Methods, compositions, and devices for making sustained biodegradable implants in tissue
This invention discloses methods and composition to form biodegradable polymer implant arrays in the live tissue. Artificial cavities are created in the live tissue by using laser ablation, oscillating needle, microneedle array and other methods. The cavities are then filled with biodegradable polymer solution. The solvent in the polymer solution is dissipated in the tissue to form a biodegradable polymer implant in artificial cavities. The cavities and implants formed are arranged to form of an array of implants. The biodegradable polymer in the cavity can also be loaded with drug to form biodegradable drug delivery array in the live tissue.
1. A method of making a sustained biodegradable implant in a tissue, the method comprising:
creating a plurality of artificial cavities of predetermined shape and volume in the tissue;
filling the plurality of artificial cavities partially or completely with an injectable liquid polymeric implant-forming composition selected from a cross-linkable composition, thermoreversible composition, or neat liquid carrier composition; and
forming the sustained biodegradable implant in the plurality of artificial cavities from the implant-forming composition.
2. The method of claim 1 , wherein the cross-linkable composition includes one or more cross-linkable precursors, wherein the one or more cross-linkable precursors are crosslinked to form a crosslinked composition as the sustained biodegradable implant.
3. The method according to claim 2 , further comprising forming a solid or a hydrogel from the crosslinking.
4. The method according to claim 3 , wherein the conversion into a solid or hydrogel is initiated by a stimulus selected from the group consisting of light, chemical reaction, or enzymatic reaction.
5. The method according to claim 2 , wherein the one or more precursors is selected from the group consisting of a macromonomer, component of condensation, polymerizable precursor, fibrin glue component, or combinations thereof.
6. The method according to claim 2 , wherein the one or more precursors includes polyethylene glycol.
7. The method according to claim 1 , further comprising forming the crosslinked composition into one or more microparticles or a film or a combination thereof.
8. The method according to claim 1 , wherein the thermoreversible composition forms a gel after implantation at about 37° C.
9. The method according to claim 1 , wherein the injectable liquid polymeric implant-forming composition comprises a polymer dissolved in an aqueous solution.
10. The method according to claim 9 , wherein the polymer shows a thermoreversible property in the aqueous solution and is selected from a group consisting of polymers or copolymers of: pluronics; poly ethyleneoxides; polypropylene oxides; reverse pluronics; polyacrylamides; gelatins; cellulose derivatives; polylactones, polylactic acids; polyglycolic acids; polylactice-co-glycolides; polyhydroxy acids; and combinations thereof.
11. The method according to claim 10 , wherein a concentration of the polymer in the aqueous solution ranges from about 2% to about 45%.
12. The method according to claim 1 , wherein the neat liquid carrier composition is polymeric or non-polymeric and substantially liquid at room temperature and/or about body temperature.
13. The method according to claim 12 , wherein the neat liquid carrier is selected from a group consisting of: polymers, dendrimers, copolymers or oligomers of glycolide, dl-lactide, d-lactide, l-lactide, caprolactone, dioxanone and trimethylene carbonate; degradable polyurethanes; polyamides; polyesters; polypeptides; polyhydroxyacids; polyorthocarbonates; polylactic acid; polyglycolic acid; polyanhydrides; and polylactones; a copolymer of polyethylene glycol and polylactone; and a copolymer of PEO-PPO-PEO and polylactone.
14. The method according to claim 12 , wherein the non-polymeric neat liquid carrier is selected from a group consisting of: sucrose acetate isobutyrate; vitamin E and its derivatives; fatty acids; oleic acids and its derivatives; fatty alcohols; liquid non-ionic surfactants; polysorbate, Tween.40 or Tween 80.
15. The method according to claim 1 , wherein the neat liquid carrier comprises a viscosity-modifying agent.
16. The method according to claim 15 , wherein the viscosity-modifying agent is a biocompatible organic solvent.
17. The method according to claim 15 , wherein the viscosity-modifying agent is selected from the group consisting of dimethyl sulfoxide, n-methyl pyrrolidinone, ethanol, glycerol, polyethylene glycol, and acetone.
18. The method according to claim 15 , wherein the viscosity-modifying agent is added in 1 to 99 percent of the neat liquid carrier.
19. The method of claim 1 , further comprising at least one of:
forming at least 4 artificial cavities per square centimeter in the live tissue;
forming from 4 artificial cavities to 6,000 artificial cavities per square centimeter in the live tissue;
forming the cavities to have a spacing between adjacent cavities to range from 1 micron to 10 mm; or
forming a volume of each artificial cavity to be in a range from about 1×10E-12 ml to about 0.05 ml.
20. The method of claim 1 , wherein the creating the plurality of artificial cavities includes at least one of displacing tissue, destroying tissue, or combination thereof.
21. The method of claim 1 , wherein the creating the plurality of artificial cavities includes at least one of laser ablation, microneedle array, oscillating needle, mechanical drilling, ultrasonic drilling, water drilling, or combination thereof.