Biodegradable cross-linked polymer and methods of preparing the same

Abstract

A biodegradable cross-linked polymer and methods of preparing same are provided. The biodegradable cross-linked polymer is formed from a biodegradable polymeric material having two or more arms, which is a random copolymer formed of a first monomer and a second monomer different from the first monomer. The first monomer is selected from the group consisting of L-lactide, DL-lactide, glycolid, -caprolactone, trimethylene carbonate, p-dioxanone, amino acid-derived polycarbonates and polyorthoesters. The second monomer is one or two selected from the group consisting of D-lactide, DL-lactide, glycolide, -caprolactone, trimethyl carbonate, salicylic acid, carbonates, amino acids and derivatives thereof. The biodegradable polymeric material has a molecular weight of from 5,000 to 1,200,000 and an intrinsic viscosity of from 0.1 to 9.0 dl/g. Each of the terminal groups on the arms of the biodegradable polymeric material is selected from the group consisting of hydroxyl amino and carboxyl groups.

Claims

1. A biodegradable cross-linked polymer for manufacturing a vascular stent, wherein the biodegradable cross-linked polymer is formed from a biodegradable polymeric material having two or more arms, wherein the biodegradable polymeric material having two or more arms is a random copolymer formed of a first monomer and a second monomer different from the first monomer, wherein the first monomer is selected from the group consisting of L-lactide, DL-lactide, glycolide, -caprolactone, trimethylene carbonate, p-dioxanone, and the second monomer is one or two selected from the group consisting of D-lactide, DL-lactide, glycolide, -caprolactone, trimethyl carbonate, salicylic acid, carbonates, amino acids and derivatives thereof, and wherein the biodegradable polymeric material having two or more arms has a number-average molecular weight of from 20,000 to 1,200,000, an intrinsic viscosity of from 0.1 to 9.0 dl/g and an elastic modulus of from 2.5 GPa to 4.5 Gpa at room temperature, and wherein each of terminal groups on the arms of the biodegradable polymeric material having two or more arms is selected from the group consisting of hydroxyl, amino and carboxyl groups.

2. The biodegradable cross-linked polymer of claim 1, wherein the biodegradable cross-linked polymer is obtained by bonding crosslinkable reactive groups to the terminal groups on the arms of the biodegradable polymeric material having two or more arms, and further crosslinking the bonded crosslinkable reactive groups.

3. The biodegradable cross-linked polymer of claim 2, wherein the crosslinkable reactive groups bonded to the terminal groups of the biodegradable polymeric material having two or more arms are selected from the group consisting of (meth)acrylate and any derivative thereof.

4. The biodegradable cross-linked polymer of claim 3, wherein the crosslinkable reactive groups bonded to the terminal groups of the biodegradable polymeric material having two or more arms are selected from the group consisting of methacrylic acid, methacryloyl chloride, methacrylic anhydride, 2-isocyanatoethyl methacrylate and epoxypropyl methacrylate.

5. The biodegradable cross-linked polymer of claim 2, wherein the crosslinking is under a thermal or light irradiation condition.

6. The biodegradable cross-linked polymer of claim 1, wherein the biodegradable cross-linked polymer is obtained by mixing a crosslinking agent and the biodegradable polymeric material having two or more arms.

7. The biodegradable cross-linked polymer of claim 6, wherein the crosslinking agent is selected from linear or star-shaped crosslinking agents containing isocyanate or epoxy group, and the crosslinking agent has a number-average molecular weight of from 500 to 100,000.

8. The biodegradable cross-linked polymer of claim 6, wherein the crosslinking agent is any one, of or a blend of any two or three of n-arm-poly(L-lactide), n-arm-poly(DL-lactide), n-arm-poly(glycolic acid), n-arm-poly(-caprolactone), n-arm-poly(trimethylene carbonate), n-arm-poly(p-dioxanone), n-arm-poly(amino acid-derived polycarbonates) and n-arm-polyorthoesters, where n=2, 3 or 4; or the crosslinking agent is a copolymer formed of a third monomer and a fourth monomer different from the third monomer, wherein the third monomer is selected from the group consisting of L-lactide, DL-lactide, glycolide, -caprolactone, trimethylene carbonate, and p-dioxanone, and the fourth monomer is one or two selected from the group consisting of D-lactide, DL-lactide, glycolide, -caprolactone, trimethyl carbonate, salicylic acid, carbonates, amino acids and derivatives thereof.

9. The biodegradable cross-linked polymer of claim 1, wherein the second monomer accounts for 1 mol % to 50 mol % of a total amount of the first and second monomers.

10. The biodegradable cross-linked polymer of claim 1, wherein the biodegradable polymeric material having two or more arms is selected from the group consisting of n-arm-poly(L-lactide-co-glycolide), n-arm-poly(L-lactide-co-D-lactide), n-arm-poly(L-lactide-co-DL-lactide), n-arm-poly(L-lactide-co--caprolactone), n-arm-poly(L-lactide-co-trimethyl carbonate), n-arm-poly(DL-lactide-co-glycolide), n-arm-poly(DL-lactide-co--caprolactone), n-arm-poly(DL-lactide-co-trimethyl carbonate), n-arm-poly(-caprolactone-co-glycolide) and n-arm-poly(-caprolactone-co-trimethyl carbonate), where n=2, 3 or 4.

11. A method of preparing a biodegradable cross-linked polymer as defined in claim 1, comprising: preparing the biodegradable polymeric material having two or more arms; bonding crosslinkable reactive groups to the terminal groups of the biodegradable polymeric material having two or more arms; and crosslinking the bonded crosslinkable reactive groups.

12. A method of preparing a biodegradable cross-linked polymer as defined in claim 1, comprising: preparing the biodegradable polymeric material having two or more arms; and mixing a crosslinking agent and the biodegradable polymeric material having two or more arms so that the crosslinking agent crosslinks with the biodegradable polymeric material.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Features of the invention will become apparent from the following description, taken in conjunction with the accompanying drawings. It is apparent that what are presented in the drawings are merely a few non-limiting specific embodiments of biodegradable prepolymers, cross-linked polymers and vascular stents described in this application.

(2) FIG. 1(a) shows synthesis of a 3-arm-star-shaped prepolymer with hydroxyl groups at its terminals, wherein x=3-300, and y=1-100.

(3) FIG. 1(b) shows formation of a crosslinkable 3-arm-star-shaped prepolymer having crosslinkable reactive groups by bonding the crosslinkable reactive groups to the terminal hydroxyl groups of the 3-arm-star-shaped prepolymer.

(4) FIGS. 2(a) to 2(c) show a process of making a polymeric tube having a three-dimensional cross-linked network structure in accordance with embodiments of the present invention, wherein FIG. 2(a) shows synthesis of a prepolymer having terminal hydroxyl group; FIG. 2(b) shows synthesis of a crosslinking agent by bonding isocyanate group to terminal groups of another prepolymer; and FIG. 2(c) shows formation of a tube from a blend blended adequately by the prepolymer having terminal hydroxyl group and the crosslinking agent having terminal isocyanate group.

(5) FIG. 3 shows examples of biodegradable vascular stents having different structures according to embodiments of the present invention.

DETAILED DESCRIPTION

(6) For a better understanding of the present invention, its preferred features are described in the following Examples. The description is provided merely for illustrating the features and advantages of the present invention rather than limiting its scope.

Example 1: Synthesis of Degradable Polymers Having Two or More Hydroxyl Groups

(7) (1a) the degradable polymers according to the present invention refers to, but not limited to, the following polymers, formed by melt ring-opening polymerization and having n arms/terminal groups, where n is determined by the number of arms of an initiator used in the polymerization and is 2, preferably 2, 3 or 4:

(8) n-arm-poly(L-lactide), where n=2, 3 or 4,

(9) n-arm-poly(L-lactide-co-glycolide), where n=2, 3 or 4,

(10) n-arm-poly(L-lactide-co-D-lactide), where n=2, 3 or 4,

(11) n-arm-poly(L-lactide-co-DL-lactide), where n=2, 3 or 4,

(12) n-arm-poly(L-lactide-co--caprolactone), where n=2, 3 or 4, and

(13) n-arm-poly(L-lactide-co-trimethyl carbonate), where n=2, 3 or 4,

(14) wherein each second comonomer is present in an amount of 1-80%;

(15) n-arm-poly(DL-lactide), where n=2, 3 or 4,

(16) n-arm-poly(DL-lactide-co-glycolide), where n=2, 3 or 4,

(17) n-arm-poly(DL-lactide-co--caprolactone), where n=2, 3 or 4, and

(18) n-arm-poly(DL-lactide-co-trimethyl carbonate), where n=2, 3 or 4,

(19) wherein each second comonomer is present in an amount of 1-80%;

(20) n-arm-poly(-caprolactone), where n=2, 3 or 4,

(21) n-arm-poly(-caprolactone-co-glycolide), where n=2, 3 or 4, and

(22) n-arm-poly(-caprolactone-co-trimethyl carbonate), where n=2, 3 or 4,

(23) wherein each second comonomer is present in an amount of 1-80%.

(24) (1b) an initiator having 2, 3 or 4 hydroxyl groups was used for each of the said biodegradable polymers, and selected from, but not limited to:

(25) initiators having two hydroxyl groups selected from:

(26) ethylene glycol, 1,4-butylene glycol, n-decanediol, tripropylene glycol, triethylene glycol, triethylene glycol dimethacrylate, triethylene glycol dimethyl ether, triethylene glycol mono-11-mercaptoundecyl ether, triethylene glycol monobutyl ether, triethylene glycol methyl ether methacrylate, polyethylene glycol (PEG) having a molecular weight of 100-10,000, poly(tetrahydrofuran) glycol (polyTHF) having a molecular weight of 100-10,000 and poly(-caprolactone) glycol (PCL) having a molecular weight of 100-10,000, wherein biodegradable linear polymeric prepolymer prepared have two terminal hydroxyl groups, wherein in case of PEG; polyTHF, or PCL selected as the initiator, the biodegradable linear polymer is a PLA-PEG-PLA, PLA-polyTHF-PLA, or PLA-PCL-PLA three-block copolymer with improved hydrophilicity, biodegradation rate and mechanical properties;

(27) initiators having three hydroxyl groups selected from:

(28) polycaprolactone triol (having a molecular weight of 300 or 900), trihydroxy polyoxypropylene ether, 1,2,3-heptanetriol, 1,2,6-hexanetriol, trimethylolpropane and 3-methyl-1,3,5-pentanetriol, wherein a star-shaped polymer prepared have three terminal hydroxyl groups;

(29) initiators having four hydroxyl groups selected from:

(30) 1,2,7,8-octanetetrol, propoxylated pentaerythritol, dipentaerythritol and pentaerythritol, wherein a star-shaped polymer prepared have four terminal hydroxyl groups.

(31) (1c) the biodegradable prepolymers had a molecular weight of from 2,000 to 100,000, preferably from 5,000 to 50,000.

(32) (1d) in the synthesis of each of the biodegradable prepolymer, stannous-2-ethylhexanote (CAS: 301-10-0) was used in an amount of from 0.01% to 0.1%, preferably from 0.01% to 0.5%.

Example 2: Functionalization of (i.e., Addition of Crosslinkable Groups to) Linear or Star-Shaped Prepolymer Containing Hydroxyl Groups

(33) Upon the molecular weight of a biodegradable prepolymer having two or more hydroxyl groups reaching a desired value, there were added in the reactor a free radical inhibitor, for example, but not limited to, 4-methoxyphenol (with an amount of 0.01 wt %-1.0 wt %), and a calculated amount of methacrylic anhydride or 2-isocyanatoethyl methacrylate. As a result, crosslinkable active group containing unsaturated double bond were bonded to the terminal groups of the prepolymer and a crosslinkable polymeric polymer was obtained.

Example 3: Synthesis and Functionalization of 3-Arm-Star-Shaped Copolymeric Prepolymer Based on Polylactic Acid

(34) Prior to the synthesis, a 3 L reactor was dried in vacuum at 80 C. for one hour. 2000 g L-lactide, 100 g glycolide and 14 g 1,2,6-hexanetriol were then added in the reactor under the protection of nitrogen gas and dried in vacuum at 60 C. for one hour. Thereafter, 2 g stannous-2-ethylhexanote was further added and the temperature was increased to 140 C. and maintained at 140 C. for 3 hours, forming a star-shaped copolymeric prepolymer based on polylactic acid having a number-average molecular weight of 20,000 (Equation 1).

(35) The molecular weight of the star-shaped copolymeric prepolymer was determined by a ratio of an amount of the initiator or a ratio of an amount of the monomers and its number-average molecular weight might be controlled in a range of from 5,000 to 50,000. Upon the molecular weight of the star-shaped polylactic acid copolymeric prepolymer reaching a designed value, 48 g (0.32 mol) of methacrylic anhydride and 0.6 g (300 ppm) of 4-methoxyphenol were directly added in drops and the system was then maintained at 150 C. for 2 hours to form a crosslinkable star-shaped polymer (Equation 2). With the completion of the reaction, the reactor was cooled down to 60 C. and 5 L of ethyl acetate was added therein to dissolve the prepolymer. The solution was then slowly poured into a mixture of hexane and ethanol and a product was obtained after a precipitate in the solution was dried.

(36) ##STR00001##

(37) where, x=3-300 and y=1-100.

(38) For the sake of clarity, the biodegradable prepolymer having three hydroxyl groups (n=3) in the Equation is represented hereinafter briefly as:

(39) ##STR00002##

(40) ##STR00003##

Example 4: Synthesis and Functionalization of 2-Arm-Linear Prepolymer Based on Polylactic Acid

(41) Prior to the synthesis, a 3 L reactor was dried in vacuum at 60 C. for one hour. 2000 g L-lactide and 50 g Poly(THF) were then added in the reactor under the protection of nitrogen gas and dried in vacuum at 60 C. for one hour. Thereafter, 2 g stannous-2-ethylhexanote was further added and the temperature was increased to 140 C. and maintained for 3 hours, forming a linear prepolymer based on polylactic acid having a number-average molecular weight of 20,000. The molecular weight of the linear prepolymer was determined by a ratio of an amount of the initiator or a ratio of an amount of the monomer and its number-average molecular weight might be controlled in a range of from 5,000 to 50,000. Upon the molecular weight of the linear prepolymer reaching a designed value, 2-isocyanatoethyl methacrylate and 300 ppm of 4-methoxyphenol were added to form a crosslinkable linear polymer (Equation 3).

(42) ##STR00004##

(43) where,

(44) ##STR00005##
represents the biodegradable prepolymer having 2 hydroxyl groups (n=2).

Example 5: Synthesis and Functionalization of 4-Arm-Star-Shaped Prepolymer Based on Polylactic Acid

(45) Prior to the synthesis, a 3 L reactor was dried in vacuum at 60 C. for one hour. 2000 g L-lactide, 100 g -caprolactone and 60 g pentaerythritol were then added in the reactor under the protection of nitrogen gas and dried in vacuum at 60 C. for one hour. Thereafter, 2 g stannous-2-ethylhexanote was further added and the temperature was increased to 140 C. and maintained for 3 hours, forming a star-shaped prepolymer having a number-average molecular weight of 18,000. The molecular weight of the star-shaped prepolymer was determined by a ratio of an amount of the initiator or a ratio of an amount of the monomers and its number-average molecular weight might be controlled in a range of from 5,000 to 50,000. Upon the molecular weight of the star-shaped copolymeric prepolymer reaching a designed value, 72 g methacrylic anhydride and 0.6 g (300 ppm) of 4-methoxyphenol were directly added and the system was then maintained to form a crosslinkable star-shaped polymer (Equation 4). With the completion of the reaction, the reactor was cooled down to 60 C. and 5 L of ethyl acetate was added therein to dissolve the prepolymer. The solution was then slowly poured into a mixture of hexane and ethanol and a product was obtained after a precipitate in the solution was dried.

(46) ##STR00006##

(47) where,

(48) ##STR00007##
represents the biodegradable polymer having 4 hydroxyl groups (n=4).

(49) In summary, various polymers with different molecular weights can be obtained through ring-opening polymerization of different monomers or comonomers in presence of initiators differing in terms of type, number of arms, etc. While many other biodegradable materials with different properties can be further prepared using the methods described above, their preparation is not exemplified herein.

Example 6: Crosslinking of Polymers

(50) Each of the above-described prepared linear and star-shaped polymeric prepolymers was adequately blended with a photoinitiator such as, but not limited to, Esacure KIP 150 (with an amount of 0.1 wt %-0.5 wt %) and then melted by heat within a space between two glass blocks. In the space, PTFE film frame were arranged to adjust a thickness of the plate being formed to a desired value. Afterward, crosslinking of the melt blended was induced by UV light irradiation, thereby obtaining a standard model. The mechanical and thermal properties of the sample presented in Table 1.

(51) In addition, biodegradation of the model was tested using a shaker equipped with a water bath kept at a constant temperature of 37 C. A sample of the formed model with given dimensions and weight was submersed in a buffer solution (pH 7) in the water bath. At intervals, the sample was taken out, dried and weighed to calculate its weight loss percentages (wt %)

(52) TABLE-US-00001 TABLE 1 Mechanical and Thermal Properties of Cross-linked Biodegradable Polymers Mechanical properties Room temperature Body temperature Biodegradation (23 C.) (37 C.) rate: weight Elastic Elongation Elastic Elongation Thermal loss percentage modulus at break modulus at break property (wt %) at the Cross-linked polymers (Gpa) (%) (Gpa) (%) (Tg/ C.) 52.sup.nd week PLGA (95/5) 4.3 3 3.3 40 58 20% PLGA (90/10) 4.0 3 3.2 75 58 35% PLGA (85/15) 3.0 76 1.7 45 55 60% PLGA (85/15)-pTHF250 3.6 18 3.0 134 50 70% PLGA (85/15)-PCL500 3.4 3 1.8 140 44 60% P(L-LA70-DL-LA30)-TERA 3.1 125 0.9 146 42 15% PLGA (85/15)-PEG400 2.5 47 40 75% PLGA (85/15)-PEG600 0.7 150 29 80% PLGA (85/15)-PEG1000 0.31 220 20 92% PLGA (85/15)-PCL540 0.12 200 24 53% PLGA (85/15)-PCL triol900 0.96 160 36 ND P(DL-LA/-CL90/10)-PCL540 2.2 145 35 ND PLGA (85/15)-PC500 3.4 3 1.8 140 44 55% In this table: PLGA represents poly(L-lactide-co-glycolide), wherein PLGA (95/5) indicates a poly(L-lactide-co-glycolide) with a ratio of its L-lactide content to glycolide content of 95:5, and the same is applied to all the others; PLLA represents a poly(L-lactide); PDLLA represents a poly(DL-lactide); P(L-LA70-DL-LA30)-TERA represents a poly(L-lactide-co-DL-lactide) having a ratio of its L-lactide content to DL-lactide content of 70:30, formed using pentaerythritol as the initiator; pTHF250 represents a poly(tetramethylene ether) glycol with a molecular weight of 250; PCL represents poly(-caprolactone) glycols, wherein PCL500 and PCL540 indicate poly(-caprolactone) glycols with molecular weights of 500 and 540, respectively; PEG400, PEG600 and PEG1000 represent polyethylene glycols with molecular weights of 400, 600 and 1000, respectively; PLGA(85/15)-PCL triol900 represents a poly(L-lactide-co-glycolide) having a ratio of its L-lactide content to glycolide content of 85:15, formed using a polycaprolactone triol with a molecular weight of 900 as the initiator; P(DL-LA/-CL 90/10)-PCL540 represents a poly(DL-lactide-co--caprolactone) having a ratio of its DL-lactide content to -caprolactone content of 90:10, formed using a polycaprolactone triol with a molecular weight of 540 as the initiator; PLGA(85/15)-PC500 represents a poly(L-lactide-co-glycolide) having a ratio of its L-lactide content to glycolide content of 85:15, formed using a polycarbonate diol with a molecular weight of 500 as the initiator; and ND is brief for not determined.

(53) It can be seen from the weight loss percentages at the 52.sup.nd week of the samples shown in Table 1, polymers with higher glycolide contents have increased biodegradation rates. Biodegradation rates of the polymers can be adjusted by using different initiators. For example, using a poly(tetramethylene ether) glycol as the initiator will lead to an increase in biodegradation rate because of its high hydrophilicity.

(54) From the data in Table 1, it can also be found that, the biodegradable cross-linked polymers have elastic moduli ranging from 0.12 GPa to 4 GPa depending on their compositions, and at the body temperature, some of them maintain high elastic moduli and show improved elongations at break. That is, such polymers are tough but not brittle. Thermal properties (glass transition temperatures) of the polymers range from 20 C. to 60 C. Biodegradation rates of these polymers can be adjusted to a range of from 3 months to 36 months. Further, other parameters may also be adjusted and diversified to satisfy more practical needs.

Example 7: Formation and Crosslinking of Polymeric Tube

(55) Each of the above-described prepared crosslinkable prepolymers was sufficiently blended with the photoinitiator Esacure KIP 150 (with an amount of 0.3 wt %) and then dried in a vacuum oven. The dried blend was extruded to form a tube or rod by a twin-screw extruder. During the extrusion, the tube or rod being formed were irradiated with UV light or other radiation to achieve rapid crosslinking.

(56) In addition, this rapid crosslinking during the extrusion might be conducted as a preliminary polymerization process. In order to increase the stability of the tube or rod, the tube or rod was further heated at a temperature lower than a glass transition temperature of the polymer, preferably 5 C. lower than the latter, and then irradiated by UV light again until the gel content of the polymer exceeded 95%.

(57) Crosslinking of the tube or rod might be further enhanced to a higher extent if desired.

Example 8: Polymeric Tubes with Cross-Linked Network Structure

(58) Biodegradable vascular stents according to the present invention were formed by laser cutting respective polymeric tubes each having a three-dimensional cross-linked network structure. The formation of the polymeric tubes is described below with reference to the following sub-examples.

Example A: Prepolymer Self-Crosslinking

(59) Synthesis of Star-Shaped Copolymeric Prepolymer Based on Polylactic Acid and Addition of Crosslinkable Groups Thereto

(60) Referring to FIG. 1(a), prior to the synthesis, a 3 L glass reactor was dried in vacuum at 80 C. for one hour, and 2100 g L-lactide, 370 g glycolide and 22 g (0.16 mol) 1,2,6-hexanetriol were then added in the reactor. After the reactor was deoxygenated by repeating the process of evacuation and argon filling, stannous-2-ethylhexanote was added therein and the reaction was run at 145 C. Upon a number-average molecular weight of the star-shaped copolymeric prepolymer reaching a designed value, 114 g (0.741 mol) methacrylic anhydride and 0.75 g free radical inhibitor such as, for example, 4-methoxyphenol, to prepare a crosslinkable star-shaped prepolymer (FIG. 1(b)). With the completion of the reaction, the reactor was cooled down to 60 C. and 5 L of ethyl acetate was added therein to dissolve the prepolymer. The solution was then slowly poured into a mixture of hexane and ethanol and a product was obtained after a precipitate in the solution was dried.

(61) The crosslinkable star-shaped polymer might be formed into a tube by means of extrusion, injection, or other forming technique. During or after the formation, crosslinking of the crosslinkable star-shaped polymer might be induced by UV light irradiation to form a polymeric tube with a three-dimensional cross-linked network structure. Their mechanical properties are provided in Table 2.

(62) Biodegradation rates of synthesized biodegradable materials were tested by a shaker at a constant temperature and indicated by their weight loss percentages, such as the data of weight loss percentages at the 52.sup.nd week shown in Table 2, from which it can also be found that, polymers with higher glycolide contents have increased biodegradation rates. Biodegradation rates of the polymers can be adjusted by using different initiators. For example, using a poly(tetramethylene ether) glycol as the initiator will lead to an increase in biodegradation rate because of its high hydrophilicity.

(63) TABLE-US-00002 TABLE 2 Mechanical Properties of Cross-linked Polymers Biodegradation Mechanical properties Rate (in vitro Room temperature Body temperature biodegradation): (23 C.) (37 C.) weight loss Elastic Elongation Elastic Elongation Thermal percentage modulus at break modulus at break property (%) at the Cross-linked polymers (Gpa) (%) (Gpa) (%) (Tg/ C.) 52.sup.th week PLGA (95/5) 4.3 3 3.3 40 58 20% PLGA (90/10) 4.0 3 3.2 75 58 35% PLGA (85/15) 3.0 76 1.7 45 55 60% PLGA (85/15)-pTHF250 3.6 18 3.0 134 50 70% PLGA (85/15)-PCL500 3.4 3 1.8 140 44 60% P(L-LA70-DL-LA30)-PCL540 3.1 125 0.9 146 42 15% In this table: PLGA represents a poly(L-lactide-co-glycolide), wherein PLGA (95/5) indicates a poly(L-lactide-co-glycolide) with a ratio of its L-lactide content to glycolide content of 95:5, and PLGA (90/10) indicates a poly(L-lactide-co-glycolide) with a ratio of its L-lactide content to glycolide content of 90:10; PLLA represents a poly(L-lactide); PDLLA represents a poly(DL-lactide); P(L-LA70-DL-LA30) represents a poly(L-lactide-co-DL-lactide) having a ratio of its L-lactide content to DL-lactide content of 70:30; pTHF250 represents a poly(tetramethylene ether) glycol with a molecular weight of 250; and PCL represents poly(-caprolactone) glycols, wherein PCL500 and PCL540 indicate poly(-caprolactone) glycols with molecular weights of 500 and 540, respectively.

(64) From data in the above table, it can be seen that the cross-linked polymers synthesized in accordance with this sub-example possess high elastic moduli (>3 GPa) at the room temperature. Particularly some of them maintain high elastic moduli (>3 GPa) and exhibit high elasticity (evidenced by their elongation of 40% at break) at 37 C. It provides stents made of them with sufficient radial strength and resistance to compression. In addition, selecting suitable comonomers can enable the adjustment of the polymer's biodegradation rate according to the duration of healing of the vascular lesion.

Example B: Crosslinking Between Prepolymer and Crosslinking Agent

(65) Referring to FIG. 2(a), in a first step, a biodegradable star-shaped polymeric copolymer serving as a first prepolymer was synthesized by ring-opening polymerization from a cyclic monomer or cyclic comonomers, such as L-lactide and -caprolactone (molar ratio of L-LA/-CL: 95/5).

(66) In a second step, a crosslinking agent was synthesized, as shown in FIG. 2(b). A hydroxyl group-containing star-shaped copolymer serving as a second prepolymer was synthesized by the same approach as in the first step. For example, the second prepolymer was made from L-lactide and -caprolactone (molar ratio of L-LA/-CL: 95/5). The second prepolymer differ from the first prepolymer obtained in the first step in the number-average molecular weight controlled within a range of from 500 to 10,000. Subsequently, isocyanate groups were boned to terminals of molecules of the second prepolymer (which might be a linear or star-shaped polymer having 2, 3 or 4 arms, preferably 3 or 4 arms which might lead to a better crosslinking effect). The prepared polymer was then precipitated and rinsed until there is no residue of the isocyanate therein, thus forming the crosslinking agent.

(67) In a third step, as shown in FIG. 2(c), the first prepolymer prepared in the first step and the crosslinking agent with terminal isocyanate groups were blended sufficiently and optionally added with a suitable amount (0.1 mol %) of a catalyst such as dibutyltin dilaurate (CAS: 77-58-7). The blend was then formed into a tube by extrusion molding or injection molding. The formed tube may be subjected to a suitable thermal treatment to obtain an enhanced crosslinking degree, thus forming a polymeric tube with the three-dimensional cross-linked network structure.

Example 9: Stents

(68) In general terms, the polymeric tubes with three-dimensional cross-linked network structures might each have an outside diameter of 2-10 mm and a wall thickness of 50-250 m. The polymeric tubes with three-dimensional cross-linked network structures obtained in accordance with the sub-examples of Example 8 might be laser cut according to practical application requirements to form biodegradable vascular stents as shown in FIG. 3.

(69) Stent Strength and Stability

(70) The stent shown in FIG. 3(b) having an outside diameter of 3 mm, a wall thickness of 150 m and a length of 2 cm was submersed in a 37 C. water bath held between two plates. A tensile test machine was used to compress the stent at a rate of 10 mm/min. When the compressive deformation of the stent reaches 15%, the stress value was recorded. For each type of the stents, 10 samples were tested and the data were averaged and shown in Table 3. Another group of samples was stored in vacuum packaging bags at the room temperature for 3 months and their strength was tested in the same way. The results showed that, the stents with three-dimensional cross-linked network structures had similar radial strength to metallic stents and the radial strength was stable with time and did not show significant decrease.

(71) TABLE-US-00003 TABLE 3 Radial strength (N/mm.sup.2) Cross-linked PLA stent On the start day 0.131 0.013 3 Months later 0.128 0.008

(72) During use of a biodegradable stent according to the present invention, it needs to be compressed over a non-inflated balloon of a stent delivery system in advance. After the stent has been delivered to a lesion site of a vessel, the balloon is inflated and the stent is expanded to form a support to the lesion site. Subsequently, the balloon is deflated and withdrawn from the body together with the delivery system. The polymeric tubes prepared in accordance with Example 8 with a three-dimensional cross-linked network structure have high mechanical strength, which provide the stents with sufficient radial compression resistance. In addition, when exposed to the body temperature, the polymeric stents according to the present invention can sense temperature increase and the three-dimensional network structures can exhibit a shape memory effect. This allows the stents to gradually regain their original diameters and reduces mechanical relaxation behavior of their polymeric materials to a maximum extent, which leads to reduced occurrence of stent retraction.

(73) Description of the foregoing examples is presented merely for facilitating the understanding of the core principles of the present invention. It is noted that while many modifications and variations can be made by those of ordinary skill in the art without departing from the inventive concept disclosed herein, it is intended that the appended claims cover all such modifications and variations.

REFERENCES

(74) (1) Kelch S, Steuer S. et al., Shape-Memory Polymer Networks from oligo[(-hydroxycaproate)-co-glycolate]dimethacrylates and Butyl Acrylate with Adjustable Hydrolytic Degradation Rate, Biomacromolecules 2007, 8, 1018-1027. (2) Lendlein et al. Shape-Memory Polymer networks from oligo(-caprolactone) dimethacrylate J. Polym. Sci. Part A. 2005, 43, 1369. (3) Langer R. et al. U.S. Pat. No. 6,388,043 B1 shape-memory polymers, 2002. (4) Wang Y. D. et al. US2003/0118692 A1, Biodegradable polymers. (5) Bettinger C. J. et al. WO2007/082305 A2 Biodegradable elastomers. (6) Susawa T et al, Biodegradable intracoronary stents in adult dogs, J. Am. Coll. Cardiol. 1993, 21(supp 1), 483A. (7) Stack R. S. et al. Interventional cardiac catheterization at Duke Medical Center. Am. J. Cardiol. 1988, 62, 3F-24F. (8) Zidar J. P. et al, Short-term and long-term vascular tissue response to the Duke biodegradable stent. J. Am. Coll. Cardiol. 1993, 21, 439A. (9) Tamai et al. Initial and 6-month results of biodegradable P-l-lactic acid coronary stents in humans. Circulation, 2000, 102, 399-404. (10) Tsuji T, Tamai H, Igaki K, et al. One year follow-up biodegradable self-expanding stent implantation in humans. J Am Coll Cardiol 2001; 37(Abstr): A47. (11) Eberhart R. C. et al. Expandable biodegradable endovascular stent. I. Fabrication and properties. Annals of biomedical engineering, 2003, 31, 667-677. (12) Eberhart R. C. et al. Mechanical properties and in vitro degradation of bioresorbable fibers and expandable fiber-based stents, 2005, J. Biomed. Mater. Res. Part B: Appl. Biomater. 2005, 74B: 792-799. (13) Hietala E. M. et al, Biodegradation of the copolymeric polylactide stent, J. Vascular Research, 2001, 38, 361-369. (14) Vlimaa T et al, Viscoelastic memory and self-expansion of self-reinforced bioabsorbable stents, Biomaterials, 2002, 23, 3575-3582. (15) Ye Y. W. et al, Bioresorbable microporous stents deliver recombinant adenovirus gene transfer vectors to the arterial wall, Annals of Biomedical Engineering, 1998, 3, 398-408. (16) Blindt R. et al, Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent, European Heart Journal, 2004, 25, 1330-1340. (17) Venkatraman S. S. et al, Biodegradable stent with elastic memory, Biomaterials, 2006, 27(8): 1573-8. (18) Gao R et al, A novel polymeric local heparin delivery stent: initial experimental study. J. Am. Coll. Cardiol. 1996, 27, 85A. (19) John A. Ormiston et al. First-in-Human Implantation of a Fully Bioabsorbable Drug-Eluting Stent: The BVS Poly-L-Lactic Acid Everolimus-Eluting Coronary Stent, Catheterization and Cardiovascular Interventions 69:128-131(2007).