electrical devices, anti-scarring agents, and therapeutic compositions

• US 20090280153A1
• Filed: 03/31/2006
• Published: 11/12/2009
• Est. Priority Date: 05/10/2005
• Status: Abandoned Application

• Current Assignee: Angiotech Pharmaceuticals Incorporated
• Original Assignee: Angiotech Pharmaceuticals Incorporated
• Inventors: Gravett, David M., McDonald-Jones, Gaye, Hutchinson, Anne, Lakhani, Fara, Takacs-Cox, Aniko, Hunter, William L., Toleikis, Philip M., Avelar, Rui, Loss, Troy A. E., Liggins, Richard T., Maiti, Arpita, Signore, Pierre E.
• Application Number:
  US11/919,274
• Publication Number:
  US 20090280153A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/40 characterised by a specific therapeutic activity or mode of action
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61N 1/3605 Implantable neurostimulators for stimulating central or peripheral nerve system
• CPC Class Codes: A61N 1/3629 in combination with non-electric therapy
• CPC Class Codes: A61N 1/37 Monitoring; Protecting
• CPC Class Codes: A61N 1/3956 Implantable devices for applying electric shocks to the heart, e.g. for cardioversion

Abstract

Electrical devices (e.g., cardiac rhythm management and neurostimulation devices) for contact with tissue are used in combination with an anti-scarring agent in order to inhibit scarring that may otherwise occur when the devices are implanted within an animal.

Claims

1. A medical device, comprising an electrical device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring between the medical device and the host into which the medical device is implanted.

2. The medical device of claim 1 wherein the electrical device is a neurostimulator for treating chronic pain, a neurostimulator for treating Parkinson'"'"'s Disease, a vagal nerve stimulator for treating epilepsy, a vagal nerve stimulator for treating a chronic or degenerative neurological disorder, a sacral nerve stimulator for treating a bladder control problem, a gastric nerve stimulator for treating a gastrointestinal disorder, a cochlear implant for treating deafness, a bone growth stimulator, a cardiac pacemaker, an implantable cardioverter defibrillator (ICD) system, a vagus nerve stimulator for treating arrhythemia, an electrical lead, a neurostimulator, or a cardiac rhythm management device.

3. The medical device of claim 1 or claim 2 wherein the anti-scarring agent is an antimicrobial compound.

4. The medical device of claim 3 wherein the antimicrobial compound is brefeldin A.

5. The medical device of claim 1 or claim 2 wherein the anti-scarring agent is selected from a histamine receptor antagonist, an alpha adrenergic receptor antagonist, an anti-psychotic compound, a CaM kinase II inhibitor, a G protein agonist, an antibiotic selected from the group consisting of apigenin, ampicillin sodium salt, puromycin, an anti-microbial agent, a DNA topoisomerase inhibitor, a thromboxane A2 receptor inhibitor, a D2 dopamine receptor antagonist, a Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor, a dopamine antagonist, an anesthetic compound, a clotting factor, a lysyl hydrolase inhibitor, a muscarinic receptor inhibitor, a superoxide anion generator, a steroid, an anti-proliferative agent, a diuretic, an anti-coagulant, a cyclic GMP agonist, an adenylate cyclase agonist, an antioxidant, a nitric oxide synthase inhibitor, an anti-neoplastic agent, a DNA synthesis inhibitor, a DNA alkylating agent, a DNA methylation inhibitor, a NSAID agent, a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, an MEK1/MEK 2 inhibitor, a NO synthase inhibitor, a retinoic acid receptor antagonist, an ACE inhibitor, a glycosylation inhibitor, an intracellular calcium influx inhibitor, an anti-emetic agent, an acetylcholinesterase inhibitor, an ALK-5 receptor antagonist, a RAR/RXT antagonist, an eIF-2a inhibitor, an S-adenosyl-L-homocysteine hydrolase inhibitor, an estrogen agonist, a serotonin receptor inhibitor, an anti-thrombotic agent, a tryptase inhibitor, a pesticide, a bone mineralization promoter, a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, an anti-inflammatory compound, a DNA methylation promoter, an anti-spasmodic agent, a protein synthesis inhibitor, an α

-glucosidase inhibitor, a calcium channel blocker, a pyruvate dehydrogenase activator, a prostaglandin inhibitor, a sodium channel inhibitor, a serine protease inhibitor, an intracellular calcium flux inhibitor, a JAK2 inhibitor, an androgen inhibitor, an aromatase inhibitor, an anti-viral agent, a 5-HT inhibitor, an FXR antagonist, an actin polymerization and stabilization promoter, an AXOR12 agonist, an angiotensin II receptor agonist, a platelet aggregation inhibitor, a CB1/CB2 receptor agonist, a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a reducing agent, and a immuno-modulator selected from Bay 11-7085, (−

)-arctigenin, idazoxan hydrochloride.

6. The medical device of claim 1 or claim 2 wherein the anti-scarring agent is selected from an angiogenesis inhibitor, an apoptosis antagonist, an apoptosis activator, a beta 1 integrin antagonist, a beta tubulin inhibitor, a blocker of enzyme production in Hepatitis C, a Bruton'"'"'s tyrosine kinase inhibitor, a calcineurin inhibitor, a caspase 3 inhibitor, a CC chemokine receptor antagonist, a cell cycle inhibitor, a cathepsin B inhibitor, a cathepsin K inhibitor, a cathepsin L inhibitor, a CD40 antagonist, a chemokine receptor antagonist, a chymase inhibitor, a collagenase antagonist, a CXCR antagonist, a cyclin dependent kinase inhibitor, a cyclooxygenase 1 inhibitor, a DHFR inhibitor, a cual integrin inhibitor, an elastase inhibitor, an elongation factor-1 alpha inhibitor, an endothelial growth factor antagonist, an endothelial growth factor receptor kinase inhibitor, an endotoxin antagonist, an epothilone and tubulin binder, an estrogen receptor antagonist, an FGF inhibitor, a farnexyl transferase inhibitor, a farnesyltransferase inhibitor, an FLT-3 kinase inhibitor, an FGF receptor kinase inhibitor, a fibrinogen antagonist, a histone deacetylase inhibitor, an HMGCoA reductase inhibitor, an ICAM inhibitor, an IL, ICE, and IRAK antagonist, an IL-2 inhibitor, an immunosuppressant, an inosine monophosphate inhibitor, an integrin antagonist, an interleukin antagonist, an inhibitor of type III receptor tyrosine kinase, an irreversible inhibitor of enzyme methionine aminopeptidase type 2, an isozyme selective delta protein kinase C inhibitor, a JAK3 enzyme inhibitor, a JNK inhibitor, a kinase inhibitor, a kinesin antagonist, a leukotriene inhibitor and antagonist, a MAP kinase inhibitor, a matrix metalloproteinase inhibitor, an MCP-CCR2 inhibitor, an mTOR inhibitor, an mTOR kinase inhibitor, a microtubule inhibitor, an MIF inhibitor, a neurokinin antagonist, an NF kappa B inhibitor, a nitric oxide agonist, an ornithine decarboxylase inhibitor, a p38 MAP kinase inhibitor, a palmitoyl-protein thioesterase inhibitor, a PDGF receptor kinase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a phosphatase inhibitor, a phosphodiesterase inhibitor, a PKC inhibitor, a platelet activating factor antagonist, a prolyl hydroxylase inhibitor, a polymorphonuclear neutrophil inhibitor, protein kinase B inhibitor, protein kinase C stimulant, purine nucleoside analogue, a purineoreceptor P2X antagonist, a Raf kinase inhibitor, reversible inhibitor of ErbB1 and ErbB2, ribonucleoside triphosphate reductase inhibitor, an SDF-1 antagonist, a sheddase inhibitor, an SRC inhibitor, a stromelysin inhibitor, an Syk kinase inhibitor, a telomerase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist or TACE inhibitor, a tumor necrosis factor antagonist, a Toll receptor inhibitor, a tubulin antagonist, a protein tyrosine kinase inhibitor, a VEGF inhibitor, and a vitamin D receptor agonist.

7. The medical device of claim 1 or claim 2 wherein the anti-scarring agent is selected from a retinoic acid receptor antagonist, a heat shock protein 90 antagonist, a steroid, a cell cycle inhibitor, a histone deacetylase inhibitor, an anti-microbial agent, an intracellular calcium flux inhibitor, an microtubule inhibitor, an HMGCoA reductase inhibitor, an actin polymerization and stabilization promoter, a tyrosine kinase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist, a TACE inhibitor, a calcineurin inhibitor, a peptidyl-prolyl cis/trans isomerase inhibitor, an apoptosis activator, an antimetabolite and anti-neoplastic agent, a TGF beta inhibitor, a DNA methylation promoter, and a PKC inhibitor.

8. The medical device of claim 1 or claim 2 wherein the anti-scarring agent is selected from ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

9. The medical device of any one of claims 1-8 further comprising a coating wherein the coating comprises (a) the anti-scarring agent or (b) the anti-scarring agent and a polymer.

10. The medical device of any one of claims 1-8 further comprising a coating wherein the anti-scarring agent is present in the coating in an amount ranging between (a) about 0.0001% to about 1% by weight;

(b) about 1% to about 10% by weight;

(c) about 10% to about 25% by weight;

or (d) about 25% to about 70% by weight.

11. The medical device of any one of claims 1-8 further comprising a polymer or further comprising a polymeric carrier.

12. The medical device of claim 11 wherein the polymeric carrier comprises a copolymer, a block copolymer, a random copolymer, a biodegradable polymer, a non-biodegradable polymer, a hydrophilic polymer, a hydrophobic polymer, a polymer having hydrophilic domains, or a polymer having hydrophobic domains.

13. The medical device of any one of claims 1-8 further comprising a polymeric carrier, wherein the polymeric carrier comprises a non-conductive polymer, an elastomer, a hydrogel, a silicone polymer, a hydrocarbon polymer, a styrene-derived polymer, a butadiene polymer, a macromer, a poly-ethylene glycol) polymer, and an amorphous polymer.

14. The medical device of any one of claims 1-8 further comprising a second pharmaceutically active agent.

15. The medical device of any one of claims 1-8 further comprising at least one of an anti-inflammatory agent, an agent that inhibits infection, anthracycline, doxorubicin, mitoxantrone, fluoropyrimidine, 5-fluorouracil, a folic acid antagonist, methotrexate, podophylotoxin, etoposide, camptothecin, hydroxyurea, a platinum complex, cisplatin, an anti-thrombotic agent, a visualization agent, and an echogenic material.

16. The medical device of any one of claims 1-8 wherein the device is adapted for delivering the anti-scarring agent locally to tissue proximate to the device.

17. The medical device of any one of claims 1-8 wherein the anti-scarring agent is released into tissue in the vicinity of the device after deployment of the device.

18. The medical device of any one of claims 1-8 wherein the anti-scarring agent is released in effective concentrations from the device over a period ranging from the time of deployment of the device to about 1 year.

19. The medical device of any one of claims 1-8 wherein the anti-scarring agent is released in effective concentrations from the device at a constant rate, an increasing rate, or a decreasing rate.

20. The medical device of any one of claims 1-8 wherein the device comprises (a) about 0.01 μ

g to about 10 μ

g of the anti-scarring agent;

(b) about 10 μ

g to about 10 mg of the anti-scarring agent;

(c) about 10 mg to about 250 mg of the anti-scarring agent;

(d) about 250 mg to about 1000 mg of the anti-scarring agent;

or (e) about 1000 mg to about 2500 mg of the anti-scarring agent.

21. The medical device of any one of claims 1-8 wherein the device comprises (a) about 0.01 μ

g to about 1 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 1 μ

g to about 10 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(c) about 10 μ

g to about 250 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(d) about 250 μ

g to about 1000 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (e) about 1000 μ

g to about 2500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

22. The medical device of any one of claims 1-8 wherein the device comprises (a) about 0.01 μ

g to about 100 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 0.01 μ

g to about 200 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (c) about 0.01 μ

g to about 500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

23. A method for inhibiting scarring comprising placing an electrical device and an anti-scarring agent or a composition comprising an ant-scarring agent into an animal host, wherein the agent inhibits scarring.

24. The method of claim 23 wherein the electrical device is a neurostimulator for treating chronic pain, a neurostimulator for treating Parkinson'"'"'s Disease, a vagal nerve stimulator for treating epilepsy, a vagal nerve stimulator for treating a chronic or degenerative neurological disorder, a sacral nerve stimulator for treating a bladder control problem, a gastric nerve stimulator for treating a gastrointestinal disorder, a cochlear implant for treating deafness, a bone growth stimulator, a cardiac pacemaker, an implantable cardioverter defibrillator (ICD) system, a vagus nerve stimulator for treating arrhythemia, an electrical lead, a neurostimulator, or a cardiac rhythm management device.

25. The method of claim 23 or claim 24 wherein the anti-scarring agent is an antimicrobial compound.

26. The method of claim 25 wherein the antimicrobial compound is brefeldin A.

27. The method of claim 23 or claim 24 wherein the anti-scarring agent is selected from a histamine receptor antagonist, an alpha adrenergic receptor antagonist, an anti-psychotic compound, a CaM kinase II inhibitor, a G protein agonist, an antibiotic selected from the group consisting of apigenin, ampicillin sodium salt, puromycin, an anti-microbial agent, a DNA topoisomerase inhibitor, a thromboxane A2 receptor inhibitor, a D2 dopamine receptor antagonist, a Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor, a dopamine antagonist, an anesthetic compound, a clotting factor, a lysyl hydrolase inhibitor, a muscarinic receptor inhibitor, a superoxide anion generator, a steroid, an anti-proliferative agent, a diuretic, an anti-coagulant, a cyclic GMP agonist, an adenylate cyclase agonist, an antioxidant, a nitric oxide synthase inhibitor, an anti-neoplastic agent, a DNA synthesis inhibitor, a DNA alkylating agent, a DNA methylation inhibitor, a NSAID agent, a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, an MEK1/MEK 2 inhibitor, a NO synthase inhibitor, a retinoic acid receptor antagonist, an ACE inhibitor, a glycosylation inhibitor, an intracellular calcium influx inhibitor, an anti-emetic agent, an acetylcholinesterase inhibitor, an ALK-5 receptor antagonist, a RAR/RXT antagonist, an eIF-2a inhibitor, an S-adenosyl-L-homocysteine hydrolase inhibitor, an estrogen agonist, a serotonin receptor inhibitor, an anti-thrombotic agent, a tryptase inhibitor, a pesticide, a bone mineralization promoter, a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, an anti-inflammatory compound, a DNA methylation promoter, an anti-spasmodic agent, a protein synthesis inhibitor, an α

-glucosidase inhibitor, a calcium channel blocker, a pyruvate dehydrogenase activator, a prostaglandin inhibitor, a sodium channel inhibitor, a serine protease inhibitor, an intracellular calcium flux inhibitor, a JAK2 inhibitor, an androgen inhibitor, an aromatase inhibitor, an anti-viral agent, a 5-HT inhibitor, an FXR antagonist, an actin polymerization and stabilization promoter, an AXOR12 agonist, an angiotensin II receptor agonist, a platelet aggregation inhibitor, a CB1/CB2 receptor agonist, a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a reducing agent, and a immuno-modulator selected from Bay 11-7085, (−

)-arctigenin, idazoxan hydrochloride.

28. The method of claim 23 or claim 24 wherein the anti-scarring agent is selected from an angiogenesis inhibitor, an apoptosis antagonist, an apoptosis activator, a beta 1 integrin antagonist, a beta tubulin inhibitor, a blocker of enzyme production in Hepatitis C, a Bruton'"'"'s tyrosine kinase inhibitor, a calcineurin inhibitor, a caspase 3 inhibitor, a CC chemokine receptor antagonist, a cell cycle inhibitor, a cathepsin B inhibitor, a cathepsin K inhibitor, a cathepsin L inhibitor, a CD40 antagonist, a chemokine receptor antagonist, a chymase inhibitor, a collagenase antagonist, a CXCR antagonist, a cyclin dependent kinase inhibitor, a cyclooxygenase 1 inhibitor, a DHFR inhibitor, a cual integrin inhibitor, an elastase inhibitor, an elongation factor-1 alpha inhibitor, an endothelial growth factor antagonist, an endothelial growth factor receptor kinase inhibitor, an endotoxin antagonist, an epothilone and tubulin binder, an estrogen receptor antagonist, an FGF inhibitor, a farnexyl transferase inhibitor, a farnesyltransferase inhibitor, an FLT-3 kinase inhibitor, an FGF receptor kinase inhibitor, a fibrinogen antagonist, a histone deacetylase inhibitor, an HMGCoA reductase inhibitor, an ICAM inhibitor, an IL, ICE, and IRAK antagonist, an IL-2 inhibitor, an immunosuppressant, an inosine monophosphate inhibitor, an integrin antagonist, an interleukin antagonist, an inhibitor of type III receptor tyrosine kinase, an irreversible inhibitor of enzyme methionine aminopeptidase type 2, an isozyme selective delta protein kinase C inhibitor, a JAK3 enzyme inhibitor, a JNK inhibitor, a kinase inhibitor, a kinesin antagonist, a leukotriene inhibitor and antagonist, a MAP kinase inhibitor, a matrix metalloproteinase inhibitor, an MCP-CCR2 inhibitor, an mTOR inhibitor, an mTOR kinase inhibitor, a microtubule inhibitor, an MIF inhibitor, a neurokinin antagonist, an NF kappa B inhibitor, a nitric oxide agonist, an ornithine decarboxylase inhibitor, a p38 MAP kinase inhibitor, a palmitoyl-protein thioesterase inhibitor, a PDGF receptor kinase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a phosphatase inhibitor, a phosphodiesterase inhibitor, a PKC inhibitor, a platelet activating factor antagonist, a prolyl hydroxylase inhibitor, a polymorphonuclear neutrophil inhibitor, protein kinase B inhibitor, protein kinase C stimulant, purine nucleoside analogue, a purineoreceptor P2X antagonist, a Raf kinase inhibitor, reversible inhibitor of ErbB1 and ErbB2, ribonucleoside triphosphate reductase inhibitor, an SDF-1 antagonist, a sheddase inhibitor, an SRC inhibitor, a stromelysin inhibitor, an Syk kinase inhibitor, a telomerase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist or TACE inhibitor, a tumor necrosis factor antagonist, a Toll receptor inhibitor, a tubulin antagonist, a protein tyrosine kinase inhibitor, a VEGF inhibitor, and a vitamin D receptor agonist.

29. The method of claim 23 or claim 24 wherein the anti-scarring agent is selected from a retinoic acid receptor antagonist, a heat shock protein 90 antagonist, a steroid, a cell cycle inhibitor, a histone deacetylase inhibitor, an anti-microbial agent, an intracellular calcium flux inhibitor, an microtubule inhibitor, an HMGCoA reductase inhibitor, an actin polymerization and stabilization promoter, a tyrosine kinase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist, a TACE inhibitor, a calcineurin inhibitor, a peptidyl-prolyl cis/trans isomerase inhibitor, an apoptosis activator, an antimetabolite and anti-neoplastic agent, a TGF beta inhibitor, a DNA methylation promoter, and a PKC inhibitor.

30. The method of claim 23 or claim 24 wherein the anti-scarring agent is selected from ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

31. The method of any one of claims 23-30 wherein the electrical device further comprises a coating, and wherein the coating comprises (a) the anti-scarring agent or (b) the anti-scarring agent and a polymer.

32. The method of any one of claims 23-30 wherein the electrical device further comprises a coating, and wherein the anti-scarring agent is present in the coating in an amount ranging between (a) about 0.0001% to about 1% by weight;

(b) about 1% to about 10% by weight;

(c) about 10% to about 25% by weight;

or (d) about 25% to about 70% by weight.

33. The method of any one of claims 23-30 wherein the electrical device further comprises a polymer or further comprises a polymeric carrier.

34. The method of claim 33 wherein the polymeric carrier comprises a copolymer, a block copolymer, a random copolymer, a biodegradable polymer, a non-biodegradable polymer, a hydrophilic polymer, a hydrophobic polymer, a polymer having hydrophilic domains, or a polymer having hydrophobic domains.

35. The method of any one of claims 23-30 wherein the electrical device further comprises a polymeric carrier, and wherein the polymeric carrier comprises a non-conductive polymer, an elastomer, a hydrogel, a silicone polymer, a hydrocarbon polymer, a styrene-derived polymer, a butadiene polymer, a macromer, a poly-ethylene glycol) polymer, and an amorphous polymer.

36. The method of any one of claims 23-30 wherein the electrical device further comprises a second pharmaceutically active agent.

37. The method of any one of claims 23-30 wherein the electrical device further comprises at least one of an anti-inflammatory agent, an agent that inhibits infection, anthracycline, doxorubicin, mitoxantrone, fluoropyrimidine, 5-fluorouracil, a folic acid antagonist, methotrexate, podophylotoxin, etoposide, camptothecin, hydroxyurea, a platinum complex, cisplatin, an anti-thrombotic agent, a visualization agent, and an echogenic material.

38. The method of any one of claims 23-30 wherein the electrical device is adapted for delivering the anti-scarring agent locally to tissue proximate to the device.

39. The method of any one of claims 23-30 wherein the anti-scarring agent is released into tissue in the vicinity of the electrical device after deployment of the device.

40. The method of any one of claims 23-30 wherein the anti-scarring agent is released in effective concentrations from the electrical device over a period ranging from the time of deployment of the device to about 1 year.

41. The method of any one of claims 23-30 wherein the anti-scarring agent is released in effective concentrations from the electrical device at a constant rate, an increasing rate, or a decreasing rate.

42. The method of any one of claims 23-30 wherein the electrical device comprises (a) about 0.01 μ

g to about 10 μ

g of the anti-scarring agent;

(b) about 10 μ

g to about 10 mg of the anti-scarring agent;

(c) about 10 mg to about 250 mg of the anti-scarring agent;

(d) about 250 mg to about 1000 mg of the anti-scarring agent;

or (e) about 1000 mg to about 2500 mg of the anti-scarring agent.

43. The method of any one of claims 23-30 wherein the electrical device comprises (a) about 0.01 μ

g to about 1 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 1 μ

g to about 10 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(c) about 10 μ

g to about 250 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(d) about 250 μ

g to about 1000 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (e) about 1000 μ

g to about 2500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

44. The method of any one of claims 23-30 wherein the electrical device comprises (a) about 0.01 μ

g to about 100 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 0.01 μ

g to about 200 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (c) about 0.01 μ

g to about 500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

45. A method for making a medical device comprising:

combining an electrical device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring between the device and a host into which the device is implanted.

46. The method of claim 45 wherein the electrical device is a neurostimulator for treating chronic pain, a neurostimulator for treating Parkinson'"'"'s Disease, a vagal nerve stimulator for treating epilepsy, a vagal nerve stimulator for treating a chronic or degenerative neurological disorder, a sacral nerve stimulator for treating a bladder control problem, a gastric nerve stimulator for treating a gastrointestinal disorder, a cochlear implant for treating deafness, a bone growth stimulator, a cardiac pacemaker, an implantable cardioverter defibrillator (ICD) system, a vagus nerve stimulator for treating arrhythemia, an electrical lead, a neurostimulator, or a cardiac rhythm management device.

47. The method of claim 45 or claim 46 wherein the anti-scarring agent is an antimicrobial compound.

48. The method of claim 47 wherein the antimicrobial compound is brefeldin A.

49. The method of claim 45 or claim 46 wherein the anti-scarring agent is selected from a histamine receptor antagonist, an alpha adrenergic receptor antagonist, an anti-psychotic compound, a CaM kinase II inhibitor, a G protein agonist, an antibiotic selected from the group consisting of apigenin, ampicillin sodium salt, puromycin, an anti-microbial agent, a DNA topoisomerase inhibitor, a thromboxane A2 receptor inhibitor, a D2 dopamine receptor antagonist, a Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor, a dopamine antagonist, an anesthetic compound, a clotting factor, a lysyl hydrolase inhibitor, a muscarinic receptor inhibitor, a superoxide anion generator, a steroid, an anti-proliferative agent, a diuretic, an anti-coagulant, a cyclic GMP agonist, an adenylate cyclase agonist, an antioxidant, a nitric oxide synthase inhibitor, an anti-neoplastic agent, a DNA synthesis inhibitor, a DNA alkylating agent, a DNA methylation inhibitor, a NSAID agent, a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, an MEK1/MEK 2 inhibitor, a NO synthase inhibitor, a retinoic acid receptor antagonist, an ACE inhibitor, a glycosylation inhibitor, an intracellular calcium influx inhibitor, an anti-emetic agent, an acetylcholinesterase inhibitor, an ALK-5 receptor antagonist, a RAR/RXT antagonist, an eIF-2a inhibitor, an S-adenosyl-L-homocysteine hydrolase inhibitor, an estrogen agonist, a serotonin receptor inhibitor, an anti-thrombotic agent, a tryptase inhibitor, a pesticide, a bone mineralization promoter, a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, an anti-inflammatory compound, a DNA methylation promoter, an anti-spasmodic agent, a protein synthesis inhibitor, an α

-glucosidase inhibitor, a calcium channel blocker, a pyruvate dehydrogenase activator, a prostaglandin inhibitor, a sodium channel inhibitor, a serine protease inhibitor, an intracellular calcium flux inhibitor, a JAK2 inhibitor, an androgen inhibitor, an aromatase inhibitor, an anti-viral agent, a 5-HT inhibitor, an FXR antagonist, an actin polymerization and stabilization promoter, an AXOR12 agonist, an angiotensin II receptor agonist, a platelet aggregation inhibitor, a CB1/CB2 receptor agonist, a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a reducing agent, and a immuno-modulator selected from Bay 11-7085, (−

)-arctigenin, idazoxan hydrochloride.

50. The method of claim 45 or claim 46 wherein the anti-scarring agent is selected from an angiogenesis inhibitor, an apoptosis antagonist, an apoptosis activator, a beta 1 integrin antagonist, a beta tubulin inhibitor, a blocker of enzyme production in Hepatitis C, a Bruton'"'"'s tyrosine kinase inhibitor, a calcineurin inhibitor, a caspase 3 inhibitor, a CC chemokine receptor antagonist, a cell cycle inhibitor, a cathepsin B inhibitor, a cathepsin K inhibitor, a cathepsin L inhibitor, a CD40 antagonist, a chemokine receptor antagonist, a chymase inhibitor, a collagenase antagonist, a CXCR antagonist, a cyclin dependent kinase inhibitor, a cyclooxygenase I inhibitor, a DHFR inhibitor, a cual integrin inhibitor, an elastase inhibitor, an elongation factor-1 alpha inhibitor, an endothelial growth factor antagonist, an endothelial growth factor receptor kinase inhibitor, an endotoxin antagonist, an epothilone and tubulin binder, an estrogen receptor antagonist, an FGF inhibitor, a farnexyl transferase inhibitor, a farnesyltransferase inhibitor, an FLT-3 kinase inhibitor, an FGF receptor kinase inhibitor, a fibrinogen antagonist, a histone deacetylase inhibitor, an HMGCoA reductase inhibitor, an ICAM inhibitor, an IL, ICE, and IRAK antagonist, an IL-2 inhibitor, an immunosuppressant, an inosine monophosphate inhibitor, an integrin antagonist, an interleukin antagonist, an inhibitor of type III receptor tyrosine kinase, an irreversible inhibitor of enzyme methionine aminopeptidase type 2, an isozyme selective delta protein kinase C inhibitor, a JAK3 enzyme inhibitor, a JNK inhibitor, a kinase inhibitor, a kinesin antagonist, a leukotriene inhibitor and antagonist, a MAP kinase inhibitor, a matrix metalloproteinase inhibitor, an MCP-CCR2 inhibitor, an mTOR inhibitor, an mTOR kinase inhibitor, a microtubule inhibitor, an MIF inhibitor, a neurokinin antagonist, an NF kappa B inhibitor, a nitric oxide agonist, an ornithine decarboxylase inhibitor, a p38 MAP kinase inhibitor, a palmitoyl-protein thioesterase inhibitor, a PDGF receptor kinase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a phosphatase inhibitor, a phosphodiesterase inhibitor, a PKC inhibitor, a platelet activating factor antagonist, a prolyl hydroxylase inhibitor, a polymorphonuclear neutrophil inhibitor, protein kinase B inhibitor, protein kinase C stimulant, purine nucleoside analogue, a purineoreceptor P2X antagonist, a Raf kinase inhibitor, reversible inhibitor of ErbB1 and ErbB2, ribonucleoside triphosphate reductase inhibitor, an SDF-1 antagonist, a sheddase inhibitor, an SRC inhibitor, a stromelysin inhibitor, an Syk kinase inhibitor, a telomerase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist or TACE inhibitor, a tumor necrosis factor antagonist, a Toll receptor inhibitor, a tubulin antagonist, a protein tyrosine kinase inhibitor, a VEGF inhibitor, and a vitamin D receptor agonist.

51. The method of claim 45 or claim 46 wherein the anti-scarring agent is selected from a retinoic acid receptor antagonist, a heat shock protein 90 antagonist, a steroid, a cell cycle inhibitor, a histone deacetylase inhibitor, an anti-microbial agent, an intracellular calcium flux inhibitor, an microtubule inhibitor, an HMGCoA reductase inhibitor, an actin polymerization and stabilization promoter, a tyrosine kinase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist, a TACE inhibitor, a calcineurin inhibitor, a peptidyl-prolyl cis/trans isomerase inhibitor, an apoptosis activator, an antimetabolite and anti-neoplastic agent, a TGF beta inhibitor, a DNA methylation promoter, and a PKC inhibitor.

52. The method of claim 45 or claim 46 wherein the anti-scarring agent is selected from ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

53. The method of any one of claims 45-52 wherein the electrical device further comprises a coating, and wherein the coating comprises (a) the anti-scarring agent or (b) the anti-scarring agent and a polymer.

54. The method of any one of claims 45-52 wherein the electrical device further comprises a coating, and wherein the anti-scarring agent is present in the coating in an amount ranging between (a) about 0.0001% to about 1% by weight;

(b) about 1% to about 10% by weight;

(c) about 10% to about 25% by weight;

or (d) about 25% to about 70% by weight.

55. The method of any one of claims 45-52 wherein the electrical device further comprises a polymer or further comprises a polymeric carrier.

56. The method of claim 55 wherein the polymeric carrier comprises a copolymer, a block copolymer, a random copolymer, a biodegradable polymer, a non-biodegradable polymer, a hydrophilic polymer, a hydrophobic polymer, a polymer having hydrophilic domains, or a polymer having hydrophobic domains.

57. The method of any one of claims 45-52 wherein the electrical device further comprises a polymeric carrier, and wherein the polymeric carrier comprises a non-conductive polymer, an elastomer, a hydrogel, a silicone polymer, a hydrocarbon polymer, a styrene-derived polymer, a butadiene polymer, a macromer, a poly-ethylene glycol) polymer, and an amorphous polymer.

58. The method of any one of claims 45-52 wherein the electrical device further comprises a second pharmaceutically active agent.

59. The method of any one of claims 45-52 wherein the electrical device further comprises at least one of an anti-inflammatory agent, an agent that inhibits infection, anthracycline, doxorubicin, mitoxantrone, fluoropyrimidine, 5-fluorouracil, a folic acid antagonist, methotrexate, podophylotoxin, etoposide, camptothecin, hydroxyurea, a platinum complex, cisplatin, an anti-thrombotic agent, a visualization agent, and an echogenic material.

60. The method of any one of claims 45-52 wherein the electrical device is adapted for delivering the anti-scarring agent locally to tissue proximate to the device.

61. The method of any one of claims 45-52 wherein the anti-scarring agent is released into tissue in the vicinity of the electrical device after deployment of the device.

62. The method of any one of claims 45-52 wherein the anti-scarring agent is released in effective concentrations from the electrical device over a period ranging from the time of deployment of the device to about 1 year.

63. The method of any one of claims 45-52 wherein the anti-scarring agent is released in effective concentrations from the electrical device at a constant rate, an increasing rate, or a decreasing rate.

64. The method of any one of claims 45-52 wherein the electrical device comprises (a) about 0.01 μ

g to about 10 μ

g of the anti-scarring agent;

(b) about 10 μ

g to about 10 mg of the anti-scarring agent;

(c) about 10 mg to about 250 mg of the anti-scarring agent;

(d) about 250 mg to about 1000 mg of the anti-scarring agent;

or (e) about 1000 mg to about 2500 mg of the anti-scarring agent.

65. The method of any one of claims 45-52 wherein the electrical device comprises (a) about 0.01 μ

g to about 1 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 1 μ

g to about 10 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(c) about 10 μ

g to about 250 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(d) about 250 μ

g to about 1000 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (e) about 1000 μ

g to about 2500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

66. The method of any one of claims 45-52 wherein the electrical device comprises (a) about 0.01 μ

g to about 100 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

(b) about 0.01 μ

g to about 200 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied;

or (c) about 0.01 μ

g to about 500 μ

g of the anti-scarring agent per mm² of device surface to which the anti-scarring agent is applied.

67. A method for implanting an electrical device comprising:

(a) infiltrating a tissue of a host where the electrical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;

iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the electrical device into the host.

68. The method of claim 67 wherein the electrical device is a neurostimulator for treating chronic pain, a neurostimulator for treating Parkinson'"'"'s Disease, a vagal nerve stimulator for treating epilepsy, a vagal nerve stimulator for treating a chronic or degenerative neurological disorder, a sacral nerve stimulator for treating a bladder control problem, a gastric nerve stimulator for treating a gastrointestinal disorder, a cochlear implant for treating deafness, a bone growth stimulator, a cardiac pacemaker, an implantable cardioverter defibrillator (ICD) system, a vagus nerve stimulator for treating arrhythemia, an electrical lead, a neurostimulator, or a cardiac rhythm management device.

69. The method of claim 67 or claim 68 wherein the anti-scarring agent is an antimicrobial compound.

70. The method of claim 69 wherein the antimicrobial compound is brefeldin A.

71. The method of claim 67 or claim 68 wherein the anti-scarring agent is selected from a histamine receptor antagonist, an alpha adrenergic receptor antagonist, an anti-psychotic compound, a CaM kinase II inhibitor, a G protein agonist, an antibiotic selected from the group consisting of apigenin, ampicillin sodium salt, puromycin, an anti-microbial agent, a DNA topoisomerase inhibitor, a thromboxane A2 receptor inhibitor, a D2 dopamine receptor antagonist, a Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor, a dopamine antagonist, an anesthetic compound, a clotting factor, a lysyl hydrolase inhibitor, a muscarinic receptor inhibitor, a superoxide anion generator, a steroid, an anti-proliferative agent, a diuretic, an anti-coagulant, a cyclic GMP agonist, an adenylate cyclase agonist, an antioxidant, a nitric oxide synthase inhibitor, an anti-neoplastic agent, a DNA synthesis inhibitor, a DNA alkylating agent, a DNA methylation inhibitor, a NSAID agent, a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, an MEK1/MEK 2 inhibitor, a NO synthase inhibitor, a retinoic acid receptor antagonist, an ACE inhibitor, a glycosylation inhibitor, an intracellular calcium influx inhibitor, an anti-emetic agent, an acetylcholinesterase inhibitor, an ALK-5 receptor antagonist, a RAR/RXT antagonist, an eIF-2a inhibitor, an S-adenosyl-L-homocysteine hydrolase inhibitor, an estrogen agonist, a serotonin receptor inhibitor, an anti-thrombotic agent, a tryptase inhibitor, a pesticide, a bone mineralization promoter, a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, an anti-inflammatory compound, a DNA methylation promoter, an anti-spasmodic agent, a protein synthesis inhibitor, an α

-glucosidase inhibitor, a calcium channel blocker, a pyruvate dehydrogenase activator, a prostaglandin inhibitor, a sodium channel inhibitor, a serine protease inhibitor, an intracellular calcium flux inhibitor, a JAK2 inhibitor, an androgen inhibitor, an aromatase inhibitor, an anti-viral agent, a 5-HT inhibitor, an FXR antagonist, an actin polymerization and stabilization promoter, an AXOR12 agonist, an angiotensin II receptor agonist, a platelet aggregation inhibitor, a CB1/CB2 receptor agonist, a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a reducing agent, and a immuno-modulator selected from Bay 11-7085, (−

)-arctigenin, idazoxan hydrochloride.

72. The method of claim 67 or claim 68 wherein the anti-scarring agent is selected from an angiogenesis inhibitor, an apoptosis antagonist, an apoptosis activator, a beta 1 integrin antagonist, a beta tubulin inhibitor, a blocker of enzyme production in Hepatitis C, a Bruton'"'"'s tyrosine kinase inhibitor, a calcineurin inhibitor, a caspase 3 inhibitor, a CC chemokine receptor antagonist, a cell cycle inhibitor, a cathepsin B inhibitor, a cathepsin K inhibitor, a cathepsin L inhibitor, a CD40 antagonist, a chemokine receptor antagonist, a chymase inhibitor, a collagenase antagonist, a CXCR antagonist, a cyclin dependent kinase inhibitor, a cyclooxygenase 1 inhibitor, a DHFR inhibitor, a cual integrin inhibitor, an elastase inhibitor, an elongation factor-1 alpha inhibitor, an endothelial growth factor antagonist, an endothelial growth factor receptor kinase inhibitor, an endotoxin antagonist, an epothilone and tubulin binder, an estrogen receptor antagonist, an FGF inhibitor, a farnexyl transferase inhibitor, a farnesyltransferase inhibitor, an FLT-3 kinase inhibitor, an FGF receptor kinase inhibitor, a fibrinogen antagonist, a histone deacetylase inhibitor, an HMGCoA reductase inhibitor, an ICAM inhibitor, an IL, ICE, and IRAK antagonist, an IL-2 inhibitor, an immunosuppressant, an inosine monophosphate inhibitor, an integrin antagonist, an interleukin antagonist, an inhibitor of type III receptor tyrosine kinase, an irreversible inhibitor of enzyme methionine aminopeptidase type 2, an isozyme selective delta protein kinase C inhibitor, a JAK3 enzyme inhibitor, a JNK inhibitor, a kinase inhibitor, a kinesin antagonist, a leukotriene inhibitor and antagonist, a MAP kinase inhibitor, a matrix metalloproteinase inhibitor, an MCP-CCR2 inhibitor, an mTOR inhibitor, an mTOR kinase inhibitor, a microtubule inhibitor, an MIF inhibitor, a neurokinin antagonist, an NF kappa B inhibitor, a nitric oxide agonist, an ornithine decarboxylase inhibitor, a p38 MAP kinase inhibitor, a palmitoyl-protein thioesterase inhibitor, a PDGF receptor kinase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a phosphatase inhibitor, a phosphodiesterase inhibitor, a PKC inhibitor, a platelet activating factor antagonist, a prolyl hydroxylase inhibitor, a polymorphonuclear neutrophil inhibitor, protein kinase B inhibitor, protein kinase C stimulant, purine nucleoside analogue, a purineoreceptor P2X antagonist, a Raf kinase inhibitor, reversible inhibitor of ErbB1 and ErbB2, ribonucleoside triphosphate reductase inhibitor, an SDF-1 antagonist, a sheddase inhibitor, an SRC inhibitor, a stromelysin inhibitor, an Syk kinase inhibitor, a telomerase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist or TACE inhibitor, a tumor necrosis factor antagonist, a Toll receptor inhibitor, a tubulin antagonist, a protein tyrosine kinase inhibitor, a VEGF inhibitor, and a vitamin D receptor agonist.

73. The method of claim 67 or claim 68 wherein the anti-scarring agent is selected from a retinoic acid receptor antagonist, a heat shock protein 90 antagonist, a steroid, a cell cycle inhibitor, a histone deacetylase inhibitor, an anti-microbial agent, an intracellular calcium flux inhibitor, an microtubule inhibitor, an HMGCoA reductase inhibitor, an actin polymerization and stabilization promoter, a tyrosine kinase inhibitor, a TGF beta inhibitor, a TNF-alpha antagonist, a TACE inhibitor, a calcineurin inhibitor, a peptidyl-prolyl cis/trans isomerase inhibitor, an apoptosis activator, an antimetabolite and anti-neoplastic agent, a TGF beta inhibitor, a DNA methylation promoter, and a PKC inhibitor.

74. The method of claim 67 or claim 68 wherein the anti-scarring agent is selected from ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

75. The method of any one of claims 67-74 wherein the anti-infective agent is selected from an anthracycline, doxorubicin, mitoxantrone, fluoropyrimidine, 5-fluorouracil, a folic acid antagonist, methotrexate, podophylotoxin, etoposide, camptothecin, hydroxyurea, a platinum complex, and cisplatin.

76. The method of any one of claims 67-74 wherein the composition comprises an anti-thrombotic agent.

77. The method of any one of claims 67-74 wherein the polymer is formed from reactants comprising a naturally occurring polymer;

protein;

carbohydrate;

biodegradable polymer;

nonbiodegradable polymer;

collagen;

methylated collagen;

fibrinogen;

thrombin;

blood plasma;

calcium salt;

an antifibronolytic agent;

fibrinogen analog;

albumin;

plasminogen;

von Willebrands factor;

factor VIII;

hypoallergenic collagen;

atelopeptidic collagen;

crosslinked collagen;

aprotinin;

epsilon-amino-n-caproic acid;

gelatin;

protein conjugates;

gelatin conjugates;

a synthetic polymer;

isocyanate-containing compound;

a synthetic thiol-containing compound;

a synthetic compound containing at least two thiol groups;

a synthetic compound containing at least three thiol groups;

a synthetic compound containing at least four thiol groups;

a synthetic amino-containing compound;

a synthetic compound containing at least two amino groups;

a synthetic compound containing at least three amino groups;

a synthetic compound containing at least four amino groups;

a synthetic compound comprising a carbonyl-oxygen-succinimidyl group;

a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups;

a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups;

a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups;

a synthetic polyalkylene oxide-containing compound;

a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks;

a synthetic polyalkylene oxide-containing compound having reactive amino groups;

a synthetic polyalkylene oxide-containing compound having reactive thiol groups;

a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups;

a synthetic compound comprising a biodegradable polyester block;

a synthetic polymer formed in whole or part from lactic acid or lactide;

a synthetic polymer formed in whole or part from glycolic acid or glycolide;

polylysine;

(a) protein and (b) a compound comprising a polyalkylene oxide portion;

(a) protein and (b) polylysine;

(a) protein and (b) a compound having at least four thiol groups;

(a) protein and (b) a compound having at least four amino groups;

(a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups;

(a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone;

(a) collagen and (b) a compound comprising a polyalkylene oxide portion;

(a) collagen and (b) polylysine;

(a) collagen and (b) a compound having at least four thiol groups;

(a) collagen and (b) a compound having at least four thiol groups;

(a) collagen and (b) a compound having at least four amino groups;

(a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups;

(a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone;

(a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion;

(a) methylated collagen and (b) polylysine;

(a) methylated collagen and (b) a compound having at least four thiol groups;

(a) methylated collagen and (b) a compound having at least four amino groups;

(a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups;

(a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone;

hyaluronic acid;

a hyaluronic acid derivative;

pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000;

pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000;

or (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.