Degradable implantable medical devices

• US 20060229711A1
• Filed: 04/04/2006
• Published: 10/12/2006
• Est. Priority Date: 04/05/2005
• Status: Abandoned Application

• Current Assignee: Elixir Medical Corporation
• Original Assignee: Elixir Medical Corporation
• Inventors: Yan, John, Bhat, Vinayak D., Cryer, Brett, Sirhan, Motasim
• Application Number:
  US11/398,363
• Publication Number:
  US 20060229711A1
• Time in Patent Office: Days
• US Class Current: 623/1.380
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/07 Stent-grafts
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2/90 characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2220/0058 soldered or brazed or welded
• CPC Class Codes: A61F 2250/003 differing in adsorbability or resorbability, i.e. in adsorption or resorption time
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: B23K 2101/06 Tubes
• CPC Class Codes: B23K 2103/02 Iron or ferrous alloys
• CPC Class Codes: B23K 2103/12 Copper or alloys thereof
• CPC Class Codes: B23K 2103/50 Inorganic material, e.g. metals, not provided for in B23K2103/02 – B23K2103/26
• CPC Class Codes: B23K 26/0006 taking account of the properties of the material involved B23K26/32, B23K26/40 take precedence
• CPC Class Codes: B23K 26/0624 using ultrashort pulses, i.e. pulses of 1ns or less
• CPC Class Codes: B23K 26/355 Texturing
• CPC Class Codes: B23K 26/382 by boring
• CPC Class Codes: B23K 26/40 taking account of the properties of the material involved

Abstract

Devices and methods are provided for an implantable medical device which is degradable over a clinically relevant period of time. The medical devices may have the form of implants, graft implants, vascular implants, non vascular implants, wound closure implants, sutures, drug delivery implants, biologic delivery implants, urinary tract implants, inter-uterine implants, organ implants, bone implants including bone plates, bone screws, dental implants, spinal disks, or the like. In preferred embodiments, the implantable medical device comprises an implantable luminal prosthesis, such as vascular and non-vascular stents and stents grafts.

Claims

1. A degradable, implantable structure comprising:

an implantable body having at least one surface; and

at least one corrosion inducing feature on the at least one surface which causes at least a portion of the body to degrade at a rate greater than the rate without the feature in a physiologic environment.

2. A structure as in claim 1, wherein the implantable body comprises a metal, a metal alloy or a combination thereof.

3. A structure as in claim 2, wherein the metal, metal alloy, or a combination thereof comprises at least one of cobalt, tungsten, bismuth, silver, copper, iron, zinc, magnesium, zirconium, niobium, iridium, indium, bismuth, tin, nickel, and alloys thereof.

4. A structure as in claim 1, wherein the at least one corrosion inducing feature comprises a pit, pore, partial hole, void or combination of these.

5. A structure as in claim 1, wherein the at least one corrosion inducing feature comprises a surface irregularity, score, scratch, streak, ridge, bump, texture, sintered porous metal or alloy, roughened surface or combination of these.

6. A structure as in claim 1, wherein the at least one corrosion inducing feature comprises a hole, thru hole, thru sintered pore or combination of these.

7. A structure as in claim 1, wherein the implantable body has a first surface with a first associated portion of the body and a second surface with a second associated portion of the body, and wherein the first surface has corrosion inducing features present in a density which causes the first associated portion to degrade at a rate which differs from the second associated portion.

8. A structure as in claim 1, wherein the implantable body comprises a stent.

9. A degradable, implantable structure comprising:

an implantable body having

a first layer which degrades at a first degradation rate, wherein the first layer comprises a metal, metal alloy or combination thereof, and

a second layer which degrades at a second degradation rate which differs from the first rate, wherein the second layer comprises a metal, metal alloy or combination thereof,

wherein the layers cause at least a portion of the structure to degrade in a physiologic environment.

10. A structure as in claim 9, wherein the first and second layers have different passive states.

11. A structure as in claim 9, wherein the first and second layers differ in electrochemical states.

12. A structure as in claim 9, wherein the degradation rates differ due to differing thicknesses of the layers.

13. A structure as in claim 9, wherein the implantable body comprises a stent.

14. A degradable, implantable structure comprising:

an implantable body comprising a metal, metal alloy or combination thereof having a degradation rate; and

a layer which covers at least a portion of the implantable body, wherein the layer controls the degradation rate of the implantable body.

15. A structure as in claim 14, wherein the layer comprises a passivation layer.

16. A structure as in claim 15, wherein at least one of the thickness, chemical composition, durability, amount of coverage of the implantable structure of the passivation layer is selected to control the degradation rate.

17. A structure as in claim 16, wherein an amount of corrosion-resistant oxides present in the passivation layer is selected to control the degradation rate.

18. A structure as in claim 14, wherein the layer comprises a ceramic, polymer, metal, metal alloy, therapeutic agent, corrosive agent, radiopaque agent or combination of these.

19. A structure as in claim 18, wherein the layer has openings which reveal underlying portions of the implantable body, wherein the openings assist in controlling the degradation rate of the implantable body.

20. A structure as in claim 14, wherein the implantable body comprises a stent.

209. A structure as in claim 14, wherein at least one of the thickness, chemical composition, durability, and/or coverage of implantable structure of the coating is selected to control the degradation rate.

21. A degradable, implantable structure comprising:

an implantable body comprising a metal, metallic alloy or combination thereof which has at least a portion which degrades at a degradation rate, wherein the degradation rate has at least two phases of differing degradation rates.

22. A structure as in claim 21, wherein the at least two phases comprises an initial degradation rate which is slower than a later degradation rate.

23. A structure as in claim 21, wherein the at least two phases comprises an initial degradation rate which is faster than a later degradation rate.

24. A structure as in claim 21, wherein the implantable body comprises a stent.

25. A degradable structure comprising:

an implantable body comprising a metal, metallic alloy or combination thereof which has at least a portion which degrades at a degradation rate which varies along its length.

26. A structure as in claim 25, wherein the implantable body comprises a stent.

27. A degradable structure comprising:

an implantable body comprising a metal, metallic alloy or combination thereof, wherein its geometry affects the degradation rate.

28. A structure as in claim 27, wherein the geometry comprises surface area to volume ratio.

29. A structure as in claim 27, wherein the implantable body comprises a stent.

30. A structure as in claim 29, wherein the stent includes a strut having a strut width and a strut thickness, and wherein the geometry comprises strut width to strut thickness or strut thickness to strut width ratios of greater than 1.4:

1.

31. A degradable structure comprising:

an implantable body comprising a metal, metal alloy or combination thereof having a degradation rate; and

at least one therapeutic agent which elutes from the implantable structure.

32. A structure as in claim 31, wherein the at least one therapeutic agent includes a an anti-platelet, anti-proliferative, immunosuppressant, pharmacological agent, an anti-cancer agent, an anti-inflammatory agent, a pharmaceutical agent, or a combination of these.

33. A structure as in claim 31, further comprising a coating which at least partially covers the implantable body.

34. A structure as in claim 33, wherein the at least one therapeutic agent elutes from the coating.

35. A structure as in claim 31, wherein the at least one therapeutic agent comprises one therapeutic agent which elutes in one phase of degradation and another therapeutic agent which elutes in another phase of degradation.

36. A structure as in claim 31, wherein the at least one therapeutic agent is at least partially contained in a corrosion inducing feature.

37. A degradable structure comprising:

an implantable body comprising a metal, metallic alloy or combination thereof which has at least a portion which degrades at a rate to approximate dissolution in the physiologic environment in a period between one month to 5 years.

38. A degradable implant comprising:

a body composed of a metal and having a structure, wherein said metal and structure are selected to allow the body to degrade in a physiologic environment in a period of from 1 month to 5 years.

39. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade in a period of from 4 months to 2 years.

40. An implant as in claim 38, wherein the metal and structure are selected to allow the structure to degrade in a period of from 6 months to 12 months.

41. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of mass from 0.05% to 3% per day.

42. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of mass from 0.1% to 0.75% per day.

43. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of mass from 0.25% to 0.5% per day.

44. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of volume from 0.05% to 3% per day.

45. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of volume from 0.1% to 0.75% per day.

46. An implant as in claim 38, wherein the metal and structure are selected to allow the body to degrade with a average loss of volume from 0.25% to 0.5% per day.

47. An implant as in claim 38, wherein the metal is selected from the group consisting of iron, cobalt, tungsten, molybdenum, silver, copper, and zirconiumindium, bismuth, tin, and nickel.

48. An implant as in claim 47, wherein the metal has a purity of at least 90%.

49. An implant as in claim 47, wherein the purity is at least 95%.

50. An implant as in claim 47, wherein the purity is at least 99.5%.

51. An implant as in claim 38, wherein the metal is an iron alloy.

52. An implant as in claim 51, wherein the iron alloy contains at least 25% iron.

53. An implant as in claim 51, wherein the iron alloy contains at least 50% iron.

54. An implant as in claim 51, wherein the iron alloy contains at least 75% iron.

55. An implant as in claim 51, wherein the iron alloy contains at least 90% iron.

56. An implant as in claim 51, wherein the iron alloy contains at least 99% iron.

57. An implant as in claim 51, wherein the iron alloy is a carbon steel.

58. An implant as in claim 57, wherein the carbon steel contains at least 0.05% to 3% carbon.

59. An implant as in claim 57, wherein the carbon steel contains at least 0.05% to 1% carbon.

60. An implant as in claim 57, wherein the carbon steel contains at least 0.1% to 0.6% carbon.

61. An implant as in claim 57, wherein the carbon steel is a 1000 series carbon steel.

62. An implant as in claim 51, where in the iron alloy is a 1300 series manganese steel.

63. An implant as in claim 51, where in the iron alloy is a 4000 series molybdenum steel.

64. An implant as in claim 51, where in the iron alloy is a 4100 series chromium-molybdenum steel.

65. An implant as in claim 51, where in the iron alloy is a 4300 series chromium-molybdenum steel.

66. An implant as in claim 51, where in the iron alloy is a 8600 series chromium-molybdenum steel.

67. An implant as in claim 51, where in the iron alloy is a 4600 series nickel chromium-molybdenum steel.

68. An implant as in claim 51, where in the iron alloy is a 5100 series chromium steel.

69. An implant as in claim 51, where in the iron alloy is a 6100 series chromium-vanadium steel.

70. An implant as in claim 51, where in the iron alloy is a 9200 series silicon steel.

71. An implant as in claim 51, where in the iron alloy is a cast iron containing at least 80% iron.

72. An implant as in claim 51, wherein the metal alloy comprises silver.

73. An implant as in claim 72, wherein the silver is present at at least 25% by weight.

74. An implant as in claim 72, wherein the silver is present at at least 50% by weight.

75. An implant as in claim 72, wherein the silver is present at at least 75% by weight.

76. An implant as in claim 72, wherein the silver is present at at least 90% by weight.

77. An implant as in claim 72, wherein the silver is present at at least 95% by weight.

78. An implant as in claim 72, wherein the silver is present at at least 98% by weight.

79. An implant as in claim 38, wherein the metal comprises tin.

80. An implant as in claim 79, wherein the tin is present at at least 25% by weight.

81. An implant as in claim 79, wherein the tin is present at at least 50% by weight.

82. An implant as in claim 79, wherein the tin is present at at least 75% by weight.

83. An implant as in claim 79, wherein the tin is present at at least 90% by weight.

84. An implant as in claim 79, wherein the tin is present at at least 95% by weight.

85. An implant as in claim 79, wherein the tin is present at at least 98% by weight.

86. An implant as in claim 38, wherein the metal comprises cobalt.

87. An implant as in claim 86, wherein the cobalt is present at at least 25% by weight.

88. An implant as in claim 86, wherein the cobalt is present at at least 50% by weight.

89. An implant as in claim 86, wherein the cobalt is present at at least 75% by weight.

90. An implant as in claim 86, wherein the cobalt is present at at least 90% by weight.

91. An implant as in claim 86, wherein the cobalt is present at at least 95% by weight.

92. An implant as in claim 86, wherein the cobalt is present at at least 98% by weight.

93. An implant as in claim 38, wherein the metal comprises tungsten.

94. An implant as in claim 93, wherein the tungsten is present at at least 25% by weight.

95. An implant as in claim 93, wherein the tungsten is present at at least 50% by weight.

96. An implant as in claim 93, wherein the tungsten is present at at least 75% by weight.

97. An implant as in claim 93, wherein the tungsten is present at at least 90% by weight.

98. An implant as in claim 93, wherein the tungsten is present at at least 95% by weight.

99. An implant as in claim 93, wherein the tungsten is present at at least 98% by weight.

100. An implant as in claim 38, wherein the metal comprises molybdenum.

101. An implant as in claim 100, wherein the molybdenum is present at at least 25% by weight.

102. An implant as in claim 100, wherein the molybdenum is present at at least 50% by weight.

103. An implant as in claim 100, wherein the molybdenum is present at at least 75% by weight.

104. An implant as in claim 100, wherein the molybdenum is present at at least 90% by weight.

105. An implant as in claim 100, wherein the molybdenum is present at at least 95% by weight.

106. An implant as in claim 100, wherein the molybdenum is present at at least 98% by weight.

107. An implant as in claim 38, wherein the metal has a corrosion current (Icorr) value in the range from 0.0001 amps/cm² to 0.1 amps/cm².

108. An implant as in claim 107, wherein the Icorr value is in the range from 0.001 amps/cm² to 0.01 amps/cm².

109. An implant as in claim 107, wherein the Icorr value is in the range from 0.0025 amps/cm² to 0.008 amps/cm².

110. An implant as in claim 38, wherein the metal degrades to biologically compatible degradation products.

111. An implant as in claim 110, wherein the degradation products are chemically the same as substances found naturally in a human body.

112. An implant as in claim 38, wherein the metal is ductile.

113. An implant as in claim 112, wherein the metal can be elongated by a factor of at least 1.2 before breaking.

114. An implant as in claim 112, wherein the metal can be elongated by a factor of at least 1.3 before breaking.

115. An implant as in claim 112, wherein the metal can be elongated by a factor of at least 1.4 before breaking.

116. An implant as in claim 112, wherein the metal can be elongated by a factor of at least 1.6 before breaking.

117. An implant as in claim 38, which comprises an expandable prosthesis having a reduced width for delivery and an expanded width for implantation.

118. An implant as in claim 117, wherein the prosthesis comprises a plurality of struts.

119. An implant as in claim 118, wherein the struts have a thickness no greater than 0.004 in.

120. An implant as in claim 118, wherein the struts have a thickness no greater than 0.003 in.

121. An implant as in claim 118, wherein the struts have a thickness no greater than 0.002 in.

122. An implant as in claim 118, wherein the struts have a thickness no greater than 0.0015 in.

123. An implant as in claim 118, wherein the struts have a thickness no greater than 0.001 in.

124. An implant as in claim 118, wherein the struts have a ratio of width to thickness of at least 1.4:

1.

125. An implant as in claim 118, wherein the struts have a ratio of width to thickness of at least 2:

1.

126. An implant as in claim 118, wherein the struts have a ratio of width to thickness of at least 3 to 1.

127. An implant as in claim 118, wherein the struts have a ratio of width to thickness of at least 4 to 1.

128. An implant as in claim 118, wherein the struts have a ratio of thickness to width of at least 1.4 to 1.

129. An implant as in claim 118, wherein the struts have a ratio of thickness to width of at least 2 to 1.

130. An implant as in claim 118, wherein the struts have a ratio of thickness to width of at least 3 to 1.

131. An implant as in claim 118, wherein the struts have a ratio of thickness to width of at least 4 to 1.

132. An implant as in claim 118, wherein the struts after degrading in the physiologic environment for one month still retain at least 25% of their initial strength.

133. An implant as in claim 118, wherein the struts after degrading in the physiologic environment for one month still retain at least 50% of their initial strength.

134. An implant as in claim 118, wherein the struts after degrading in the physiologic environment for one month still retain at least 60% of their initial strength.

135. An implant as in claim 38, wherein the metal and structure are selected to degrade substantially uniformly over an exposed surface thereof.

136. An implant as in claim 38, wherein the metal and structure are selected to degrade non-uniformly over an exposed surface thereof.

137. An implant as in claim 38, wherein the implant structure comprises at least one feature on an exposed surface of the implant which promote corrosion.

138. An implant as in claim 137, wherein the features include one or more of pits, pores, voids, sintering, bumps, ridges, and scoring.

139. An implant as in claim 137, wherein the features increase the rate of degradation by weight in the physiologic environment by at least 10% compared to the implant without the features.

140. An implant as in claim 137, wherein the features increase the rate of degradation by weight in the physiologic environment by at least 20% compared to the implant without the features.

141. An implant as in claim 137, wherein the features increase the rate of degradation by weight in the physiologic environment by at least 40% compared to the implant without the features.

142. An implant as in claim 137, wherein the features provide a mean surface roughness of at least 100 nm.

143. An implant as in claim 137, wherein the features provide a mean surface roughness of at least 400 nm.

144. An implant as in claim 137, wherein the features provide a mean surface roughness of at least 1000 nm.

145. An implant as in claim 38, wherein at least a portion of an exposed surface of the implant is coated with a material.

146. An implant as in claim 145, wherein the coating material is degradable in the physiologic environment.

147. An implant as in claim 146, wherein the material has a degradation rate greater than that of the body.

148. An implant as in claim 146, wherein the material has a degradation rate less than that of the body.

149. An implant as in claim 145, wherein the coating material is non-degradable in the physiologic environment.

150. An implant as in claim 145, wherein the coating is patterned to control exposure of the body to the physiologic environment.

151. An implant as in claim 145, wherein the coating is porous.

152. An implant as in claim 145, wherein the coating is non-porous.

153. An implant as in claim 145, wherein the coating is metallic.

154. An implant as in claim 145, wherein the coating is non-metallic.

155. An implant as in claim 145, wherein the coating is ceramic.

156. An implant as in claim 145, wherein the coating comprises a polymer.

157. An implant as in claim 145, wherein the coating comprises a therapeutic agent.

158. An implant as in claim 157, wherein the polymer comprises a porosity control agent.

159. An implant as in claim 158, wherein the porosity control agent is selected from the group consisting of salts and blowing agents, wherein the agents will at least partially leach after implantation.

160. An implant as in claim 145, comprising two or more coating materials.

161. An implant as in claim 160, wherein the two or more coating materials have different degradation rates.

162. An implant as in claim 160, wherein the two or more coating materials are layered.

163. An implant as in claim 160, wherein the two or more coating materials are coated over different regions of the exposed surface.

164. An implant as in claim 156, wherein the polymeric coating material has a thickness over the body in the range from 0.1 μ

m to 100 μ

m.

165. An implant as in claim 156, wherein the polymeric coating material has a thickness over the body in the range from 1 μ

m to 50 μ

m.

166. An implant as in claim 156, wherein the polymeric coating material has a thickness over the body in the range from 5 μ

m to 25 μ

m.

167. An implant as in claim 153, wherein the metallic coating material has a thickness over the body in the range from 0.1 nm to 100 μ

m.

168. An implant as in claim 154, wherein the coating material has a thickness over the body in the range from 1 nm to 50 μ

m.

169. An implant as in claim 154, wherein the coating material has a thickness over the body in the range from 5 nm to 25 μ

m.

170. An implant as in claim 145, wherein the coating comprises a therapeutic agent.

171. An implant as in claim 170, wherein the agent is present on the body in an amount from 1 ng/cm² to 1000 μ

g/cm².

172. An implant as in claim 170, wherein the agent is present on the body in an amount from 1 ng/cm² to 500 μ

g/cm².

173. An implant as in claim 170, wherein the agent is present on the body in an amount from 10 ng/cm² to 400 μ

g/cm².

174. An implant as in claim 170, wherein the therapeutic agent is released at a rate in the physiologic environment from 1 ng/cm²/day to 1000 μ

g/cm² day.

175. An implant as in claim 170, wherein the therapeutic agent is released at a rate in the physiologic environment from 1 μ

g/cm²/day to 200 μ

g/cm² day.

176. An implant as in claim 170, wherein the therapeutic agent is released at a rate in the physiologic environment from 5 mcg/cm²/day to 100 mcg/cm² day.

177. An implant as in claim 170, wherein the therapeutic agent is released from the body in the physiologic environment over a period in the range from 1 day to 3 years.

178. An implant as in claim 170, wherein the therapeutic agent is released from the body in the physiologic environment over a period in the range from 2 weeks to 1 year.

179. An implant as in claim 170, wherein the therapeutic agent is released from the body in the physiologic environment over a period in the range from 1 month to 6 months.

180. An implant as in claim 170, wherein the therapeutic agent comprises an anti-proliferative drug.

181. An implant as in claim 170, wherein the therapeutic agent comprises an immunosuppressant drug.

182. An implant as in claim 170, wherein the therapeutic agent comprises an anti-neoplastic drug.

183. An implant as in claim 170, wherein the therapeutic agent comprises an anti-inflammatory drug.

184. An implant as in claim 170, wherein the therapeutic agent comprises an anti-platelet drug.

185. An implant as in claim 170, wherein the therapeutic agent comprises sirolimus and analogs thereof.

186. An implant as in claim 170, wherein the therapeutic agent comprises paclitaxol and analogs thereof.

187. An implant as in claim 111, wherein the metal includes iron and the compounds are iron species.

188. An implant as in claim 187, wherein the metal consists essentially of iron or an iron alloy.

189. An implant as in claim 188, wherein the compounds are produced in an amount which is less than ten fold the amount naturally present in a human body.

190. An implant as in claim 188, wherein the compounds are produced in an amount which is less than five fold the amount naturally present in a human body.

191. An implant as in claim 188, wherein the compounds are produced in an amount which is less than two fold the amount naturally present in a human body.

192. An implant as in claim 188, wherein the compounds are produced in an amount which is no greater than the amount naturally present in a human body.

193. An implant as in claim 137, wherein the features are distributed uniformly over said exposed surface.

194. An implant as in claim 137, wherein said features are exposed non-uniformly over said exposed surface.

195. An implant as in claim 137, wherein the features have dimensions selected from diameter, depth, width and length in the range from 1 nm to 1 mm.

196. An implant as in claim 137, wherein the features have dimensions selected from diameter, depth, width and length in the range from 10 nm to 100 micrometer.

197. An implant as in claim 137, wherein the features have dimensions selected from diameter, depth, width and length in the range from 100 nm to 1 micrometer.

198. An implant as in claim 137, wherein the features have a surface density in the range from 1/cm² to 10¹⁴/cm².

199. An implant as in claim 137, wherein the features have a surface density in the range from 100/cm² to 108/cm².

200. An implant as in claim 137, wherein the features have a surface density in the range from 1000/cm² to 106/cm².

201. An implant as in claim 137, wherein the percentage of surface area covered with features is in the range from 0.1% to 99.9%.

202. An implant as in claim 137, wherein the percentage of surface area covered with features is in the range from 5% to 75%.

203. An implant as in claim 137, wherein the percentage of surface area covered with features is in the range from 10% to 50%.

204. An implant as in claim 145, wherein the coating contains or is next to a therapeutic agent.

205. An implant as in claim 145, wherein the coating protects adjacent tissue from the degrading implant.

206. An implant as in claim 145, wherein the coating preferentially directs degradation products away from adjacent tissue or blood.

207. An implant as in claim 145, wherein the coating preferentially directs degradation products toward adjacent tissue or blood.

208. An implant as in claim 145, wherein the coating neutralizes degradation products.

210. An implant as in claim 158, wherein the porosity control agent is selected from the group consisting of salts and blowing agents, wherein the agents will at least partially leach before implantation.