Claims: Claims:
1. A process for manufacturing a self-expanding bioresorbable braided scaffold with improved radial and axial flexibility, the process including
a. braiding of degradable monofilament on a mandrel to form a braided scaffold; and
b. subjecting the braided scaffold to two or more stages of heat treatment to stabilize and impart high strength to the braided scaffold, the two or more stages of heat treatment including a primary heat treatment stage and a secondary heat treatment stage, the secondary heat treatment stage melts the braided scaffold at one or more crossover points leading to fusion at the one or more crossover points and imparting high strength and axial flexibility to the braided scaffold.
2. The process as claimed in claim 1, wherein the degradable monofilament is made of biodegradable polymer, the biodegradable polymer is selected from a group consisting of poly-L-lactide-co-caprolactone (PLC), Poly dioxanone, Poly trimethylene carbonate (PTMC), polycaprolactone (PCL), poly-DL-lactic acid (PDLLA), polyglycerol sebacate (PGS), Poly L-lactide (PLLA), Poly (glycolic acid) (PGA), Poly L-lactide-co-glycolic acid (PLGA) and/or a mixture thereof.
3. The process as claimed in claim 1, wherein number of carrier forming the braided scaffold is 16 to 96 carriers and more preferably between 24 to 48 carriers.
4. The process as claimed in claim 1 wherein the braiding is done at high yarn tension to achieve a uniform braid angle between 110° to 140°.
5. The process as claimed in claim 1 wherein the primary heat treatment is performed at a temperature of 100°C to 120°C for a duration of 08 hours to 16 hours thereby relieving internal stress and residual monomer from the degradable monofilament.
6. The process as claimed in claim 1 wherein the secondary heat treatment is performed at a temperature of 130°C to 145°C for a duration of 02 hours to 04 hours thereby merging one or more crossover points and imparting high strength and axial flexibility to the braided scaffold.
7. The process as claimed in claim 1 wherein post the subjecting step, the process comprises one or more of
a. attaching one or more radio-opaque markers to the heated braided scaffold;
b. securing an elastomer coating to the braided scaffold of step a;
c. subjecting the braided scaffold of step b to a thermal curing process;
d. cutting the thermal cured braided scaffold of step c at free ends to achieve smooth edges and desired length of a scaffold;
e. coating at least an antiproliferative drug on the braided scaffold of step d for therapeutic effect to control release of the antiproliferative drug to minimize rate of in-scaffold restenosis;
f. braided scaffold of step e is placed with delivery apparatus to yield a delivery assembly; and
g. sealing the delivery assembly in a pouch containing oxygen absorber followed by sterilization.
8. The process as claimed in claim 7 wherein the one or more radio-opaque markers is a C-shape platinum marker.
9. The process as claimed in claim 7 wherein the elastomer coating is prepared from a polymer consisting of poly-L-lactide-co-caprolactone (PLC), polycaprolactone (PCL), poly-dl-lactic acid (PDLLA), polyglycerol sebacate (PGS), Poly L - lactide (PLLA), Poly(glycolic acid) (PGA), Polydioxane (PDO), Poly L-lactide co-glycolic acid (PLGA) or a mixture thereof.
10. The process as claimed in claim 7, wherein the elastomer coating comprises of Poly L-lactide-co caprolactone (PLC), Polycaprolactone (PCL) and 1, 6 hexa methylene diisocyanate.
11. The process as claimed in claim 7 wherein thickness of the elastomer coating is in range of 30 µm to 50 µm.
12. The process as claimed in claim 7 wherein the thermal curing process is performed at a temperature between 110°C to 120°C for time duration of 16 hours to 24 hours.
13. The process as claimed in claim 7 wherein cutting comprises cutting the braided scaffold by laser cutting.
14. The process as claimed in claim 7 wherein the antiproliferative drug comprises of sirolimus drug with Poly DL-lactide (PDLLA) polymer.
15. The process as claimed in claim 7 wherein antiproliferative drug coating thickness is less than 5 µm.
16. The process as claimed in claim 7 wherein the sterilization comprises sterilization via an e-beam radiation sterilization process.
17. A self-expanding bioresorbable braided scaffold assembly, the assembly comprising:
a. a braided scaffold formed of a degradable monofilament with shape memory effect, the braided scaffold including one or more crossover points fused together during subjecting of the braided scaffold to two or more stages of heat treatment, the two or more stages of heat treatment including a primary heat treatment stage and a secondary heat treatment stage, the secondary heat treatment stage melts the braided scaffold at one or more crossover points leading to fusion at the one or more crossover points and imparting high strength and axial flexibility to the braided scaffold; and
b. a loading mechanism comprising a basket and a delivery catheter, the basket mounts the braided scaffold onto the delivery catheter and prevents trapping of free ends of the braided scaffold.
18. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17, wherein the degradable monofilament is made of biodegradable polymer, the biodegradable polymer is selected from a group consisting of poly-L-lactide-co-caprolactone (PLC), Poly dioxanone, Poly trimethylene carbonate (PTMC), polycaprolactone (PCL), poly-dl-lactic acid (PDLLA), polyglycerol sebacate (PGS), Poly L-lactide (PLLA), Poly (glycolic acid) (PGA), Poly L-lactide co-glycolic acid (PLGA) and/or a mixture thereof.
19. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein thickness of the degradable monofilament is between 100 µm to 200 µm.
20. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein number of carrier forming the braided scaffold is selected from 16 to 96 carriers and more preferably between 24 and 48 carriers.
21. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the braided scaffold comprises one or more radio-opaque markers.
22. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 21 wherein the one or more radio-opaque markers is a C-shape platinum marker.
23. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the braided scaffold comprises an elastomer coating.
24. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 23 wherein the elastomer coating is selected from a polymer group consisting of Poly lactide-co-caprolactone, poly caprolactone, poly trimethylene carbonate, Poly (glycerol sebacate) (PGS), poly lactide co-dioxanone and combination, more preferably Poly L-lactide co-caprolactone.
25. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 23 wherein the elastomer coating comprises of Poly L-lactide-co caprolactone, Polycaprolactone and 1, 6 hexa methylene diisocyanate.
26. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 25 wherein inherent viscosity of the Polycaprolactone (PCL) polymer is between 1.0 dl/g and 1.3 dl/g.
27. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 25 wherein molecular weight of the Polycaprolactone (PCL) polymer is between 1,15,000 g/mol to 2,44,660 g/mol.
28. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 25 wherein inherent viscosity of the Poly-L-lactide-co-caprolactone polymer is between 1.2 dl/g and 1.8 dl/g.
29. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 25 wherein molecular weight of the Poly-L-lactide-co-caprolactone polymer is between 1,47,000 g/mol and 2,61,000 g/mol.
30. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the free ends of the braided scaffold are closed with respective bioresorbable hollow sleeves.
31. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 30 wherein the bioresorbable hollow sleeves are connected alternately by leaving one braided crossover point in between.
32. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 30 wherein the bioresorbable hollow sleeve is made from PLGA or PLC material.
33. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the braided scaffold comprises a coating of at least an antiproliferative drug.
34. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the braided scaffold is loaded prior to implantation with the loading mechanism and braided scaffold is intended to acutely function as a metal stent and eventually resorbs over a period of time.
35. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the basket is laser cut to a hopper design.
36. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein the basket is fully covered with one of silicone or PTFE coating.
37. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein an uncrimped braided scaffold is stored in a vial, the vial being designed having a tapered shape, the tapered shape of the vial helps to radially compress both the basket and braided scaffold to load onto the delivery catheter.
38. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 17 wherein a disc is fixed at a distal part of the delivery catheter, the disc helps to axially compress the braided scaffold during deployment.
39. The self-expanding bioresorbable braided scaffold assembly as claimed in claim 38 wherein the disc is fabricated by braiding 32 to 72 carriers.
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)

1. TITLE OF THE INVENTION:
BRAIDED SCAFFOLD AND METHOD OF MANUFACTURING THEREOF
2. APPLICANTS:
Meril Life Sciences Pvt. Ltd., an Indian company, of the address Survey No. 135/139, Bilakhia House, Muktanand Marg, Chala, Vapi, Gujarat - 396191

The following specification particularly describes the invention:

FIELD OF INVENTION
[001] The present invention discloses a bioresorbable scaffold. More specifically, to a self-expanding bioresorbable scaffold.
BACKGROUND
[002] Scaffolds are cylindrical hollow shape structures inserted into blood vessels to restore normal blood flow when the blood vessels are obstructed. In order to perform adequate functions, scaffolds must possess characteristics, such as biocompatibility, high mechanical strength, radiopacity, longitudinal flexibility, ease of handling, corrosion resistance, high strength, radial expansion and shape memory.
[003] Scaffolds may be fabricated of metallic materials, such as stainless steel, alloys such as nickel, titanium, etc. due to their properties of high tensile strength. However, use of metallic material may cause some disadvantages such as corrosion, restenosis or bleeding complications. Restenosis occurs in, approximately, 30% of patients in the period of about nine months after the procedure, and is associated with high mortality rate and high cost of health care. One of the main factors associated with restenosis is damage to arteries caused by the metal rods of the scaffold, which causes immune and/or inflammatory responses by the organism.
[004] In order to minimize or eliminate the disadvantages associated with metallic scaffolds, fiber scaffolds or scaffolds with fiber components are being considered. The fiber scaffolds combined with metal, as nitinol, and coated with polytetrafluoroethylene (PTFE), polyester scaffolds, polyamide scaffolds, etc. have been in use. Advantageously, self-expanding (SE) scaffolds may also be used. The self-expanding scaffolds may have diameter larger than that of the target vessel. The scaffolds may be crimped, restrained in a delivery system and/or elastically released into the target vessel.
[005] A surgical implant such as a scaffold endoprosthesis must preferably be made of biocompatible material in order to minimize the foreign-body response of the host tissue. The implant must also have sufficient structural strength, biostability, size and durability and shape memory to withstand the conditions and confinement in a body lumen.
SUMMARY
[006] The present invention discloses a self-expanding bioresorbable braided scaffold with improved radial and axial flexibility is disclosed. The scaffold comprises a degradable monofilament with shape memory effect, the process includes braiding of the degradable monofilament on a mandrel to form a braided scaffold, subjecting the braided scaffold to two or more stages of heat treatment to stabilize and impart high strength to the braided scaffold, the two or more stages of heat treatment including a primary heat treatment stage and a secondary heat treatment stage, the secondary heat treatment stage melts the braided scaffold at one or more crossover points leading to fusion at the one or more crossover points and imparting high strength and axial flexibility to the braided scaffold.
BRIEF OF DESCRIPTION OF DRAWINGS
[007] The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those in the art will understand that the drawings are not to scale.
[008] FIG.1 illustrates a flow chart depicting process involved in manufacturing of a braided scaffold in accordance with an embodiment of the present invention.
[009] FIG. 2 illustrates an exemplary view of a braided scaffold with compressed crossover points in accordance with an embodiment of the present invention.
[0010] FIG. 3 illustrates a schematic view of a delivery catheter attached with a nitinol basket points in accordance with an embodiment of the present invention.
[0011] FIG. 4 illustrates an exemplary architecture of loading of the braided scaffold in accordance with an embodiment of the present invention.
[0012] FIG. 5 illustrates a front view of a braided disc in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF DRAWINGS
[0013] Prior to describing the invention in detail, definitions of certain words or phrases used throughout this patent document will be defined: the terms "include" and "comprise", as well as derivatives thereof, mean inclusion without limitation; the term "or" is inclusive, meaning and/or; the phrases "coupled with" and "associated therewith", as well as derivatives thereof, may mean to include, be included within, interconnect with, contain, be contained within, connect to or with, couple to or with, be communicable with, cooperate with, interleave, juxtapose, be proximate to, be bound to or with, have, have a property of, or the like; Definitions of certain words and phrases are provided throughout this patent document, and those of ordinary skill in the art will understand that such definitions apply in many, if not most, instances to prior as well as future uses of such defined words and phrases.
[0014] Particular embodiments of the present disclosure are described herein below with reference to the accompanying drawings, however, it is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.
[0015] In accordance with the present disclosure, a braided scaffold having self-expansion and/or enhanced shape memory properties is disclosed. The braided scaffold can be used in various applications such as, for treatment of stenosed lumen like Superficial femoral artery (SFA), popliteal, BTK, carotid, pulmonary, biliary, or esophageal), treatment of veins (such as femoral vein, subclavian vein, inferior vena cava and superior vena cava), treatment of stenosed peripheral lumen (like tapered blood vessel), etc. In another embodiment, the braided scaffold is manufactured by providing multiple heat treatments in order to achieve enhanced shape memory, radial strength and/or axial flexibility of the braided scaffold for treatment of obstructed peripheral vasculature. In an embodiment, crossover points of the braided scaffold are merged together by application of heat treatment and coating process to the braided scaffold.
[0016] Now referring specifically to drawings, FIG.1 illustrates a flow chart depicting a process involved in manufacturing of the braided scaffold. In accordance with an embodiment of the present invention, the process includes the steps of without limitation braiding, heat treatment, cutting, marker placement, coating and packaging steps.
[0017] The process of manufacturing the braided scaffold commences by braiding of monofilaments at the step 101. The braided scaffold may be made of monofilaments derived from polymer granules. The polymer granules may be made of without limitation, the poly-L-lactide-co-caprolactone (PLC), Poly dioxanone, Poly trimethylene carbonate (PTMC), polycaprolactone (PCL), poly-dl-lactic acid (PDLLA), polyglycerol sebacate (PGS), Poly L-lactide (PLLA), Poly (glycolic acid) (PGA), Poly L-lactide co-glycolic acid (PLGA) and/or a mixture thereof. In an embodiment, the polymer granules are extruded to form monofilaments before start of braiding process. The polymer granules may be extruded by means of without limitation an extrusion process. The extruded monofilaments may be optionally annealed at a temperature between 100°C to 130°C for time duration of 30 minutes to 4 hours to enhance strength of monofilaments. The annealed monofilaments may withstand high yarn tension braiding which enhances the strength of the braided configuration.
[0018] In an embodiment, the braided scaffold is made of braided PLGA monofilaments. The PLGA granules comprise of 85% mol L-Lactide and 15% mol Glycolide with 1.80 dl/g - 2.5 dl/g density, melting point ranging from 126°C to 145°C and glass transition temperature ranges from 40°C to 45°C. In an embodiment, the PLGA granules are extruded by means of an extrusion process producing oriented PLGA monofilaments having a tensile strength values 8-10 fold higher strength than of non-oriented polymer monofilament. The extruded monofilament may be annealed between a temperature ranging from 100°C and 130°C for time duration of approximately 30 minutes to 04 hours to enhance strength of the monofilaments. The annealed PLGA monofilaments may withstand high yarn tension braiding which enhance the strength of braided configuration. In an embodiment, the break load of PLGA monofilament with diameter between 150 µm and 200 µm ranges from 2.1 lbf to 2.9 lbf, elongation ranges from 30 % to 45 %, modulus of monofilament ranges from 710 Ksi to 980 Ksi.
[0019] The extruded monofilaments are braided together with the help of horizontal and/or vertical braiding machines for example, a teflon mandrel. The mandrel may use a plurality of spool carriers to carry filament bobbins in serpentine-like paths about a track plate. The numbers of spool carriers used may be approximately 16-96, preferably 24-48. The track plate may consist of two separate paths, each path 180 degrees out of phase from the other. One path moves clockwise, while the other path moves counter clockwise. Half the carriers travel in the clockwise path around the braiding point following one serpentine path while the other half of the carriers travel in the anticlockwise path around the braiding point. Two sets of carriers travel in opposite directions around the braiding point thereby making an interweaving braided scaffold on the mandrel. The point of interweaving or intersection is also known as crossover points 200 as shown in FIG.2. Braiding parameters may include constant take-up speed between 2.0 V/Hz and 6.0 V/Hz and rotation vary between 30 V/Hz and 60 V/Hz.
[0020] The braiding pattern may include any regular pattern such as half load pattern (1x1), full load pattern (1x2) and/or diamond pattern (2x2) etc. In an embodiment, the braided scaffold comprises of braid with 1x2 braid pattern with biodegradable monofilaments ranging from 24 to 144 carriers with a braid angle of approximately 100° to 150° preferably between 110° and 135°.
[0021] In another embodiment, the braiding at free ends is dense as compared to the middle portion. Denser braiding at free ends ensures that the braided scaffold maintains the shape and thus, avoids damage to blood vessels due to deformation of the free ends of the braided scaffold. In an exemplary embodiment, due to dense braiding at the free ends, the braided scaffold is thicker at the free ends (for example, approximately 5mm to 10mm). In yet another embodiment, free ends of the braided scaffold can be slightly tapered in a way such as outer diameter (OD) of middle portion of braided scaffold is less than OD of braided scaffold free ends. This tapered free ends may help in anti-migration of braided scaffold after implantation.
[0022] Following braiding of the monofilaments in previous step, the braided scaffold is subjected to heat treatment at the step 103. The heat treatment may be provided in order to impart enhanced shape memory, higher elasticity and mechanical strength and to avoid deformation during loading and deployment of the braided scaffold.
[0023] For imparting heat treatment, the braided scaffold is mounted on the mandrel and may be tied at the free ends with the help of a tie wrap. The mandrel may be subjected to heat treatment with the help of without limitation an oven, preferably a vacuum oven, in controlled conditions of around 700 mm Hg pressure and a temperature range between 70°C to 140°C (above glass transition temperature and below melting temperature of the polymer) for a time duration of around 08 hours to 24 hours. The temperature and time duration of heat treatment is predefined.
[0024] The braided scaffold may be subjected to two or more cycles of heat treatment in order to release internal stress, impart shape memory and/or stability to the braided scaffold. In an embodiment, heat treatment is provided in two stages for example, a primary heat treatment and a secondary heat treatment. The primary heat treatment temperature may range between 90°C to 120°C for time duration of around 08 hours to 24 hours. The primary heat treatment aids in relieving internal stress of the monofilaments of the braided scaffold and removal of residual monomer.
[0025] In an embodiment, the secondary heat treatment is provided at a temperature ranging between 120°C to 145°C, preferably between 130°C to 140°C for time duration of around 01 hours to 05 hours. The secondary heat treatment temperature range is near melting point of polymer and may facilitate merging of the crossover points 200 of the braided scaffold as shown in FIG.2. In an embodiment, during secondary heat treatment, the crossover points 200 are slightly melted and merged together, thereby increasing the mechanical strength of the braided scaffold. Further, secondary heat treatment helps in reducing change in length of braided scaffold after deployment from a delivery sheath. The present invention achieves compression of the crossover points 200 due to secondary heat treatment as opposed to application of adhesive and/ or spot welding of the crossover points with laser beam.
[0026] In another embodiment, during secondary heat treatment, the crossover points 200 of the braided scaffold on the mandrel are compressed by application of pressure. Pressure may be applied using two rectangular Teflon blocks at a temperature of around the melting point of the polymer in a vacuum oven. The Teflon blocks facilitate melting of the polymer at the crossover points, thereby fusing the polymer at the crossover points. Melting of the polymer imparts high radial strength to the braided scaffold, minimizes change in length of the braided scaffold and gains maximum recovery towards its original diameter.
[0027] Additionally, following heat treatment, the annealed or heat treated braided scaffold is cut to a predefined desired length. The braided scaffold may be cut by means of without limitation a sharp surgical scissor.
[0028] Following heat treatment, a plurality of markers is attached on the braided scaffold in step 105. In an embodiment, a plurality of markers is attached at one or more free ends of the braided scaffold. The markers may be attached to the braided scaffold in order to make the braided scaffold visible under fluoroscopy inside the body of a patient during treatment. The markers may be of any shape such as without limitation, hollow tube, coil, sphere, C-cut, or flat ribbon. The markers may be made of biocompatible radiopaque material. The material may include without limitation platinum, Iridium, tantalum, gold and/or their combination.
[0029] The process of placement of markers may be facilitated by means of vacuum tweezers which can generate vacuum of 10 to 15 inch. The markers may alternately be press fitted over the braided scaffold by means of without limitation marker crimper.
[0030] In an embodiment, four C cut shaped platinum markers are attached at each free ends of the braided scaffold equidistant from each other. The markers may have a thickness ranging from 0.025 mm to 0.06mm, preferably between 0.035mm to 0.05mm. The markers may be attached to the braided scaffold by means of without limitation thermal bonding, adhesive, etc. The markers are attached in a way so as to conform to the expanded and/or deployed state of the braided scaffold.
[0031] In step 107, a hollow sleeve may be attached at one or more free end of the braided scaffold. The sleeve may be made of a radiopaque and/or polymeric material. The material may include without limitation PLGA, PLC, platinum, gold, etc.
[0032] In an embodiment, the free ends of the braided scaffold are closed completely by attaching respective hollow sleeves. In another embodiment, the free ends of the braided scaffold are welded to the respective hollow sleeve to hold free ends firmly. Close ends may enhance the strength of the free ends of the braided scaffold.
[0033] Following sleeve attachment, the braided scaffold is coated with an elastomer formulation at step 109. The formulation may be prepared with biocompatible polymers. The polymers may also be mixed with cross-linkers. The polymers may include without limitation poly-L-lactide-co-caprolactone (PLC), polycaprolactone (PCL), poly-DL-lactic acid (PDLLA), polyglycerol sebacate (PGS), Poly L - lactide (PLLA), Poly(glycolic acid) (PGA), Polydioxane (PDO), Poly L-lactide co-glycolic acid (PLGA) or a mixture thereof. The cross-linkers may include without limitation polyurethanes derived from diisocynates, butane diisocyanate (BDI), hexamethylene diisocyanate (HDI), Isophorone diisocyanate (IPD), Lysine diisocyanate (LDI) etc. The use of cross-linker may enhance the mechanical strength and elasticity of the braided scaffold.
[0034] The elastomer coating may be applied on the braided scaffold by means of without limitation, spray coating with the help of a spray gun. The distance between the braided scaffold and the spray gun may be maintained between 2 cm to 4 cm, rotational speed between 20 rpm to 30 rpm in order to obtain smooth and uniform coating. The elastomer formulation spray release rate may be maintained between 0.15 to 0.30 ml/min and pressure of nitrogen or other inert gas may be maintained between 2 kg/cm2 to 4 kg/cm2 in order to achieve good adhesion and immediate drying of elastomeric formulation on the braided scaffold. Elastomer coated braided scaffold may be kept in a vacuum chamber for a time duration of approximately 24 hours for the purpose of evaporation of solvents from the braided scaffold.
[0035] Additionally, the elastomer coated braided scaffold may be thermally cured to achieve desired elastic properties and to impart high strength to the braided scaffold. The thermal curing may be performed without limitation in a vacuum oven at a temperature ranging between 110°C to 120°C for time duration of 08 hours to 16 hours and then allowed to cool to the ambient temperature.
[0036] In an embodiment, the Poly (glycerol sebacate) (PGS) is used in the elastomer formulation. The PGS can easily degrade into glycerol and sebacic acid inside patient’s body. The inherent viscosity of PGS is 0.11 dl/g - 0.19 dl/g with molecular weight ranging from 25,000 g/mol to 35,000 g/mol. The PGS has high strength ranging between 0.28 ± 0.004 MPa, young’s modulus ranging between 0.122±0.0003 MPa and elongation ranging between 237.8 ± 0.64 %. The PGS formulation may be dissolved in any suitable organic solvents such as chloroform, dichloro methane, acetone, methanol or their mixture in a concentration of approx. 05 % to 15 %. The solvent may be spray coated until predetermined thick coating is achieved. In an embodiment, the thickness of coating ranges between 20 µm to 60 µm, preferably between 30 µm to 50 µm.
[0037] The elastomer coated braided scaffold is thermo set in a vacuum oven at a temperature of around 100°C to 130°C for time duration of around 48 hours to 96 hours to increase strength, durability and/or regain original diameter after deployment from catheter.
[0038] The advantages of using PGS may include degradation through surface erosion method, reduction in inflammation, late thrombosis, and/or fracture formation by increasing braided scaffold durability which may lead to ease of treatment in complex anatomy such as superficial femoral artery, femoral vein and varicose vein.
[0039] In an embodiment, blend of PGS and PCL is used for elastomer formulation in order to increase the mechanical properties of the braided scaffold. PCL degradation time is approximately one year while PGS typically degrades within three months.
[0040] In another embodiment, mixture of PLC and PCL in a ratio of around 88:12 with a cross-linker hexamethylene diisocyanate is used to formulate elastomer formulation. Inherent viscosity of the Poly-L-lactide-co-caprolactone (PLC) polymer is between 1.2 dl/g and 1.8 dl/g and molecular weight is between 1,47,000 g/mol and 2,61,000 g/mol. PCL polymer has molecular weight between 1,15,000 g/mol and 2,44,660 g/mol with inherent viscosity ranging from 1.0 dl/g to 1.3 dl/g. The formulation prepared may be kept in an ultra-sonication apparatus for a period of 20 minutes to 60 minutes to get a homogeneous solution. The formulation may be dissolved in methylene chloride and acetone in a ratio of around 1:19. In an embodiment, the concentration of polymer in elastomer formulation is approximately between 0.4 % to 1.0 % to achieve high radial strength, high regaining ability or self-expansion properties. In an embodiment, the thickness of coating ranges between 10 µm to 40 µm, preferably between 20 µm to 30 µm. Elastomer coating and/or thermal curing also support better securement of radio-opaque platinum marker on a braided scaffold.
[0041] Following elastomeric coating of the previous step, the braided scaffold may be laser cut at the step 111. The cutting may be performed with the help of without limitation, femto-seconds equipment. The laser cutting of edges of the braided scaffold results in smooth free ends. The smooth free ends may help in avoiding any damage to strands during loading into delivery sheath and after deployment from catheter to the treatment site.
[0042] The laser beam wavelength may range from 1300nm to 1600nm. In another embodiment, inert gas for example argon, oxygen, helium, nitrogen, etc. is used. The pressure may be maintained between 0.6 bar to 1.0 bar.
[0043] Following laser cutting, the braided scaffold is coated with formulation of antiproliferative drug at the step 113. The drug coating may be obtained by means of without limitation spray coating. The antiproliferative drug may be formulated with a carrier that allows release of the drug in controlled manner. The carrier may include without limitation Poly-DL- lactide (PDLLA), Poly-L-Lactide (PLLA), Poly-L-lactide co-caprolactone (PLC), Polycaprolactone (PCL), Poly-DL-lactide co-glycolide (PDLG), Poly-L-lactide co-glycolide (PLGA). The drug and the carrier may be dissolved in a solvent such as methylene chloride, chloroform, acetone, methanol and mixtures thereof in order to facilitate spray coating.
[0044] In order to obtain a uniform coat over the braided scaffold, the drug formulation may be spray released at a rate of approximately 0.10 to 0.40 ml/min, preferably between 0.15 to 0.30 ml/min. Distance between the spray gun and the braided scaffold may be maintained between 03 cm to 06 cm. After coating, the braided scaffold may be kept under vacuum to remove excess solvents.
[0045] In an embodiment, a formulation of Sirolimus drug and PDLLA polymer as carrier in a proportion of around 50:50 is dissolved in acetone solvent. Sirolimus drug dose may be maintained at 1.25 µg per mm2 area of the braided scaffold. An uniform and smooth coating is obtained by spraying the solution on the braided scaffold by spray coating machine. The thickness of the drug coating may range between 02 µm to 08 µm.
[0046] Lastly, the braided scaffold is subjected to sterilization and sealed in an aluminum pouch with inert gas purge. In another embodiment, prior to sterilization, oxygen absorbers are placed in an aluminum pouch containing braided scaffold to eliminate oxygen and prevent polymer properties from deterioration due to presence of oxygen. The oxygen absorbers may be evicted, cut-off from the pouch by additional sealing over a period of 12 to 36 hours after absorbing or removal of oxygen from the pouch. The concentration of residual oxygen content may reduce to 0.05% or less. Further, the aluminum pouch containing braided scaffold with delivery catheter may be then subjected to e-beam sterilization process.
[0047] In an embodiment, the e-beam radiation may range from 15 to 30 kGy and more preferably between 18 to 23 kGy. The sterilization process for the braided scaffold can be carried out at a temperature between 15 to 25°C. In an embodiment, the braided scaffold maintains its structural integrity for a period of approximately six months and then eventually resorbs over time duration of approximately one to two years. The braided scaffold may resorb through body natural metabolism and excreted in form of carbon dioxide and water.
[0048] Loading of braided scaffold to a delivery catheter may be performed prior to implantation in the body. The loading may be done 15 minutes to 30 minutes before the implantation in order to maintain structural integrity of the braided scaffold. To facilitate loading of the braided scaffold into the delivery system, a basket 302 may be attached to the delivery catheter 300 as shown in FIG.3. The delivery catheter 300 may be a delivery catheter that can be used as per the teachings of the present invention and is capable of holding a basket 302.
[0049] The basket 302 may be made of shape memory materials such as without limitation, nitinol, copper-aluminium-nickel alloy and elgiloy-copper alloy etc. The number of crowns in the basket 302 may be maintained in a range of 5-10 as per dimensions of the braided scaffold. The basket 302 may be fully covered with a coating of without limitation silicon or PTEF. The coating may be provided by means of without limitation dip coating or electrospin coating. The coating thickness may be maintained between 30 µm to 50 µm.
[0050] In an embodiment, the basket 302 is made of nitinol. The basket 302 may be fabricated by means of without limitation laser cutting process. In an embodiment, the basket 302 is designed in a shape of a hopper. This shape may prevent the braided scaffold to be pulled away after deployment to the treatment site during retrieval of the delivery catheter 300. The basket 302 is designed in a way such that, free ends of the braided scaffold are not trapped or locked inside the basket 302, avoid slippage during loading into the delivery catheter 300, and/or deployment to the site of treatment.
[0051] FIG.4 represents an exemplary architecture 400 for loading of the braided scaffold onto the delivery catheter 300. The architecture 400 includes the delivery catheter 300, the basket 302, a vial 304 and the braided scaffold 402. The vial 304 may be made of any material without limitation high density polyethylene (HDPE), polypropylene, polystyrene and/or polyethylene. The vial 304 may be in a shape of without limitation, an elongated circular tube with a vial cap 306. In an embodiment, the vial 304 is in a shape of a tube having a plurality of taper shaped projections 308 on walls. The vial 304 may be designed to store the braided scaffold 402 inside a packaging tray.
[0052] The advantages of using the vial 304 may include that the braided scaffold can be easily and accurately loaded onto the delivery catheter 300 without using an external tool and/or by manual compression. Other advantages may include, the braided scaffold may be uniformly compressed into the basket 302 which in turn leads to uniform self-expansion of the braided scaffold during deployment and/or prevention of damage to the braided scaffold due to manual handling.
[0053] In an embodiment, the vial cap 306 is pressed in an inward direction. The pressing of the vial cap 306 may facilitate radial compression of the braided scaffold 402 and distal end of the basket 302 due to taper shaped projections 308. The braided scaffold 402 is pushed towards the basket 302 due to radial compression. After entering of the braided scaffold 402 in the basket 302, the delivery catheter 300 is pulled in back by means of without limitation a pulling rod (not shown). This enables easy and accurate loading of the braided scaffold onto the delivery catheter 300.
[0054] In another embodiment, a braided disc 400 (shown in FIG.5) made of nitinol is utilized. The braided disc may be fixed at distal end of the delivery catheter 300. The braided disc is manufactured in a way such that outer diameter of the braided disc is less than the inner diameter of the braided scaffold. The braided disc may be fabricated by using approximately 32 to 72 carriers.
The process of manufacturing of the scaffold is explained with following example:
[0055] The scaffold is manufactured by braiding of the poly (L-lactide-co-glycolide) (PLGA) monofilaments. The oriented monofilaments are extruded from PLGA granules and annealed before braiding. The annealed monofilaments of diameter 0.0068 µm are braided on teflon mandrel. The annealed monofilament can withstand high yarn braiding tension of approximately 0.70mm to yield a tight braid composite scaffold having high strength. The braid angle is maintained between 135° to 145° with picks per inch of 50 to 55 PPI for 7 mm mandrel. The braiding is performed in a 1x2 pattern due to its higher tensile strength and kink prevention. The braided scaffold is tied with a cable on the mandrel to keep the braided geometry intact.
[0056] Post braiding, the braided scaffold is subjected to two stage heat treatment such as a primary heat treatment and a secondary heat treatment. The primary heat treatment temperature is maintained at around 110°C for around time duration of 16 hours. The primary heat treatment is immediately followed by secondary heat treatment at a temperature of around 135°C for a time duration of around 02 hours. Post heat treatment, the braided scaffold is cooled to the ambient temperature. Post heat treatment, the braided scaffold is removed from mandrel and cut to desired length with the help of sharp surgical blade. In the next step, the braided scaffold is attached with C shape platinum markers to enable visibility under fluoroscopy.
[0057] Following marker attachment, the braided scaffold is spray coated with a biodegradable elastomer formulation. The elastomer formulation comprises of Poly-L-lactide co-caprolactone (PLC), Poly caprolactone (PCL) and hexamethylene diisocyanate (HDI) in a mixture of solvent of acetone and Dichloromethane (19:1). The coating is performed until all crossover points are covered with the elastomer formulation. The thickness of the coating is maintained between 20 µm to 30 µm. Further, the scaffold is placed in a vacuum chamber for a time duration of 12 hours for removal of residual solvents. This is followed by thermal curing of the coated scaffold at a temperature of around 110°C for time duration of around 16 hours. The scaffold is now coated with an antiproliferative drug formulation, comprising of sirolimus drug and poly DL-lactide polymer (PDLLA) polymer as carrier in a proportion of around 50:50 acetone solvent. The thickness of drug coating is maintained below 05 µm. Lastly, the drug coated scaffold is sealed in an aluminum pouch and subjected to e-beam sterilization.
[0058] Post sterilization, the biodegradable scaffold possesses higher radial strength of around 25N. The molecular weight observed is around 2,62,933 g/mol, Mn is observed 1,24,331 g/mol and inherent viscosity is 1.91 dl/g.
[0059] The scope of the invention is only limited by the appended patent claims. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used.