Claims:WE CLAIM
1. A scaffold graft comprising:
a biodegradable scaffold, the biodegradable scaffold including an inner surface and an outer surface; and
a first layer coated on at least the outer surface of the biodegradable scaffold, the first layer including a biodegradable graft.
2. The scaffold graft as claimed in claim 1 wherein the biodegradable scaffold is made of poly-L-lactic acid (PLLA).
3. The scaffold graft as claimed in claim 1 wherein the biodegradable graft is made of at least one of poly-L-lactide-co-caprolactone (PLCL), 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) or a mixture thereof .
4. The scaffold graft as claimed in claim 1 wherein the first layer includes a cross-linker.
5. The scaffold graft as claimed in claim 4 wherein the cross-linker includes at least one of hexamethylene diisocyanate (HDI), Lysine diisocyanate (LDI).
6. The scaffold graft as claimed in claim 1 wherein the thickness of the first layer is between 40 to 100 micron.
7. The scaffold graft as claimed in claim 1 wherein the first layer is coated with an antiproliferative formulation of Sirolimus and poly-DL-lactide (PDLLA).
8. A method for manufacturing of the scaffold graft, the method comprising:
providing a biodegradable scaffold, the biodegradable scaffold including an inner surface and an outer surface;
coating a first layer on the outer surface of the biodegradable scaffold to form a covered scaffold, the first layer including a biodegradable graft;
annealing the covered scaffold at a predetermined temperature and duration to form an annealed scaffold; and
crimping of the annealed scaffold to form a scaffold graft.
9. The scaffold graft as claimed in claim 8 wherein, the coating of the first layer is performed by means of a spray coating technique.
10. The scaffold graft as claimed in claim 8 wherein, the covered scaffold is coated with an antiproliferative formulation of Sirolimus and poly-DL-lactide (PDLLA).
11. The scaffold graft as claimed in claim 8 wherein, predetermined temperature is between 40°C to 120°C.
12. The scaffold graft as claimed in claim 8 wherein, predetermined duration is between 3hrs to 20hrs.
13. The scaffold graft as claimed in claim 8 wherein the biodegradable scaffold is made of poly-L-lactic acid (PLLA).
14. The scaffold graft as claimed in claim 8 wherein, the first layer is made of at least one of poly-L-lactide-co-caprolactone (PLCL), 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) or a mixture thereof.
15. The scaffold graft as claimed in claim 8 wherein, the first layer includes a cross-linker.
16. The scaffold graft as claimed in claim 15 wherein, the cross-linker includes at least one of hexamethylene diisocyanate (HDI), Lysine diisocyanate (LDI).
, Description:FIELD OF INVENTION
[1] The present disclosure relates to a graft cover, more specifically, the disclosure relates to a biodegradable graft cover coated on a biodegradable scaffold.

BACKGROUND
[2] Stents (or scaffolds) are medical devices that are generally used to keep the lumen of blood vessels intact and to facilitate adequate blood flow to the organs. However, the walls of vessels may suffer from dissection or tear during percutaneous interventions. Perforations may be a consequence of guide wire advancement, balloon or stent advancement, balloon or stent inflation, over sizing or ruptured balloon or stent, or from sub-intimal passage of the balloon or stent into a vessel with severe dissection during the percutaneous interventions.
[3] Moreover, increased blood flow in the vessel may cause the bulging out of the weakened portion of the vessel wall leading to the condition of the aneurysm. The most detrimental stage of the aneurysm is reached when the balloon (and/or bulged out portion) is burst (and/or ruptured) leading to stroke, massive internal bleeding, etc.
[4] Covered metal stents have revolutionized the treatment of the arterial perforations and effective seal perforations. The covered metal stents have been extensively used in occluding the aneurysms (coronary, peripheral and neurovascular). Conventionally, metal stents are covered by a synthetic material like PTFE or a biological material like treated pericardium tissue. However, the metal scaffold grafts are permanent implants which may lead to long term complications like in-stent restenosis, inflammation and the implant requires lifetime follow up to the site.
SUMMARY
[5] The present invention discloses a scaffold graft used for treatment of treatment of arterial perforations and/or condition of aneurysm. The scaffold may be made of a biodegradable material. The scaffold is coated with a biodegradable layer of polymer on an outer surface. The biodegradable scaffold is made of poly-L-lactic acid (PLLA). The biodegradable graft may be made of poly-L-lactide-co-caprolactone (PLCL), 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) or a mixture thereof. Additionally, the scaffold graft may be coated with an antiproliferative drug formulation. The process of manufacturing of the scaffold graft may include coating of the graft over the scaffold, followed by annealing of coated graft. Annealed scaffold graft is further crimped to form a crimped scaffold graft.

BRIEF DESCRIPTION OF THE DRAWINGS
[6] 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.
[7] FIG.1 shows a schematic view of the scaffold graft in accordance with an embodiment of the present invention.
[8] FIG.2 shows a flowchart depicting steps involved in manufacturing of the scaffold graft in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE DRAWINGS
[9] 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.
[10] 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.
[11] In accordance with the present disclosure, a scaffold graft for treatment of arterial perforations and/or condition of aneurysm and method of manufacturing the same is provided. In an embodiment, the scaffold and the graft is made of a biodegradable material. In another embodiment, the biodegradable scaffold graft is additionally coated with an anti-proliferative drug to reduce neointimal proliferation and/or to prevent any inflammatory reaction of the vessel.
[12] Now referring specifically to the drawings, FIG. 1 illustrates a schematic view of the scaffold graft 100. The scaffold graft 100 may be a biodegradable assembly. The scaffold graft 100 has high radial strength and durability. In an embodiment, the scaffold graft 100 has controlled degradation rate inside the body. The degradation rate is dependent upon the properties of the biodegradable material used for making the scaffold.
[13] The scaffold graft 100 includes a stent or scaffold 10 and a graft cover 20. In an embodiment, the scaffold graft 100 may be constructed by coating a graft cover 20 over the scaffold 10.
[14] The scaffold 10 may be a balloon expandable scaffold. The scaffold 10 may be made of any biodegradable material, such as, without limitation, poly-L-lactide, poly-L-lactide-co-glycolide, poly-L-lactide-co-caprolactone and likewise. In an embodiment, the scaffold 10 is made of a polylactic acid (PLLA) polymer. An exemplary biodegradable material may include biodegradable metal alloy for example magnesium and/or iron alloy. The scaffold 10 may be manufactured using a known process. As per an exemplary process, first, the polymer granules are extruded to obtain an extruded tube. The extruded tube may then be processed further to obtain a scaffold 10. In an embodiment, the extruded tube is deformed to obtain the required outer and/or inner diameter. The tube may then be laser cut and annealed at a pre-defined temperature.
[15] In an embodiment, the thickness of the struts of the scaffold 10 is approximately 100µm. In an embodiment, the scaffold 10 is provided with a plurality of markers 12 each on the joints of the proximal and distal ends of scaffold strut. In an embodiment, the scaffold 10 includes 6 markers on the joints of the proximal and distal ends of scaffold strut. The marker 12 may include, without limitation, radiopaque markers. The radiopaque markers may be made of without limitation platinum.
[16] The scaffold 10 which is a tubular structure includes an outer surface and an inner surface (not shown). In an embodiment, the first layer of graft cover 20 is coated on the outer surface of the scaffold 10. In an embodiment, the graft cover 20 on the scaffold 10 increases expansion performance, prevents any micro cracks and notches at the strut edges of the scaffold 10.
[17] The first layer of graft cover 20 of the present invention may be constructed by coating one or more layers of any biodegradable polymer(s) known in the art, such as, but not limited to, poly-L-lactide-co-caprolactone (PLCL), 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) or a mixture thereof. The biodegradable polymers utilized for graft cover 20 may be referred as graft polymers. The graft polymer may be formulated in solvents, such as, without limitation, benzyl alcohol, chloroform, acetone, acetonitrile and dichloromethane and mixtures thereof. Further, the molecular weight of a polymer can be varied to achieve longer degradation times. The high molecular weight polymer coating can be used to lengthen the degradation time of the scaffold graft. Such coating of graft cover 20 may be of any predefined thickness. In an embodiment, the thickness of graft cover 20 may range from 40 to 100 micron, more preferably between 50 and 80 micron.
[18] The coating techniques utilized in the present invention may include, without limitation, spray coating, spin coating, electro-spin coating, rolling, painting, sputtering, vapor deposition and the like. The graft cover 20 may be coated directly on the scaffold 10 or can be applied over a primer layer (say, parylene) on the scaffold 10.
[19] In an embodiment, a single layer of the poly-L-lactide-co-caprolactone (PLCL) is used as a graft cover 20 over the stent 10. The poly-l-lactide-co-caprolactone (PLCL) comprises of l-lactide and caprolctone in concentration of around 70% and 30% respectively. The physical properties of the poly-L-lactide-co-caprolactone (PLCL) may include flexibility and strength. The caprolactone constituting the poly-L-lactide-co-caprolactone (PLCL) has additional chain of carbohydrates which provides flexibility and the l-lactide provides strength to the polymer material. In an embodiment, the graft cover 20 is prepared by dissolving PLCL in a concentration of approximately 0.5% to 2% in a mixture of dichloromethane and acetone solvents. The solution may be subjected to ultra-sonication for a period of 10 minutes to 60 minutes.
[20] In another embodiment, the scaffold 10 is covered with a layer of the Poly (glycerol sebacate) (PGS) polymer. The PGS is a strong biodegradable elastomer made of biocompatible monomers. The two main monomers constituting the PGS are glycerol and sebacic acid, found naturally in the human body. Glycerol is the basic building block for lipids, while sebacic acid is a substance for metabolisation of fatty acids. Hence, the degradation products of PGS are often naturally metabolized in the body. The PGS possess high tensile strength and provides strength and longevity to the scaffold 10 during course of treatment inside body.
[21] In another embodiment, PCL in combination with PGS is used as a graft cover 20. The PCL is a semi-crystalline polymer having a glass transition temperature of 60°C and melting point ranging between 59°C and 64 °C. The inherent viscosity of PLCL is 1.1 dl/g - 1.3 dl/g with a molecular weight ranging from 80000 g/mol to 110000 g/mol. It is a degradable polymer that degrades in the body within about 24 to 36 months through body’s natural metabolism into carbon dioxide and water. The PCL is a semi-crystalline and easy to electrospin polymer. In an embodiment, the different blends of PGS and PCL in a ratio of approximately 30:70, 50:50 and preferably 70:30 are prepared. In an embodiment, the blend of PGS and PCL is prepared in dichloromethane solvent.
[22] In an embodiment, a cross-linker may be used in order to enhance the performance properties of the graft cover 20. Exemplary cross-linkers include polyurethanes derived from diisocynates like hexamethylene diisocyanate (HDI), Lysine diisocyanate (LDI), etc. In an embodiment, the cross-linkers are used to enhance mechanical strength and elasticity of the scaffold graft 100.
[23] In another embodiment, the polymers used for the formation of graft cover 20 are a mixture of poly-l-lactide-co-caprolactone (PLCL) and polycaprolactone (PCL). The polymers (PLCL and PCL) may be blended in various ratios approximately 50:50, 70:30, 80:20, or 90:10. In an embodiment, the mixture is prepared in a solvent for example, acetone.
[24] In an embodiment, a mixture of PLCL and PCL in ratio of approximately 80:20 with the cross-linker hexamethylene diisocyanate (HDI) is prepared to form the graft cover 20. The obtained graft cover 20 forms a uniform cover over the scaffold 10 including the struts 12.
[25] In accordance with an embodiment of the present invention, FIG. 2 illustrates a flow chart depicting a process involved in fabrication of the scaffold graft 100. The process of fabrication of the scaffold graft 100 commences by coating of the graft formulation over the scaffold 10 at step 101. The coating of the scaffold 10 can be executed by for example a spray coating technique. In the present invention, spray coating is achieved with the help of, without limitation a mandrel and a spray gun. In an embodiment, the mandrel may be any inflatable balloon known in the art. The mandrel may function to mount the scaffold 10. The mandrel holds and rotates the scaffold 10 during the coating process.
[26] The coating of the scaffold 10 may be achieved by drop wise/micro droplets spray of the polymer formulation over the surface of the scaffold 20. In an embodiment, the distance between spray gun and the mandrel is maintained approximately 2cm to 8cm to achieve smooth cover surface. The pressure of nitrogen gas during the coating process may be set between 1.0 to 3.0 kg/cm2. The solution flow rate may range from about 0.075 ml/min to 2.0 ml/min. The oscillation of spraying gun may be between 30-80 oscillations per minute more preferably 50-60 oscillations per minute. The rotation of mandrel may be between 50 to 90 rotations per minute and more preferably 60-70 rotations per minute.
[27] In order to avoid damage to the graft cover 20, the covered scaffold is allowed to rest for appropriate time, say, approximately 10-15 minutes before removing it from the mandrel. The scaffold graft 100 may then be kept for another 12 hours under a vacuum desiccator to remove the residual solvents.
[28] The scaffold graft 100 is then annealed in the vacuum desiccator at the step 103. The annealing temperature may be fixed based on melting and glass transition temperature of the graft polymer. In an embodiment, the scaffold graft 100 is annealed at a temperature ranging from 40°C to 120°C for a time period of approximately 3 hours to 20 hours under the vacuum of 700 mmHg.
[29] The scaffold graft 100 is further allowed to cool-down to an ambient temperature before detaching it from the mandrel. In an embodiment, annealing of the scaffold graft 100 helps in relieving internal stresses of the scaffold 10 and further enhances the strength, durability and transparency of the graft cover 20.
[30] Optionally, the scaffold graft 100 is coated with an antiproliferative drug in the step 105. Or, a formulation of antiproliferative drug as well as a polymer may be coated on the scaffold graft 100. Such a coating may be executed by any method known in the art, such as spray coating. The said coating may be performed on the inner surface, outer surface or both surfaces of the scaffold graft 100.
[31] In an embodiment, a formulation of the antiproliferative drug includes Sirolimus and polymer like PDLLA (poly-DL-lactide). Such a formulation may be prepared in any solvent known in the art such as without limitation, methylene chloride, chloroform, acetone, methanol and mixtures thereof. The inclusion of PDLLA in the coating may control drug release rate. In an embodiment, the formulation is coated on the outer surface of the scaffold graft 100 with a drug dose of approximately 1.25 µg/mm2 of the scaffold surface area.
[32] The drug coated scaffold graft 100 is crimped on a balloon catheter at step 107. In an embodiment, the scaffold graft 100 may be protected with the help of protective peel away sheath made of without limitation, Polytetrafluoroethylene (PTFE). Such sheath maintains the crimped profile, prevents recoiling and avoids damage to the scaffold graft 100 during storage and shipping.
[33] In an embodiment, the crimping temperature is fixed based upon the glass transition temperature of the polymers used in fabrication of the scaffold graft 100. The crimping is performed in a manner such that upon deployment, the scaffold graft 100 has uniform expansion and the graft cover 20 is not damaged.
[34] In an embodiment, the crimping is performed in nearly 6 to 8 stages with a dwell time of approximately 200-310 seconds. In an embodiment, in the last stage of the crimping process, the protective peel away sheath may be placed over the scaffold graft 100.
[35] The crimping temperature ranges from 20°C to 60°C and preferably between 20° to 30°C (based upon glass transition temperature of the PLLA, PLCL and PDLLA). In an embodiment, the crimped profile of the scaffold graft 100 may be in a range of around 1.4 mm to 1.7 mm preferably between 1.5-1.6 mm for coronary application. In an embodiment, for peripheral application, the profile may be between 2.5-2.8 mm.
[36] Lastly, the crimped scaffold graft with protective sheath is packed in an aluminum pouch and sterilized at step 109. In an embodiment, the scaffold graft 100 is sterilized to achieve a SAL level of 10-6. The sterilization may be performed by irradiating the pouch by without limitation, gamma rays and/or e-beam radiation. In an embodiment, dose of e-beam radiation in the range of 15-30 kGy, preferably between 18-23kGy at a temperature of around 15 to 25°C is utilized.
[37] The graft cover 20 has elastic properties which conform to the expansion of the scaffold 10 for treatment of the arterial perforations and/or condition of aneurysm. In an embodiment, the PLCL graft polymer degrades faster than the PLLA scaffold polymer. In this case the graft cover 20 treats the arterial perforations and/or aneurysm while the scaffold 10 stays in the body to support newly generated vessel walls.
[38] In an embodiment, the PLCL polymer maintains its structural integrity for a period of around 04-06 months and it is expected to completely degrade in about 12 to 15 months through natural metabolism of body and excreted in form of carbon dioxide and water.