separate
pore-forming agent that is capable of generating pores within the
polymer matrix of the solid implant, as for example, sucrose,
sodium chloride, a cellulose-based polymer, and the like.
[0011] The resulting solid implant is biodegradable, bioabsorbable,
and/or bioerodible, and will be gradually absorbed into the
surrounding tissue fluids, as for example, blood serum, lymph,
cerebral spinal fluid (CSF), saliva, and the like, and become
disintegrated through enzymatic, chemical or cellular hydrolytic
action. Generally, the implant will be absorbed over a period of up
to about 2 years to about 3 years, preferably within about 1-9
months, preferably within about 60-180 days. The implant may be
used, for example, for selective enhancement of cell growth and
tissue regeneration, delivery of biologically-active substances to
the animal, and the like.
[0012] The implant precursor may also include a biologically-active
agent, or bioactive agent, as for example, an anti-inflammatory
agent, an antiviral agent, an antibacterial or antifungal agent
useful for treating and preventing infections in the implant site,
a growth factor, a hormone, and the like. The implant resulting
from the in situ coagulation of the implant precursor, may then
serve as a system for delivering the biologically-active agent to
the animal.
[0013] A release rate modification agent may also be included in
the implant precursor for controlling the rate of breakdown of the
implant matrix and/or the rate of release of a bioactive agent in
vivo from the implant matrix. Examples of suitable substances for
inclusion as a release rate modification agent include dimethyl
citrate, triethyl citrate, ethyl-heptanoate, glycerin, hexanediol,
and the like.
[0014] The invention also includes a method of making the implant
precursor. The implant precursor may be formed in vivo or ex vivo
by (a) coating the surface of a suitable support substrate with an
effective amount of an aqueous medium to form a layer; (b)
dispensing onto the aqueous layer, an effective amount of a liquid
polymer solution made of a water-coagulable, biodegradable
thermoplastic polymer such as polylactide, polycaprolactone,
polyglycolide, or copolymer thereof, and a water-soluble,
pharmaceutically-acceptable organic solvent such as
N-methyl-2-pyrrolidone; (c) applying an effective amount of an
aqueous medium onto the surface of the polymer solution; and (d)
allowing the polymer adjacent the aqueous medium to coagulate to
form the implant precursor having an outer sac with a liquid
content. Preferably, the thickness of the implant precursor is
controlled, for example, by compressing the coagulating polymer
mass between two solid flat surfaces such as a glass plate, porous
plastic, and the like. The aqueous medium is applied onto the
surface of the support substrate and the surface of the polymer
solution in a minor but effective amount to initiate coagulation of
the polymer to form the outer sac of the implant precursor.
[0015] The implant precursor may be formed in vivo by dispensing
the polymer solution onto a soft or hard tissue or other support
substrate in the body of an animal. The precursor may also be
formed ex vivo by dispensing the polymer solution onto a support
substrate made, for example, from glass, a porous plastic, sintered
stainless steel, porcelain, bone material, and other like
materials.
[0016] In a variation of forming an implant precursor, an amount of
the foregoing liquid polymer solution is applied to the surface of
the support substrate to form a line which delineates a boundary
around a defined area. The implant precursor may then be formed
within the confines of the boundary line area. When the foregoing
boundary line is formed on a tissue defect in vivo, an implant
precursor may be prepared outside the body and applied to the
defect within the confines of the boundary line.
[0017] Optionally, a support layer may be applied to the tissue
surface to provide an adhesive substrate for securing the implant
precursor onto the surface of the tissue defect. Useful substances
for forming an adhesive support layer include, for example, the
foregoing liquid polymer solution, a water-soluble substance such
as gelatin, and the like. The support layer may be in the form of a
bead, a film or coating, and the like, having a thickness as
desired.
[0018] The invention also includes an apparatus for forming an
implant precursor ex vivo. The apparatus is preferably a two-part
assembly comprising support means for maintaining the polymer
solution on a surface during formation of an implant precursor such
as a porous plate or block, and means for compressing the polymer
solution during formation of the implant precursor. Preferably, the
support means and compressing means are connected together by
hinging means positioned along one edge of the support means and
the compressing means, such that the compressing means may be
pivoted and placed onto the polymer solution on the support means.
The support means and/or compressing means are preferably made of a
porous material, as for example, a porous plastic, sintered
stainless steel, porcelain, and other like materials which are
absorptive to water. An aqueous medium is applied as a layer over
the surface of the support means, the polymer solution applied over
the aqueous layer, and a second aqueous layer is applied over the
polymer solution. Preferably, two or more spacers such as a washer,
are arranged on the surface of the support means to form a defined
area thereinbetween, and the implant precursor is formed on the
area between the spacers. The compressing means is then positioned
over the support means with the spacers and coagulating polymer
solution sandwiched thereinbetween, preferably compressing the
coagulating polymer mass. The support means and compressing means
of the apparatus are maintained in a sandwich arrangement until the
outer sac of the implant precursor is formed. The support means and
compressing means are then separated and the resulting implant
precursor is removed from the apparatus, trimmed as desired, and
placed into the implant site.
[0019] Also provided is a kit containing, in combination, the
precursor-forming apparatus, one or more barrier means, an amount
of the aforedescribed polymer solution in one or more vials or
other containers, and an amount of an aqueous medium preferably a
phosphate buffered saline in one or more vials or other like
container. The kit may also include a tweezers or other like means
for picking up the formed implant precursor; a calibrated tweezers
or other like means for measuring the dimensions of the tissue
defect and/or the implant precursor; a gridded template or other
like means for measuring the dimensions of the implant precursor; a
scalpel, razor or other like means for trimming the implant
precursor to a desired size; and/or a cotton pad or other like
means for blotting the aqueous medium from the surface of the
implant precursor.
[0020] The invention also includes a method for treating a tissue
defect in an animal. The implant precursor may be used, for
example, for enhancing cell growth and tissue regeneration, wound
and organ repair, nerve regeneration, soft and hard tissue
regeneration, and the like. According to the invention, the
foregoing implant precursor is applied to the tissue defect and
allowed to coagulate to an implant having a solid microporous
matrix.
[0021] As used herein, the term "implant site" is meant to include
a site, in or on which the implant precursor is formed or applied,
as for example, a soft tissue such as muscle or fat, or a hard
tissue such as bone. Examples of implant sites include a tissue
defect such as a tissue regeneration site; a void space such as a
periodontal pocket, surgical incision or other formed pocket or
cavity; a natural cavity such as the oral, vaginal, rectal or nasal
cavities, the cul-de-sac of the eye, and the like; and other sites
into which the implant precursor may be placed and formed into a
solid implant. The term "biodegradable" means that the polymer
and/or polymer matrix of the implant will degrade over time by the
action of enzymes, by hydrolytic action and/or by other similar
mechanisms in the human body. By "bioerodible," it is meant that
the implant matrix will erode or degrade over time due, at least in
part, to contact with substances found in the surrounding tissue
fluids, cellular action, and the like. By "bioabsorbable," it is
meant that the polymer matrix will be broken down and absorbed
within the human body, for example, by a cell, a tissue, and the
like.
[0022] Since the implant precursor does not flow like a liquid, it
provides easy manipulation and placement of a liquid polymer system
for forming an implant on a select area of a tissue defect without
the uncontrolled flow of the polymer solution outside the area of
the implant site. The present implant precursor provides a system
for forming an implant with a desired thickness, size, and shape.
Unlike a solid implant, the implant precursor is easy to manipulate
and may be shaped and molded within the defect site as it
solidifies. Advantageously, the moldability of the implant
precursor allows it to conform to irregularities, crevices, cracks,
holes, and the like, in the tissue defect site. In addition, the
surface of the implant precursor is tacky to the touch and tends to
remain in place where it is applied to a tissue defect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a perspective view of an embodiment of a
precursor-forming apparatus of the invention.
[0024] FIG. 2 is a perspective view of the precursor-forming
apparatus of FIG. 1, showing the placement of a series-of spacers
thereon.
[0025] FIG. 3 is a side view of the precursor-forming apparatus of
FIG. 2, showing the placement of the aqueous layers and polymer
solution layer in the area between the spacers.
[0026] FIG. 4 is a side view of the precursor-forming apparatus of
FIG. 3, showing the apparatus in a closed position during formation
of an implant precursor.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provides an implant precursor in the
form of an outer sac with a liquid content for implantation in an
animal. The outer sac of the implant precursor has a firm
consistency ranging from gelatinous to moldable and waxen-like. The
implant precursor is composed of a biodegradable, water-coagulable,
thermoplastic polymer in combination with a water-soluble,
non-toxic organic solvent.
[0028] Upon implantation in the body of an animal, the organic
solvent of the precursor implant dissipates into surrounding tissue
fluids and the polymer coagulates to form a solid, microporous
implant. The resulting solid implant has a variety of uses, as for
example, a barrier system for enhancing cell growth and tissue
regeneration, delivery of biologically-active agents such as drugs
and medicaments, and the like.
Polymer Solution
[0029] To prepare the implant precursor, a liquid polymer solution
is formulated which comprises a biodegradable, water-coagulable,
thermoplastic polymer, such as a polylactide, polycaprolactone,
polyglycolide, or copolymer thereof, in combination with a
water-soluble, non-toxic, organic solvent, such as
N-methylpyrrolidone, as disclosed in U.S. Pat. No. 4,938,763 to
Dunn et al. (issued Jul. 3, 1990), the disclosure of which is
incorporated by reference herein. The polymer solution may
optionally include a pore-forming agent.
[0030] The polymers or copolymers are substantially insoluble in
water and body fluids, and biodegradable and/or bioerodible within
the body of an animal. The implant precursor and resulting solid
implant are biocompatible in that neither the polymer, the solvent
nor the polymer matrix cause substantial tissue irritation or
necrosis at the implant site.
[0031] Thermoplastic Polymers
[0032] Thermoplastic polymers useful in the liquid polymer solution
for forming the implant precursor include
pharmaceutically-compatible polymers that are biodegradable,
bioabsorbable, and soften when exposed to heat but return to the
original state when cooled. The thermoplastic polymers are capable
of substantially dissolving in a water-soluble carrier, or solvent,
to form a solution. The thermoplastic polymers are also capable of
coagulating, or solidifying, to form an outer sac having a firm
consistency ranging from gelatinous to waxen-like, and of
eventually coagulating to a solid microporous matrix upon the
dissipation of the solvent component from the polymer solution, and
the contact of the polymer with an aqueous medium.
[0033] Thermoplastic polymers that are suitable for use in the
polymer solution generally include any having the foregoing
characteristics. Examples are polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthoesters, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malic acid), poly(amino acids),
poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan,
and copolymers, terpolymers, or combinations or mixtures therein.
Polylactides, polycaprolactones, polyglycolides and copolymers
thereof are highly preferred thermoplastic polymers.
[0034] The thermoplastic polymer is combined with a suitable
organic solvent to form a solution. The solubility or miscibility
of a polymer in a particular solvent will vary according to factors
such as crystallinity, hydrophilicity, capacity for
hydrogen-bonding, and molecular weight of the polymer.
Consequently, the molecular weight and the concentration of the
polymer in the solvent are adjusted to achieve desired solubility.
Highly preferred thermoplastic polymers are those that have a low
degree of crystallization, a low degree of hydrogen-bonding, low
solubility in water, and high solubility in organic solvents.
[0035] Solvents
[0036] Suitable solvents for use in the thermoplastic polymer
solution are those which are biocompatible,
pharmaceutically-acceptable, miscible with the polymer ingredient
and water, and capable of diffusing into an aqueous medium, as for
example, tissue fluids surrounding the implant site, such as blood
serum, lymph, cerebral spinal fluid (CSF), saliva, and the like.
Preferably, the solvent has a Hildebrand (HLB) solubility ratio of
from about 9-13(cal/cm.sup.3).sup.1/2. The degree of polarity of
the solvent should be effective to provide at least about 10%
solubility in water, and to dissolve the polymer component.
[0037] Solvents that are useful in the liquid polymer solution
include, for example, N-methyl-2-pyrrolidone, 2-pyrrolidone,
C.sub.2 to C.sub.6 alkanols, propylene glycol, acetone, alkyl
esters such as methyl acetate, ethyl acetate, ethyl lactate, alkyl
ketones such as methyl ethyl ketone, dialkylamides such as
dimethylformamide, dimethyl sulfoxide, dimethyl sulfone,
tetrahydrofuran, cyclic alkyl amides such as caprolactam,
decylmethylsulfoxide, oleic acid, propylene carbonate, aromatic
amides such as N,N-diethyl-m-toluamide,
1-dodecylazacycloheptan-2-one, and the like. Preferred solvents
according to the invention include N-methyl-2-pyrrolidone,
2-pyrrolidone, dimethyl sulfoxide, ethyllactate, and propylene
carbonate.
[0038] A mixture of solvents providing varying degrees of
solubility for the polymer components may be used to increase the
coagulation rate of polymers that exhibit a slow coagulation or
setting rate. For example, the polymer may be combined with a
coagulant-promoting solvent system composed of a mixture of a good
solvent (i.e., solvent providing a high degree of solubility) and a
poorer solvent (i.e., solvent providing a low degree of solubility)
or a non-solvent (i.e., one in which the polymer is insolvent)
relative to the polymer component. It is preferred that the solvent
mixture contain an effective amount of a good solvent and a poorer
or non-solvent, in admixture such that the polymer will remain
soluble while in solution but coagulate upon dissipation or
diffusion of the solvents into surrounding tissue fluids at the
implant site.
[0039] The concentration of polymer in the liquid polymer
composition will generally accomplish rapid and effective
dissipation of the solvent and coagulation of the polymer. This
concentration may range from about 0.01 gram of polymer per ml of
solvent to an about saturated concentration, preferably from about
0.1 gram per ml to an about saturated concentration.
[0040] Upon contact with an aqueous medium such as water, a body
fluid such as blood serum, lymph, and the like, the solvent
diffuses from the polymer solution into the aqueous medium. This
causes the polymer at the surface of the polymer solution and
adjacent the aqueous medium to coagulate to form a two-part
structure comprising an outer sac with a liquid content. The liquid
content of the implant precursor may range in consistency from
watery to viscous. The outer sac may range in consistency from
gelatinous to an impressionable, moldable and waxen-like. The
resulting device, or implant precursor, may then be applied to an
implant site. Upon implantation, the solvent from the implant
precursor diffuses into the surrounding tissue fluids to form an
implant having a solid polymer matrix. Preferably, the implant
precursor solidifies in situ to a solid matrix within about 0.5-4
hours after implantation, preferably within about 1-3 hours,
preferably within about 2 hours.
[0041] Pore-formation and Pore Forming Agents
[0042] When placed into an implant site in an animal, the implant
precursor eventually coagulates to a solid, microporous matrix
structure. Preferably, the matrix is composed of a microporous
inner core portion and an outer microporous skin. The pores of the
inner core portion are preferably substantially uniform and the
skin of the solid implant is essentially non-porous compared to the
porous nature of the core. Preferably, the outer skin portion of
the implant has pores with diameters significantly smaller in size
than these pores in the inner core portion.
[0043] Pores may be formed within the matrix of the implant by
several means. The dissipation, dispersement or diffusion of the
solvent out of the solidifying polymer matrix into the adjacent
tissue fluids may generate pores, including pore channels, in the
polymer matrix. The dissipation of the solvent from the coagulating
mass creates pores within the solid implant. The size of the pores
of the solid implant are in the range of about 1-1000 microns,
preferably the size of pores of the skin layer are about 3-500
microns. The solid microporous implant has a porosity in the range
of about 5-95%.
[0044] Optionally, a pore-forming agent may be included in the
polymer solution to generate additional pores in the polymer
matrix. The pore-forming agent may be any
pharmaceutically-acceptable, organic or inorganic, water-soluble
substance that is substantially soluble in water and body fluids,
and will dissipate from the coagulating polymer matrix and/or the
solid matrix of the implant into surrounding body fluids at the
implant site. The porous matrices formed through the inclusion of a
pore-forming agent have a pore structure in which the pores are
substantially similar in size.
[0045] It is preferred that the pore-forming agent is soluble or
dispersible in the organic solvent to form a uniform mixture with
the polymer, either as a dispersion or suspension, or as a
solution. The pore-forming agent may also be a water-immiscible
substance that rapidly degrades to a water-soluble substance.
Preferably, the pore-forming agent is combined with the
thermoplastic polymer and solvent in admixture, before the matrix
is formed. Suitable pore-forming agents that may be used in the
polymer composition include, for example, sugars such as sucrose
and dextrose, salts such as sodium chloride and sodium carbonate,
polymers such as hydroxylpropylcellulose, carboxymethylcellulose,
polyethylene glycol, and polyvinylpyrrolidone, and the like. Solid
crystals that will provide a defined pore size, such as salt or
sugar, are preferred.
[0046] When the implant precursor is applied to an implant site,
the solvent and/or pore-forming agent dissipates into surrounding
tissue fluids. This causes the formation of microporous channels
within the coagulating polymer matrix. Optionally, the pore-forming
agent may dissipate from the matrix into the surrounding tissue
fluids at a rate slower than that of the solvent, or be released
from the matrix over time by biodegradation or bioerosion of the
matrix. Preferably, the pore-forming agent dissipates from the
coagulating implant matrix within a short time following
implantation such that a matrix is formed with a porosity and pore
structure effective to perform the particular purpose of the
implant, as for example, a barrier system for a tissue regeneration
site, a matrix for timed-release of a drug or medicament, and the
like.
[0047] Porosity of the solid implant matrix may be varied by the
concentration of water-soluble or water-miscible ingredients, such
as the solvent and/or pore-forming agent, in the polymer
composition. For example, a high concentration of water-soluble
substances in the thermoplastic composition may produce a polymer
matrix having a high degree of porosity. The concentration of the
pore-forming agent relative to polymer in the composition may be
varied to achieve different degrees of pore-formation, or porosity,
in the matrix. Generally, the polymer composition will include
about 0.01-1 gram of pore-forming agent per gram polymer.
[0048] The size or diameter of the pores formed in the matrix of
the solid implant may be modified according to the size and/or
distribution of the pore-forming agent within the polymer matrix.
For example, pore-forming agents that are relatively insoluble in
the polymer mixture may be selectively included in the polymer
composition according to particle size in order to generate pores
having a diameter that corresponds to the size of the pore-forming
agent. Pore-forming agents that are soluble in the polymer mixture
may be used to vary the pore size and porosity of the implant
matrix by the pattern of distribution and/or aggregation of the
pore-forming agent within the polymer mixture and coagulating and
solid polymer matrix.
[0049] Where the implant is used to promote guided tissue
regeneration, it is preferred that the diameter of the pores in the
matrix are effective to deter growth of epithelial cells and
enhance growth of connective tissue cells into the polymer matrix
of the implant. It is further preferred that the size of the pores
and porosity of the matrix of the implant facilitate diffusion of
nutrients and other growth-promoting substances such as growth
factors, to cells which have grown into the matrix. Preferably, the
degree of porosity of the matrix provides an implant that is
capable of substantially maintaining structural integrity for the
desired period of time without breakage or fracturing during
use.
[0050] To provide an effective implant for bone cell regrowth and
tissue regeneration, it is preferred that the diameter of the pores
of the implant is about 3-500 microns, more preferably about 3-200
microns, more preferably about 75-150 microns. It is further
preferred that the matrix has a porosity of about 5-95%, preferably
about 25-85%, in order to provide optimum cell and tissue ingrowth
into the matrix and optimum structural integrity.
[0051] Pore diameter and distribution within the polymer matrix of
the solid implant may be measured, as for example, according to
scanning electron microscopy methods by examination of
cross-sections of the polymer matrix. Porosity of the polymer
matrix may be measured according to suitable methods known in the
art, as for example, mercury intrusion porosimetry, specific
gravity or density comparisons, calculation from scanning
electronic microscopy photographs, and the like. Additionally,
porosity may be calculated according to the proportion or percent
of water-soluble material included in the polymer composition. For
example, a polymer composition which contains about 30% polymer and
about 70% solvent and/or other water-soluble components will
generate an implant having a polymer matrix of about 70%
porosity.
[0052] Biologically-active Agent
[0053] Optionally, the polymer solution may include a
biologically-active agent, either singly or in combination, such
that the implant precursor and implant will provide a delivery
system for the agent to adjacent or distant tissues and organs in
the animal. Biologically-active agents which may be used alone or
in combination in the implant precursor and implant include, for
example, a medicament, drug, or other suitable biologically-,
physiologically-, or pharmaceutically-active substance which is
capable of providing local or systemic biological, physiological or
therapeutic effect in the body of an animal including a mammal, and
of being released from the solid implant matrix into adjacent or
surrounding tissue fluids.
[0054] The biologically-active agent may be soluble in the polymer
solution to form a homogeneous mixture, or insoluble in the polymer
solution to form a suspension or dispersion. Upon implantation, the
biologically-active agent preferably becomes incorporated into the
implant matrix. As the matrix degrades over time, the
biologically-active agent is released from the matrix into the
adjacent tissue fluids, preferably at a controlled rate. The
release of the biologically-active agent from the matrix may be
varied, for example, by the solubility of the biologically-active
agent in an aqueous medium, the distribution of the agent within
the matrix, the size, shape, porosity, solubility and
biodegradability of the implant matrix, and the like.
[0055] The polymer solution, implant precursor and implant include
the biologically-active agent in an amount effective to provide the
desired level of biological, physiological, pharmacological and/or
therapeutic effect in the animal. There is generally no critical
upper limit on the amount of the bioactive agent included in the
polymer solution. The only limitation is a physical limitation for
advantageous application, i.e., the bioactive agent should not be
present in such a high concentration that the solution or
dispersion viscosity is too high for injection. The lower limit of
the amount of bioactive agent incorporated into the polymer
solution will depend on the activity of the bioactive material and
the period of time desired for treatment.
[0056] The biologically-active agent may stimulate a biological or
physiological activity with the animal. For example, the agent may
act to enhance cell growth and tissue regeneration, function in
birth control, cause nerve stimulation or bone growth, and the
like. Examples of useful biologically-active agents include a
substance, or metabolic precursor thereof, which is capable of
promoting growth and survival of cells and tissues, or augmenting
the functioning of cells, as for example, a nerve growth promoting
substance such as a ganglioside, a nerve growth factor, and the
like; a hard or soft tissue growth promoting agent such as
fibronectin (FN), human growth hormone (HGH), protein growth factor
interleukin-1 (IL-1), and the like; a bone growth promoting
substance such as hydroxyapatite, tricalcium phosphate, and the
like; and a substance useful in preventing infection at the implant
site, as for example, an antiviral agent such as vidarabine or
acyclovir, an antibacterial agent such as a penicillin or
tetracycline, an antiparasitic agent such as quinacrine or
chloroquine.
[0057] Suitable biologically-active agents for use in the invention
also include anti-inflammatory agents such as hydrocortisone,
prednisone and the like; anti-bacterial agents such as penicillin,
cephalosporins, bacitracin and the like; antiparasitic agents such
as quinacrine, chloroquine and the like; antifungal agents such as
nystatin, gentamicin, and the like; antiviral agents such as
acyclovir, ribarivin, interferons and the like; antineoplastic
agents such as methotrexate, 5-fluorouracil, adriamycin,
tumor-specific antibodies conjugated to toxins, tumor necrosis
factor, and the like; analgesic agents such as salicylic acid,
acetaminophen, ibuprofen, flurbiprofen, morphine and the like;
local anaesthetics such as lidocaine, bupivacaine, benzocaine and
the like; vaccines such as hepatitis, influenza, measles, rubella,
tetanus, polio, rabies and the like; central nervous system agents
such as a tranquilizer, B-adrenergic blocking agent, dopamine and
the like; growth factors such as colony stimulating factor,
platelet-derived growth factor, fibroblast growth factor,
transforming growth factor B, human growth hormone, bone
morphogenetic protein, insulin-like growth factor and the like;
hormones such as progesterone, follicle stimulating hormone,
insulin, somatotropins and the like; antihistamines such as
diphenhydramine, chlorphencramine and the like; cardiovascular
agents such as digitalis, nitroglycerine, papaverine, streptokinase
and the like; anti-ulcer agents such as cimetidine hydrochloride,
isopropamide iodide, and the like; bronchodilators such as
metaproternal sulfate, aminophylline and the like; vasodilators
such as theophylline, niacin, minoxidil, and the like; and other
like substances. For other examples of biologically-active agents
that may be used in the present invention, see Applicants'
corresponding U.S. patent application Ser. No. 07/783,512, filed
Oct. 28, 1991, the disclosure of which is incorporated by reference
herein.
[0058] Accordingly, the formed implant may function as a delivery
system of drugs, medicaments and other biologically-active agents
to tissues adjacent to or distant from the implant site. The
biologically-active agent is preferably incorporated into the
polymer matrix, and subsequently released into surrounding tissue
fluids and to the pertinent body tissue or organ.
[0059] Control of Release of the Bioactive Agent
[0060] The rate of breakdown of the implant and/or release of a
bioactive agent in vivo may be controlled by varying the type and
molecular weight of the polymer(s), by including a release rate
modification agent, and/or varying the combination and
concentrations of ingredients that comprise the polymer
solution.
[0061] The rate of release of a bioactive agent from the implant
matrix may be modified by varying the molecular weight of the
polymer included in the polymer solution. It has been found that
for implant matrices formed through intermediacy of the foregoing
liquid polymer solution, the release rate of a bioactive agent
follows a "U" shaped curve as the molecular weight of the polymer
increases. That is, the rate of release of the bioactive agent will
decrease, pass through a minimum, and then again increase as the
molecular weight of a polymer is increased. As a result, a polymer
solution can be formulated with an optimum polymer molecular weight
range for the release of a bioactive substance over a selected
length of time. For example, to achieve a relatively quick release
of a bioactive agent from the implant matrix, a polymer molecular
weight on either side of the minimum for that particular polymer
would be used in the polymer solution. For release of a bioactive
agent over a relatively long period of time, a polymer molecular
weight at or about the minimum for the particular polymer would be
preferred.
[0062] With the present polymer system, the typical minimum rate of
release of a bioactive agent from the solid implant matrix occurs
at an inherent viscosity (I.V. in deciliters/gm) of about 0.2 but
can vary depending on the ingredients of the polymer solution. To
achieve a sustained release of the bioactive agent from the implant
matrix, it is preferred to adjust the molecular weight of the
polymer to at least about 0.1 inherent viscosity (I.V.) or about
2,000 molecular weight as determined by gel permeation
chromatography (comparison to polystyrene). Typically, acceptable
sustained release rates are obtained if the molecular weight of the
polymer is below about 0.8 I.V., or a molecular weight of about
100,000. More preferably, the molecular weight is adjusted to be
within a range of about 0.1-0.5 I.V., for effective sustained
release. For a poly(DL-lactide) or a lactide-co-glycolide system,
the desired molecular weight range is about 0.1-0.5 I.V. If a
molecular weight of a specific polymer is chosen from these
parameters and the release of the bioactive substance is too slow
or too fast, the rate can be varied simply by determining a few
experimental points along the U curve for that polymer and
adjusting the molecular weight accordingly.
[0063] The molecular weight of a polymer can be varied by any of a
variety of methods known in the art. The choice of method is
typically determined by the type of polymer solution being
formulated. For example, if a thermoplastic polymer is used that is
biodegradable by hydrolysis, the molecular weight can be varied by
controlled hydrolysis, such as in a steam autoclave. Typically, the
degree of polymerization can be controlled, for example, by varying
the number and type of reactive groups and the reaction times.
[0064] For other examples and further discussion of controlling the
rate of release of a bioactive agent from the implant matrix by
varying the polymer composition of the polymer solution, see
Applicants' corresponding U.S. patent application Ser. No.
07/776,816, filed Oct. 15, 1991, the disclosure of which is
incorporated by reference herein.
[0065] Release Rate Modification Agents
[0066] The polymer solution may include a release rate modification
agent to provide controlled, sustained release of a bioactive agent
from the solid implant matrix. Although not intended to be a
limitation to the present disclosure, it is believed the release
rate modification agent alters the release rate of a bioactive
agent from the implant matrix by changing the hydrophobicity of the
polymer implant.
[0067] The use of a release rate modification agent may either
decrease or increase the release of the bioactive agent in the
range of multiple orders of magnitude (e.g., 1 to 10 to 100),
preferably up to a ten-fold change, as compared to the release of a
bioactive agent from a solid matrix without the release rate
modification agent. For example, naltrexone and doxycycline are
substantially completely released from a polymer matrix comprised
of poly(DL-lactide) within about 2-3 days ex vivo. With the
addition of a release rate modification agent such as ethyl
heptanoate which is hydrophobic to the polymer solution, and
formation of the implant matrix through interaction of the polymer
solution and an aqueous medium, the release rate of naltrexone or
doxycycline can be slowed to produce substantially complete release
of the drug within about seven days. With the inclusion of a
greater amount of a release rate modification agent into the
polymer solution, the time period of the release can be increased
to about fourteen days. Other release rate modification agents
which are hydrophilic such as polyethylene glycol may increase the
release of the bioactive agent. By an appropriate choice of the
polymer molecular weight in combination with an effective amount of
the release rate modification agent, the release rate and extent of
release of a bioactive agent from the implant matrix may be varied,
for example, from relatively fast to relatively slow.
[0068] Useful release rate modification agents include, for
example, organic substances which are water-soluble,
water-miscible, or water insoluble (i.e., water immiscible), with
water-insoluble substances preferred.
[0069] The release rate modification agent is preferably an organic
compound which will substitute as the complementary molecule for
secondary valence bonding between polymer molecules, and increases
the flexibility and ability of the polymer molecules to slide past
each other. Such an organic compound preferably includes a
hydrophobic and a hydrophilic region so as to effect secondary
valence bonding. It is preferred that a release rate modification
agent is compatible with the combination of polymers and solvent
used to formulate polymer solutions It is further preferred that
the release rate modification agent is a
pharmaceutically-acceptable substance.
[0070] Useful release rate modification agents include, for
example, fatty acids, triglycerides, other like hydrophobic
compounds, organic solvents, plasticizing compounds and hydrophilic
compounds. Suitable release rate modification agents include, for
example, esters of mono-, di-, and tricarboxylic acids, such as
2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl
phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate,
dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl
citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol
triacetate, di(n-butyl) sebecate, and the like; polyhydroxy
alcohols, such as propylene glycol, polyethylene glycol, glycerin,
sorbitol, and the like; fatty acids; triesters of glycerol, such as
triglycerides, epoxidized soybean oil, and other epoxidized
vegetable oils; sterols, such as cholesterol; alcohols, such as
C.sub.6-C.sub.12 alkanols, 2-ethoxyethanol, and the like. The
release rate modification agent may be used singly or in
combination with other such agents. Suitable combinations of
release rate modification agents-include, for example,
glycerin/propylene glycol, sorbitol/glycerine, ethylene
oxide/propylene oxide, butylene glycol/adipic acid, and the like.
Preferred release rate modification agents include dimethyl
citrate, triethyl citrate, ethyl heptanoate, glycerin, and
hexanediol.
[0071] The amount of the release rate modification agent included
in the polymer solution will vary according to the desired rate of
release of the bioactive agent from the implant matrix. Preferably,
the polymer solution contains about 0.5-15%, preferably about
5-10%, of a release rate modification agent.
[0072] For other examples and further discussion of release rate
modification agents, or rate modifying agents, for use in the
present invention, see Applicants' corresponding U.S. patent
application Ser. No. 07/776,816, filed Oct. 15, 1991, the
disclosure of which is incorporated by reference herein.
Other Factors for Release Rate Modification
[0073] The release rate of the bioactive agent from the implant
matrix may also be adjusted by varying the concentration of the
polymer in the polymer solution. For example, the more dilute the
polymer concentration, the more readily the bioactive agent will be
released from the implant matrix. For example, in a system
containing about 5% flurbiprofen and a polymer concentration of
about 55% poly(DL-lactide), cumulative release of about 11.4% at
day 1 and about 23% day 7 may be provided. With a polymer
concentration of about 45%, the cumulative percent release is about
23% at day 1 and about 40% at day 7.
[0074] This effect can be used in combination with other means to
more effectively control the release of the bioactive agent from
the implant matrix as desired. For example, by adjusting the
concentration of the polymer and/or the bioactive agent, together
with control of the molecular weight and the amount of the release
rate modification agent, a wide range of release rates can be
achieved.
[0075] The release rate of a bioactive agent from the implant
matrix may also be varied by the addition of additives such as a
pore forming agent, as discussed herein.
Formation of the Implant Precursor
[0076] A number of methods may be used to form the implant
precursor. In general, the implant precursor is formed by
dispensing a portion of the liquid polymer solution onto the
surface of a support substrate. An aqueous medium is then placed in
contact with the polymer solution. Solvent then diffuses out of the
polymer solution and the aqueous medium diffuses into the solution.
This causes coagulation of the polymer adjacent to the aqueous
medium to form the outer sac of the implant precursor.
[0077] Suitable support substrates include, for example, hard or
soft tissue of the animal or an ex vivo material, as for example,
glass, stainless steel, porcelain, solid plastic or porous plastic.
These ex vivo materials may optionally have either an attached
layer of a different material, such as a nylon filter, or a coating
or a surface treatment or an additive that allows the support to
absorb or wick an aqueous medium. Aqueous media can be blood,
saliva or other body fluids when the substrate is in the animal.
Aqueous media which can be used either in vivo or ex vivo included
water and saline solutions. Other aqueous media can be used if they
cause coagulation of the polymer solution and are clinically
acceptable.
[0078] The aqueous medium can be present at the surface of the
support substrate or inside the support substrate prior to the
dispensing of the polymer solution or the aqueous medium can be
applied on top and around the polymer solution after it is in
place. In this last case coagulation of the bottom surface of the
polymer solution requires the aqueous medium to travel underneath
the polymer solution.
[0079] The amount of aqueous medium used and the time that the
polymer solution and aqueous medium are held in contact depends on
the composition of the polymer solution and the aqueous medium, the
nature of the support substrate, the geometry of the apparatus, the
amount and dimensions of the polymer solution and the consistency
desired for the implant precursor. For a given procedure and set of
materials the consistency of the implant precursor can be varied
from gelatinous to formable and impression-retaining to fairly
rigid by increasing the time the polymer solution and aqueous
medium are in contact.
[0080] After the implant precursor has been formed, the aqueous
medium may be removed by tipping the support and/or the implant
precursor to allow the aqueous layer to run off or by blotting the
aqueous layer with an absorbent material such as a cotton swab,
gauze pad or a sponge. The implant precursor may optionally then be
trimmed to the desired size and shape and then placed in the
implant site. It is trimmed and implanted into the animal within
about 1 to 60 minutes, preferably 1 to 10 minutes, of the
conclusion of the coagulation process. If not implanted or placed
back into contact with an aqueous medium, the implant precursor
will soften and eventually revert to an all liquid phase. This
process is caused by an interaction between the outer sac layer and
the liquid contents. The solvent and aqueous medium redistribute in
the implant precursor which destroys the sac formed in the
coagulation process and results in one continuous liquid phase.
[0081] The dimensions of the implant precursor can be controlled by
a number of methods. It is preferred that the thickness of the
implant precursor is about 300-1500 .mu.m, preferably about
600-1200 .mu.m. The length and width desired depend on the
dimensions of the implant site in the animal. In the preferred
methods the thickness is controlled during the coagulation process
and the length and width are controlled in a subsequent trimming
step. The polymer solution is dispensed onto a flat support
substrate and a second flat piece of support substrate is placed on
top of the polymer solution and forced down causing the polymer
solution to thin out and spread until the desired gap between the
support substrates is obtained. This gap may be defined by spacers
which hold the support substrate pieces apart or other means. The
aqueous medium may be present during this process or applied after
this process. The coagulation of the polymer solution in this
defined space results in a sheet of implant precursor material with
a center section of substantially uniform thickness with thinner
portions at the edges. The implant precursor is then cut out of the
center section of the sheet using a razor blade, surgical prep
blade, scalpel or other means. This trimming step allows control of
the implant precursor length, width and shape.
[0082] Alternate methods of controlling the dimensions of the
implant precursor include dispensing the polymer solution onto a
support substrate on which the desired area (i.e., width, length)
have been defined by some type of barrier. They can be then
controlled as previously described or by drawing a flat article
such as a spatula across the surface of the coagulating polymer
mass or like means. The polymer solution may also be dispensed into
a recessed area or void as, for example, in a pre-cast die or mold
or template, or other like device, which has the dimensions (i.e.,
width, length, depth or thickness) of the implant precursor.
Additional amounts of the polymer solution may be applied to the
surface(s) or edges of the coagulating polymer mass to adjust the
dimensions.
[0083] Various devices may be used to form the implant precursor.
One such device, which may be used ex vivo or in vivo, is a
"tweezer wiper". A "tweezer wiper" is constructed by attaching a
plate with a hole or a wire loop to one blade of the tweezer at a
right angle to the tweezer blades such that the second blade sweeps
across the surface of the plate or wire loop when the tweezer
blades are spread apart. The plate or wire loop is placed on the
tissue or ex vivo support substrate os that the hole in the pate or
the inside of the wire loop defines the area for the implant
precursor. The polymer solution is then dispensed into this area
and leveled off to control the thickness by passing the second
blade of the tweezer over the polymer solution. An aqueous medium
is then applied to cause coagulation. Alternatively, the aqueous
medium is applied prior to the leveling procedure. Once the implant
precursor is sufficiently coagulated the "tweezer wiper" is
separated from the substrate. The resulting implant precursor can
then be left in place in the in vivo case or otherwise used
according to the method of the invention.
[0084] In another embodiment of the invention, an implant precursor
may be formed in vivo or ex vivo by forming a boundary line on the
surface of the support substrate to contain the polymer solution
within a confined area. To form the boundary line on a substrate,
an amount of water or other aqueous medium is applied as a coating
on the surface of the support substrate, the polymer solution is
dispensed as a line over the water layer to define a confined area,
and an amount of water is then applied to the surface of the
polymer solution resulting in surface coagulation of the polymer
solution. The resulting boundary line is a two-part, tube-like
structure made of an outer sac with a liquid center. An implant
precursor may then be formed within the confines of the boundary
line by dispensing an amount of the polymer solution onto an
aqueous layer coated on the support substrate within the boundary
line area, and applying an aqueous medium to the polymer layer to
form the two-part structure of the implant precursor. Where the
boundary line is formed in vivo on the surface of a tissue defect,
an implant precursor formed ex vivo may also be applied to the
defect within the area defined by the boundary line. It is
preferred that the implant precursor and associated boundary line
are manually worked together as the polymer further coagulates to
form the solid implant matrix such that the coagulating mass will
conform to the contours of the tissue defect and implant site.
Preferably, when treating a periodontal bone tissue defect by this
method, the boundary line is applied to the root and ligament
tissue of the bone defect site.
[0085] Implant Precursor-forming Apparatus
[0086] According to the invention, a preferred method for making an
implant precursor ex vivo is by the use of an apparatus, as shown
generally in FIG. 1. It is understood, however, that a variety of
shapes, sizes and arrangements of the implant precursor-forming
apparatus can be accommodated according to the invention.
[0087] FIG. 1 is a schematic drawing of the preferred apparatus
design, shown closed as it would be during the coagulation process.
The apparatus consists of a case which consists of upper and lower
sections (1 and 2) held together by a hinge (3) on one end and a
latching mechanism (4 and 5) on the other end. Each section
contains a sheet of porous hydrophilic plastic (6 and 7). When the
case is closed the two sheets of porous hydrophilic plastic (6 and
7) are held apart by the spacers (8 and 9) as shown in FIG. 1. This
apparatus is used by opening the case and filling the pores in the
porous hydrophilic plastic sheets (6 and 7) with an aqueous medium.
The polymer solution is then dispensed onto the porous hydrophilic
plastic sheet in the lower half of the case (7) and the case is
closed as shown in FIG. 1. The spacers (8 and 9) define the gap in
which the polymer solution is held during the coagulation process
and therefore control the thickness of the implant precursor. Once
the desired coagulation has elapsed the case is opened and the
implant precursor is trimmed and then implanted.
[0088] FIG. 2 details the preferred embodiment of the general
apparatus design shown in FIG. 1. The components are labeled with
the same numbers as in FIG. 1. This embodiment contains one section
(10) which is not present in FIG. 1. It is a trimming grid which is
a portion of the case bottom (2). The case consists of an upper and
lower section (1 and 2) joined with a hinge (3) formed by snapping
the two case sections together. The case is composed of a gamma
resistant polypropylene. Alternate case materials which can
withstand contact with the polymer solution and sterilization by
gamma irradiation and are fairly rigid could be used. The latch
mechanism is composed of portions (4 and 5) of the two case
sections (1 and 2) which readily snap together and apart to allow
opening and closing of the case and hold the case tightly closed
during the coagulation process. The hydrophilic porous plastic
sheets (6 and 7) are flat, rigid sheets with the hydrophilicity and
porosity needed to allow an aqueous medium to fill the pores of the
sheet and then allow exchange of the aqueous medium and the solvent
between the polymer solution and aqueous medium and the solvent
between the polymer solution and aqueous medium in the pores during
the coagulation process. The porosity of the sheet is one factor
which controls the rate of coagulation. The porous plastic may be
of an intrinsically hydrophilic polymer or a blend of a hydrophobic
polymer blended with or treated with a surfactant or other agent
which increases hydrophilicity. THe material used in the preferred
embodiment is a polyethylene blended with a surfactant. The spacers
(8 and 9) are rectangles of gamma resistant polypropylene.
[0089] The trimming grid (10) is a flat portion of the lower case
section (2). After the coagulation process the implant precursor is
placed on the trimming grid where it is trimmed to the desire
shape, length and width using a surgical prep blade, razor blade or
other like means. The trimming grid has a pattern of 1 mm squares
which aid in trimming to the desired dimensions. This pattern may
be present as part of the case itself or printed onto the case or
printed on a label which is then affixed to the case. In the
preferred embodiment the pattern is printed on a clear label which
is affixed to the underside of the case bottom (2). The pattern is
visible through the clear to slightly hazy case bottom (2) and the
clear label material. Having the label or printing on the underside
of the case eliminates the possibility of physical or chemical
interaction of the implant precursor and the label or printing.
[0090] The dimensions of the apparatus are dependent on the desired
dimensions of the implant precursor. For production of an implant
precursor of an approximate thickness of 675 .mu.m with a length
and width of approximately 20 mm or less the following approximate
dimensions are appropriate. The spacers (8 and 9) are 675 .mu.m
thick, 0.5 cm wide and 2.5 cm long. The porous plastic sheets are
4.5 cm long and 3.0 cm wide with a thickness of 0.3 cm. The
trimming grid pattern (10) is 3.5 cm by 3.5 cm. The case sections
(1 and 2) are approximately 7.5 cm by 5 cm with cavities for the
porous plastic sheets (6 and 7) 30 cm deep. For proper thickness
control the case must be designed to close such that the spacers (8
and 9) are tightly held between two porous plastic sheets (6 and 7)
so that the coagulation occurs in a gap which corresponds to the
thickness of the spacers.
[0091] Adhesive Layer
[0092] To enhance adhesion of the implant precursor in the implant
site, an adhesive layer may be applied to the surface of the tissue
and the formed implant precursor is then placed over the support
layer. The adhesive layer preferably helps to maintain the position
of the implant precursor as it coagulates to a solid matrix in the
implant site. The adhesive layer comprises a bioabsorbable,
biodegradable and/or bioerodible substance capable of adhering to
both the surface of the tissue defect and to the surface of the
implant precursor. An adhesive layer may be formed, for example, by
applying a minor but effective amount of the foregoing liquid
polymer solution in the form of a bead or as a coating on the
surface of the tissue defect.
[0093] Support Layer
[0094] To maintain the structure and form of the implant precursor
or to form the implant precursor directly in vivo, a support layer
may be applied to the surface of the tissue and the polymer
solution or formed implant precursor is then placed over the
support layer. Materials suitable for use in forming a support
layer include, for example, a natural body material such as a clot
of blood or other body fluid, a water-soluble substance such as
gelatin or water-soluble polymer, as for example, polyvinyl
pyrrolidone, and other like materials.
[0095] A support layer of clotted blood may be formed, for example,
by puncturing the tissue with a needle to generate a minor but
effective flow of blood which is then allowed to clot. A formed
implant precursor, or the liquid polymer solution itself may be
applied to the surface of the support layer in the implant
site.
[0096] In another embodiment, granules or small pieces of a
biodegradable porous material such as polylactic acid, oxidized
cellulose or gelatin and the like, may be used to fill in a tissue
defect or void, and then a formed implant precursor may be applied
to the granular support material, or the polymer solution may be
dispensed over the support layer to form the implant precursor.
[0097] Another useful support layer is a solid matrix having a
porous, foam-like structure. Such a matrix may be provided, for
example, by mixing air into the foregoing polymer solution to
provide a foam-like consistency, and allowing the mixture to
coagulate to a matrix having relatively large pores and/or
cavities. Air bubbles may be incorporated into the polymer
solution, for example, by vigorous stirring the polymer solution,
by blowing air into the solution using a syringe, and other like
means. It is preferred that an aqueous medium is applied to the
surface of the foamed mixture to cause the polymer to coagulate to
form a matrix having large cavities.
[0098] Large pores may also be provided in a solid support matrix
by combining the polymer solution with a gas-forming agent, as for
example, a mixture of citric acid and sodium carbonate or
bicarbonate. When contacted with an aqueous medium, the gas-forming
agent reacts to form gas bubbles such as carbon dioxide within the
coagulating polymer matrix.
[0099] Where a void space is desirable between the tissue defect
and the solid implant, the support layer is preferably formed of a
water-soluble, and/or a highly resorbable material. For example,
the support layer may comprise a water-soluble substance that will
dissolve within a few days, as for example an oxidized cellulose or
gelatin material such as Surgicel.TM. or Gelfoam.TM., commercially
available from Johnson & Johnson Company and the Upjohn
Company; a water-soluble polymer such as polyvinyl pyrrolidone,
polyethylene glycol, and hydroxypropyl cellulose, and the like; and
other like substances. Preferably, the water-soluble support layer
will dissolve within about 1-14 days, preferably about 2-4 days,
after implantation of the implant precursor.
[0100] In cases where it is desired to promote tissue ingrowth into
a substrate in the implant site, it is preferred that the support
layer comprises a porous material which has a relatively longer
rate of degradation. Suitable materials include, for example, a
polylactic acid material typically applied to molar extraction
sites to inhibit dry sockets, as for example, Drilac.TM. which is
commercially available from THM Biomedical, Inc. and a
hydroxyapatite material such as Interpore 200 which is commercially
available from Interpore International. Advantageously, a support
layer made of a porous material such as polylactic acid or
hydroxyapatite, allows the blood to infiltrate and clot within the
matrix which provides a source of nutrients to promote tissue
ingrowth. It is noted that tissue ingrowth into the support matrix
will eventually break down the support layer.
[0101] Kit for Forming an Implant Precursor
[0102] The invention also includes a kit for forming an implant
precursor ex vivo. The kit includes, in combination, (i) a
precursor-forming apparatus, as described hereinabove, which is
preferably a two-part apparatus hinged along one side; (ii) one or
more spacer means for maintaining a gap or space between the two
halves of the apparatus, for example, a washer, rod, block, and the
like; (iii) one or more vials or other like means containing the
aforedescribed polymer solution; and (iv) one or more vials or
other like means containing a source of aqueous medium such as
water, phosphate buffered saline, and the like. The kit may further
include a tweezers or other like means for lifting and holding the
formed implant precursor; a device for measuring the dimensions of
the tissue defect and/or the implant precursor, as for example, a
calibrated tweezers and the like; a gridded template and other like
means for measuring the dimensions of the implant precursor; a
scalpel, razor blade or other like means for trimming and sizing
the implant precursor; and/or a cotton pad or like other means for
removing the aqueous medium from the surface of the implant
precursor.
Use of the Implant Precursor
[0103] The implant precursor may be used for treating a variety of
tissue defects. The implant precursor may be applied to an implant
site in an animal, such as a void, a defect, surgical incision, and
the like, in a hard or soft tissue, by known surgical
techniques.
[0104] Preferably, once placed in the implant site, the implant
precursor will be substantially coagulated to a solid but moldable
matrix, within about 0.5-4 hours, more preferably about 0.75-3
hours, even more preferably about 1-2 hours.
[0105] For example, the implant precursor may be used in a method
for treating a bone tissue defect such as an arm or leg bone
fracture, a tooth defect, and the like. Preferably, the bone tissue
is surgically separated from the adjacent soft tissue to expose the
defect, and the implant precursor is placed into the bone defect,
whereupon the implant precursor hardens in situ to a solid
implant.
[0106] In a preferred use according to the invention, the implant
precursor may be used as a barrier system for guided tissue
regeneration. The implant precursor may be formed outside the body
of the animal and then administered to an implant site such as a
tissue with a void such as a periodontal pocket, a soft-tissue
defect, a surgical incision, a bone defect and the like. Once
administered to the tissue regeneration site, the implant precursor
will solidify to form a solid, microporous matrix that provides a
surface over which the cell may grow. To enhance regeneration of a
hard tissue such as bone tissue, it is preferred that the solid
implant matrix provides support for new cell growth that will
replace the matrix as it becomes gradually absorbed or eroded by
body fluids.
[0107] One example of using the implant precursor as a barrier
system is in the treatment of a periodontal disease. For such
treatment, the gingival tissue overlying the root of the tooth is
surgically incised from the tooth root and bone to form a gingival
tissue envelope or pocket, and an implant precursor is placed into
the pocket and against the bone. After placement, the tissue is
sutured to close the pocket, and the implant precursor is allowed
to harden to a solid, microporous implant.
[0108] The implant precursor may be manipulated in the implant site
to conform it to the contours of the tissue defect. For example, in
a periodontal defect, the gingival tissue flap may be urged over
the solidifying implant matrix placed against the exposed root and
bone, and pressure applied to the surface of the overlying tissue
onto the solidifying matrix. The solidifying matrix is malleable
and such manipulation shapes the implant on one side to conform to
the tissue defect and on the other side to the contours of the
overlying tissue. The tissue may be retracted to assess the profile
(i.e., shape) of the implant matrix and, optionally, additional
amounts of the polymer solution may be added to build up the matrix
and fill in irregularities as needed. In cases where the implant
precursor is too large, a portion of the congealing matrix may be
cropped along the edges of the overlying tissue, as for example,
just above the gum line of a gingival tissue pocket. The tissue may
then be secured in place over the implant matrix, as for example,
by suturing the tissue at either end of the pocket to hold the
tissue and implant in place.
[0109] To aid in the adhesion of the implant precursor to the
surface of the tissue defect, a bead or coating of the foregoing
polymer solution may be applied over the defect to provide a tacky
surface. The implant precursor or liquid polymer solution may then
be applied to the surface of bead or coating.
[0110] The implant precursor may be used for attaching a skin graft
to underlying tissue of a wound; and such use of the implant
precursor helps prevent seroma or hematoma formation, and speed the
healing process. Preferably, the implant precursor includes a
topical antibiotic agent.
[0111] The implant precursor may also be used to enhance closure of
a surgical incision as, for example, an incision through the
sternum for open heart surgery, by stabilizing the sternum and
promoting healing. In such use, the implant precursor is applied to
the two sides of the sternum prior to closure of the sternum with
metal wires and/or sutures. Preferably, the implant precursor
includes a growth factor and/or an antibiotic agent.
[0112] Advantageously, the implant precursor provides a means of
adhering an implant article to a tissue generally covered with a
mucous layer, as for example, a gingival tissue. Also, the implant
precursor provides for the application of a liquid polymer solution
in an implant site without the uncontrolled flow of liquid into
areas other than those identified for treatment. For example, in
the treatment of a periodontal defect, use of the present implant
precursor will advantageously avoid the accumulation of a polymer
solution into spaces between tooth roots and the periodontal region
where the ligament cells are located. The present precursor implant
also facilitates a better match of a barrier implant in a tissue
defect site than other devices known and used in the art.
[0113] The microporous polymer matrix of the implant is capable of
biodegradation, bioerosion and/or bioabsorption within the implant
site of the animal. The particular polymer and the molecular weight
of the polymer may be varied according to the desired duration or
time interval for maintaining the solid polymer matrix within the
implant site, as for example, a few days or weeks to several years.
When the implant is used to enhance cell growth and tissue
regeneration, it is preferred that the polymer matrix will
disintegrate at a rate effective to allow displacement of the
matrix by cell growth from the adjacent cells or tissue.
[0114] Formulation of the liquid polymer solution for preparing the
implant precursor, and administration of the implant precursor and
polymer solution in vivo will ultimately be according to the
judgment and protocol of the patient's attending health care
professional such as a physician, or if appropriate, a dentist.
Choice of the particular formulation of ingredients will be made by
the attending health care professional. Without a bioactive agent,
the solid implant resulting from the implant precursor can function
as a structure for promotion of cell growth and tissue repair. With
a bioactive agent, the implant will not only function in such
capacity but will also convey the properties of the bioactive
agent.
[0115] The amounts and concentrations of ingredients in implant
precursor administered to the patient will generally be effective
to accomplish the task intended. If that task is to fill a void
space, an implant precursor of an appropriate size and an effective
amount of ingredients will be administered to accomplish this task.
For administration of a bioactive agent, the amounts and release
rates will follow recommendations of the manufacturer of the
bioactive agent. Generally, the concentration of a bioactive agent
in the liquid polymer solution will be about 0.01-400 mg per gram
of polymer solution.
[0116] The invention will be described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
EXAMPLE 1
Ex vivo Formation of an Implant Precursor with a Porous
Polyethylene Substrate
[0117] A polymer mixture comprising about 37%
poly(DL-lactide)(DL-PLA) and about 63% N-methyl-2-pyrrolidone (NMP)
was prepared. The DL-PLA had a molecular weight of about 65,000
daltons (inherent viscosity in chloroform of about 0.50 dL/g).
Polypropylene containers were filled with this polymer mixture such
that each contained about 0.8 g of the polymer mixture. These
filled containers were then sterilized by exposure to gamma
radiation at a level of 25-35 kGy, which result in a final
molecular weight of the DL-PLA of about 38,000 daltons (inherent
viscosity in chloroform of about 0.34 dL/g).
[0118] The apparatus diagrammed in FIG. 2 was used to form an
implant precursor from the liquid polymer mixture. The porous
polyethylene-substrates on each side of the case were saturated
with about 2.5 mL of sterile saline. Two polypropylene spacers were
placed on the porous polyethylene substrate on the lower half of
the case (nearest to the trimming grid) such that they were
parallel to the hinge of the case and against the edges of the
porous polyethylene substrate. A filled container of the polymer
mixture was opened, and the contents (approximately 0.6 g) were
expelled onto the center of the porous polyethylene substrate
between the spacers. The case was closed and latched, and was then
reopened after six minutes. The semi-rigid article was removed from
the porous polyethylene substrate, placed onto the attached
trimming area, and trimmed to size using a sterile razor blade.
[0119] The implant precursor was examined visually; it was opaque,
semi-rigid, and flexible. The implant precursor had a two-part
structure which consisted of a gelatinous, semi-rigid outer layer
and a more liquid center core. Chemical analysis indicated that the
implant precursor contained about 58% NMP.
EXAMPLE 2
In Vitro Formation of an Implant Precursor
[0120] An implant precursor was formed as in Example 1 above,
except that the case remained closed for eight minutes. This
article was more rigid than the article from Example 1 above.
EXAMPLE 3
In Vitro Formation of an Implant Precursor
[0121] An implant precursor was formed as in Example 1 above,
except that the case remained closed for four minutes. This article
was less rigid than the article from Example 1 above.
EXAMPLE 4
In Vitro Formation of an Implant Precursor with a Glass
Substrate
[0122] Two spacers with approximate thicknesses of 430 .mu.m were
constructed by gluing two sets of three glass microscope cover
slips together. These were placed on a glass microscope slide
leaving a space between them. Approximately 0.3 g of the same
polymer mixture as in Example 1 was then dispensed onto the
microscope slide between the spacers using a syringe. An atomizer
was used to spray the polymer mixture with water three times. After
30 seconds the water spraying was repeated. After an additional 30
seconds, another microscope slide was sprayed with water and then
pressed onto the coagulating polymer mass and the spacers. This
second microscope slide was held in place for 60 seconds and then
removed. The coagulating polymer mass was then sprayed with water
three times and allowed to set for 60 seconds. The three water
sprays and 60 second set was then repeated. The glass microscope
slide and the coagulating polymer mass were then placed over a grid
of 1 mm squares. A sterile razor blade was then used to trim the
polymer mass to the desired size and shape. The cut piece was then
sprayed with water three times and allowed to set for 60 seconds.
The excess water was then removed using a gauze pad. The opaque and
flexible implant precursor was then ready for implantation.
EXAMPLE 5
In Vitro Formation of an Implant Precursor with a Glass
Substrate
[0123] A 2 inch.times.3 inch microscope slide with a 20 mm.times.20
mm graph inscribed on the underside is placed on a 2 inch.times.3
inch.times.1/4 inch Gray-Lite #14 dark background glass. On the top
side of the microscope slide were placed 1 inch diameter 750 micron
stainless steel washers. A washer is placed on the left and right
of the inscribed graph. A polymer mixture prepared as described in
Example 1 was then layered over the microscope slide and smoothed
to remove any bubbles or uneven areas. Sterile isotonic saline was
carefully dropped onto the middle of the liquid polymer layer where
it flowed laterally to cover the entire film. The saline was
allowed to stay in contact with the polymer mixture for 1 minute at
which time the outside surface or skin became opaque. The excess
saline was then carefully removed by air spray or sponge and the
entire process repeated again with addition of more polymer mixture
and saline to coagulate the polymer. After the second layer had set
for 1 minute, a 1 inch.times.3 inch regular microscope glass slide
moistened with saline solution was placed over the polymer mixture
and compressed to the height of the stainless steel washers (750
.mu.m). Additional saline was added to the edge of the regular
microscope glass slide to saturate the underside of the slide. The
compressed material was allowed to set for 10 more minutes. The
regular microscope slide and washers were then removed and the
implant precursor film was cut with a single razor blade to the
dimensions of the periodontal defect.
EXAMPLE 6
Application of an Implant Precursor to a Periodontal Defect
[0124] A mandibular first molar of a 65-year old man was selected
for treatment because of long-standing pocket depth and furcation
involvement. During surgery, a full-thickness periodontal flap was
elevated, the defect scaled and root planed, and the dimensions of
the defect measured. A customized implant precursor barrier
membrane prepared according to Example 5 was applied over the
periodontal defect so as to approximate the level of the crown
margin and overlay the osseous margins by 2 to 3 mm. The precursor
material adhered directly to the tooth and bone without the need
for suturing in place. The buccal flap was replaced over the defect
and the implant precursor and sutured to the lingual tissue. A
periodontal dressing material was applied to the surgical area and
systemic antibiotic therapy was used for 7 days. After one week,
the fully formed barrier was in place. At one month, the barrier
was also present but displaced buccally from the tooth surface
because of the formation of granulation tissue between the barrier
and the root surface. At the 6-month examination, the barrier was
no longer evident and epithelium had grown over the former area of
granulation tissue. The clinical probing measurements at this time
showed that the periodontal pocket depth had decreased from 5 mm to
2 mm and the level of attachment of tissue to the tooth had
increased from 7 mm to 4 mm. The horizontal furcation depth had
also decreased from 5 mm to 3 mm. All clinical measurements
indicated good tissue regeneration at the defect site.
EXAMPLE 7
Treatment Using an Implant Precursor in Combination with a Support
Layer
[0125] A polymer mixture may be prepared as described in Example 1.
A thigh bone of an anesthetized male rat may be surgically incised
to create a defect. Granules of Surgicel.TM. oxidized cellulose may
be applied to the defect to stop the bleeding and to fill in the
defect. A precursor implant prepared as described in Example 1 may
be applied over the surface of the Surgicel.TM. support layer. The
tissue is then replaced and sutured in place. The implant precursor
will further solidify to a solid barrier matrix.
EXAMPLE 8
Treatment in Which the Implant Precursor is Formed In Vivo over a
Support Layer
[0126] A thigh bone of an anesthetized male rat may be surgically
incised to create a defect and granules of Surgicel.TM. oxidized
cellulose may be applied to the defect to stop the bleeding and to
fill in the defect. A polymer mixture prepared according to Example
1 may then be applied directly over the surface of the Surgicel.TM.
support layer. The moisture from the tissue defect will cause the
liquid polymer to partially solidify to form the same type of
implant precursor as described in Example 1. The soft tissue is
then replaced and sutured into place. The implant precursor thus
formed will further solidify to a solid barrier matrix.
EXAMPLE 9
Treatment with an Implant Precursor Comprising a Biological
Agent
[0127] A polymer mixture may be prepared as described in Example 1.
To this mixture may be added 5% by weight doxycycline hyclate. An
implant article may then be prepared in vivo from the drug/polymer
mixture as described in Example 1. The implant article may be
placed into a periodontal defect as described in Example 6. The
doxycycline will be dispensed from the solid barrier implant as it
degrades and provide protection against bacterial infection.
EXAMPLE 10
In Vivo Formation of an Implant Precursor in a Bone
[0128] A polymer mixture may be prepared as described above in
Example 1.
[0129] A thigh bone of an anesthetized male rat may be surgically
incised, and the surface of the incision of the bone tissue may be
coated with a thin layer of a phosphate buffered saline (PBS)
solution. The polymer mixture (about 1-3 ml) may be dispensed from
a syringe or eye dropper onto the surface of the water-coated bone
tissue. The buffer solution (about 1-3 ml) may be dispensed onto
the layer of the polymer mixture. After 2-5 minutes, the polymer
mixture will coagulate to form a gelatinous outer layer with a
liquid content of an implant precursor.
[0130] The implant precursor may be covered with tissue, and the
tissue sutured in place. The implant precursor will gradually
solidify to a solid matrix. After 5-10 days, the implant site may
be reopened, and the implant article mass should have been
displaced by the ingrowth of bone tissue.
* * * * *