Claims:1. A process for manufacturing a biodegradable peripheral scaffold, the process comprising
a. extruding biodegradable polymer granules to form an extruded tube;
b. deforming the extruded tube to form a deformed tube with high fracture toughness and enhanced strength;
c. cutting the deformed tube to yield a scaffold;
d. annealing the scaffold in vacuum at a predefined temperature for a predefined time interval to form an annealed scaffold;
e. coating the annealed scaffold with a biodegradable polymer in order to impart flexibility to the annealed scaffold.
2. The process as claimed in claim 1 wherein the polymer granules includes one or more of PLA (poly-L-lactide) , PLGA (poly-L-lactide-co-glycolide), poly-L-lactide-co-caprolactone (PLC), Polyglycolic acid (PGA), Poly (D, L-lactide co-glycolide).
3. The process as claimed in claim 1 wherein the deforming comprises deformed the extruded tube one or more times by axial deformation and/or radial deformation.
4. The process as claimed in claim 1 wherein the cutting comprises laser cutting the deformed tube into a scaffold with hybrid cell design.
5. The process as claimed in claim 1 wherein the predefined temperature is 100°C to 150°C, preferably around 100°C to 120°C.
6. The process as claimed in claim 1 wherein the predefined time duration is 10 to 20 hrs, preferably 12 to 18 hours.
7. The process as claimed in claim 1 wherein the biodegradable polymer includes one or more of poly-l-lactide-co-caprolactone (PLC), polycaprolactone (PCL), polyglycerol sebacate (PGS).
8. The process as claimed in claim 1 wherein the deforming the extruded tube comprises deformation at a primary temperature of between 82°C- 90°C followed by a secondary temperature of 125°C-160°C.
9. The process as claimed in claim 3 wherein the axial deformation comprises an axial stretch speed between 0.1mm/sec to 0.5mm/sec and an axial stretch ratio is 1.35: 1.90.
10. The process as claimed in claim 1 wherein the coating the annealed scaffold comprises a coating thickness between 5 µm -15 µm.
11. The process as claimed in claim 1 wherein the coating the annealed scaffold is followed by heat curing at 50°C for time duration of 04 hours to form a heat cured scaffold.
12. The process as claimed in claim 12 wherein the heat cured scaffold is coated with an anti-proliferative drug and a polymer carrier with a drug dose of 1.25 µg/mm2.
, Description:
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003 5
COMPLETE SPECIFICATION
(Section 10 and Rule 13)

1. TITLE OF THE INVENTION:
BIODEGRADABLE PERIPHERAL SCAFFOLD AND A METHOD OF MANUFACTURING THEREOF
2. APPLICANTS:
Meril Life Sciences Pvt. Ltd., an Indian company, of the address Bilakhia House Muktanand Marg, Chala, Vapi, Gujarat - 396191

The following specification particularly describes the invention:

FIELD OF INVENTION
[001] The present disclosure relates to a process of manufacturing a biodegradable scaffold, more specifically to the scaffold for treatment of peripheral arteries.
BACKGROUND
[002] Atherosclerosis is a disease in which plaque builds up in the wall of an artery. Peripheral artery disease (PAD) is a disease in which plaque builds up in the arteries that carry blood to head, organs and limbs. PAD usually affects the arteries of the legs however it can also affect the arteries that carry blood from heart to head, arms, kidneys and stomach.
[003] Scaffolds may be used for the treatment of atherosclerotic peripheral arteries. The stent may treat the diseased artery by increasing the lumen diameter of the narrowed blood vessel and thus, maintain the patency of the vessel. The stent can be a metal stent or a stent coated with a therapeutic agent for reduction of inflammation and restenosis. However despite the proven efficacy of drug eluting stents in reducing restenosis, they may pose a risk of incomplete endothelialization. The incomplete endothelialization may result in neo-atherosclerosis, late restenosis or occlusion leading to clinical relapse of the peripheral arteries. Percutaneous interventions using a biodegradable scaffold have potential advantages over metallic bare metal stents/DES technology.
[004] The biodegradable scaffolds have been widely used in coronary vasculature as compared to peripheral vasculature. Scaffolds in the coronary vasculature experience only radial load however scaffolds in the peripheral artery are exposed to various biomechanical forces other than radial loading.
[005] Conventionally the biodegradable scaffolds are not used in peripheral artery as the scaffold is placed in much larger vessel and may experience a combination of axial, bending, torsional and radial loading. Therefore, there is a need to manufacture a scaffold having high strength for vasculature of peripheral arteries.
BRIEF DESCRIPTION OF DRAWINGS
[006] 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.
[007] FIG.1 represents a flow chart depicting a process involved in manufacturing of a peripheral scaffold in accordance with an embodiment of the present invention.
[008] FIG. 2 represents a front view of a peripheral scaffold in accordance with an embodiment of the present invention.
SUMMARY
[009] The present invention discloses a process for manufacturing a peripheral scaffold. The process includes extruding biodegradable polymer granules to form an extruded tube, deforming the extruded tube to form a deformed tube with high fracture toughness and enhanced strength. The deformed tube is laser cut to yield a scaffold followed by annealing the scaffold in vacuum conditions. The annealed scaffold is coated with a biodegradable polymer in order to impart flexibility to the scaffold.
DETAILED DESCRIPTION OF DRAWINGS
[010] 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.
[011] Wherever possible, same reference numbers will be used throughout the drawings to refer to same or like parts. Moreover, references to various elements described herein are made collectively or individually when there may be more than one element of the same type. However, such references are merely exemplary in nature. It may be noted that any reference to elements in the singular may also be construed to relate to the plural and vice-versa without limiting the scope of the disclosure to the exact number or type of such elements unless set forth explicitly in the appended claims.
[012] 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. In the present description and claims, the term proximal end refers to an end of an element that is closer to a user while the distal end refers to an end of the element which is farther from the user.
[013] In accordance with the present disclosure, a biodegradable scaffold for the treatment of peripheral arteries is disclosed. The scaffold may be used for treatment of arteries without limitation, below knee arteries, iliac arteries, superficial femoral artery, sub-clavian artery, renal arteries, etc. In an embodiment, the scaffold is manufactured by providing heat treatment after laser cutting of the scaffold and PCL coating after heat treatment. In another embodiment, the strut thickness of scaffold is less than or equal to 220 microns and axial stretch ratio is in a range of 1.35 to 1.90. The scaffold of the present invention possesses high radial strength, high crush recovery, high durability and/or enhanced resistance to fracture etc.
[014] Now referring specifically to drawings, FIG.1 illustrates a flow chart depicting a process involved in manufacturing of the scaffold. In accordance with an embodiment of the present invention, the process may include one or more steps of extrusion, deformation, laser cutting, annealing, marker placement, PCL coating and, drug coating etc.
[015] The process of manufacturing the scaffold commences by extrusion of biodegradable polymer granules at the step 101 to form an extruded tube (or tube). The scaffold may be made of biodegradable polymer. The biodegradable polymer may include without limitation, PLA (poly-L-lactide), PLGA (poly-L-lactide-co-glycolide), PLC (poly-L-lactide-co-caprolactone), PLLA (poly-L-lactic acid), PGA (Polyglycolic acid), Poly (D, L-lactide co-glycolide) etc. In an exemplary embodiment, the scaffold is made of PLLA polymer.
[016] The scaffold made of biodegradable polymer may undergo hydrolytic degradation in the body and gradually is eliminated from the body as carbon dioxide and water. The degradation time of the scaffold depends upon molecular weight of polymer. In an embodiment, the molecular weight, Mw of PLLA polymer granules may between 500000-600000 g/mol and average molecular weight, Mn may range between 300000 g/mol to 400000 g/mol and PDI of granules may be in a range of 1.4-2.2.
[017] The implant for peripheral application sustains several biochemical forces as compared to coronary implant. Therefore, the peripheral implant requires having high mechanical strength, enhanced elasticity and, enhanced fracturing toughness in order to serve peripheral arteries for required duration of treatment. Therefore, the tube is subjected to a process of expansion and/or deformation in the step 103.
[018] The tube may be subjected to expansion and/or deformation in axial direction and/or radial direction. The tube may be radially expanded and/or axially stretched by means of without limitation blow molding. A load may be applied on the tube that may result in change in molecular orientation of the polymer in both axial as well as radial direction. In an embodiment, the radial and axial pressure given to the tube also affects the crystallinity of the material. The semi-crystalline behavior of the PLLA may improve the crush recovery of tube. The axial expansion ratio and radial deformation ratio may influence the mechanical strength and fracture resistance of the tube. In an embodiment, the radial deformation ratio is maintained in a range of 03 to 06 and axial expansion ratio is maintained in a range of 1.35 to 1.90.
[019] In an exemplary embodiment, the axial deformation of the tube is performed at a primary temperature of approximately 82°C to 90°C preferably between 84°C and 87°C. The time duration may be maintained around 10 seconds. During deformation at the primary temperature, the axial stretch speed is kept slow and may be maintained between 0.1mm/sec to 0.5mm/sec. The slow stretch speed enables uniform distribution of crystallinity throughout the whole length of the tube. Uniform crystallinity may results in enhanced axial fracture toughness. The fracture toughness is an important criterion to implant the scaffold in the peripheral arteries. Also, the axial stretch ratio of the tube is greater for peripheral arteries in comparison to the coronary artery application. In an embodiment, the axial stretch ratio is maintained from 1.35 to 1.90.
[020] In an exemplary embodiment, the radial deformation is performed at a temperature of around 82°C to 90°C preferably between 84°C and 87°C, at a radial deformation ratio between 03 and 06. The radial deformation may be performed by applying high pressure nitrogen gas in three stages. In an embodiment, the first stage is maintained between 494 psi to 522 psi, the second stage is maintained between 566 psi to 594 psi and the third stage is maintained between 639 psi to 667 psi for time duration of 10 seconds at each stage. In an embodiment, the thickness of the resultant tube after deformation is in a range of 180 to 220 µm. The radial deformation of the tube produces molecular consistency in the scaffold. In an embodiment, the high pressure nitrogen gas renders tolerance, enhanced mechanical properties and uniform thickness to the scaffold along the whole length.
[021] In an embodiment, the axially and radially deformed tube is further heated at a secondary temperature of around 125°C to 160°C for time duration of 0.5 to 1.0 min. Following heat treatment at the secondary temperature, the tube is immediately cooled to a temperature of 20°C in 20-30 sec. The cooling at the secondary temperature results in transparency of the scaffold.
[022] The mechanical properties of the polymer depend upon its crystallinity. The percentage crystallinity of the extruded tube before deformation process may range from 3% to 5%. In an embodiment, the percentage crystallinity of the tube after deformation increases to 45% to 60%. The increase in crystallinity may result in enhancement of mechanical strength of the tube. The tensile strength of extruded PLLA tube may be around 50N/mm2 and for deformed tube is around 65 N/mm2.
[023] In the step 105, the tube is laser cut by means of without limitation, femto seconds equipment to form a scaffold. The laser beam may be in a range of 1300-1500nm wavelength. The structure of the scaffold 100 after laser cutting is depicted in FIG.2. The scaffold 100 has a hybrid cell design with alternate open and closed cells. The hybrid cell design ensures uniform distribution of pressure in peripheral arteries. The scaffold 100 may include a plurality of rows 10, peaks 20 and valleys 30. The rows are interconnected by cross-linking struts to form the scaffold structure. In an embodiment, the scaffold 100 is laser cut in a manner wherein, the peak 20 of one row 10 faces the valley 30 of front row 10 and vice versa.
[024] Additionally, a plurality of markers (not shown) may be attached on the scaffold. The marker may include radiopaque marker. In another embodiment, 03 couplets of markers are attached at equidistance at 120° at one or more ends of the scaffold.
[025] The length and width of the struts of the scaffold is maintained such that a uniform crimping may be obtained. The uniform crimping of the scaffold may enable uniform expansion with minimum recoil and adequate radial strength. In another embodiment, the length of struts of the scaffold 100 at the ends is larger as compared to the center of the scaffold 100. The larger struts at the end may facilitate marker placement on the struts and/or increases the strength of cells at the ends which may prevent dog-boning effect in the scaffold 100.
[026] In the next step 107, the scaffold is subjected to annealing process. The annealing may be performed in order to enhance fracture toughness and/or to relieve stress built up during tube deformation and laser cutting process. The process of deformation of the scaffold may lead to generation of monomers on exposure to stress. The presence of residual monomer may lead to deleterious effects on the scaffold during storage. The process of annealing may be applied in order to remove residual monomers.
[027] The annealing may be performed by means of without limitation, a vacuum annealing unit. The vacuum annealing unit may consist of a closed chamber. The air present in the chamber may be replaced with the inert nitrogen gas followed by removal of air-nitrogen mixture form the chamber to create vacuum inside the chamber.
[028] In order to perform annealing of the scaffold, the scaffold may be mounted on a mandrel (not shown). The mandrel may be loaded in the annealing unit (not shown). The mandrel may be made of without limitation, Teflon, Teflon coated stainless steel (S.S) mandrel. An appropriate mandrel size may be selected depending upon the diameter of the scaffold so as to prevent shrinkage and/or change in dimension of the scaffold. The annealing of the scaffold after performing laser cutting may impart fracture toughness and/or to relieve stress built up during tube deformation and laser cutting process. Annealing of the scaffold after laser cutting may also avoid stress generation near crown regions during crimping and deployment of the scaffold.
[029] The scaffold may be subjected to one or more of heating cycles. The heating may be performed between glass transition temperatures to the melting temperature of the polymer. In an embodiment, the annealing of the scaffold is performed at a predefined temperature of around 100°C to 150°C, preferably around 100°C to 120°C. The annealing may be performed for predefined time duration of approximately 10 to 20 hrs, preferably 12 to 18 hours in vacuum condition with a pressure of around -700mmHg to -750mmHg. Following annealing process, the chamber may be allowed to cool down to room temperature.
[030] The presence of residual monomer may be tested by Gas chromatography. The residual monomer concentration is found to be more than 3.5% before annealing, whereas residual monomer concentration is found to be less than 0.1% after annealing process.
[031] In the next step 109, following annealing of the scaffold, a biodegradable material is coated on the scaffold. The biodegradable material coating may be applied in order to enhance flexibility and/or to reduce the chance of early fracture of the scaffold on implantation to the treatment site in the peripheral arteries. The biodegradable coating material may include without limitation, poly-l-lactide-co-caprolactone (PLC), polycaprolactone (PCL), polyglycerol sebacate (PGS), or a mixture thereof etc.
[032] The coating may be performed without limitation, spray coating technique. In an exemplary embodiment, PCL coating is applied on the scaffold. The PCL polymer has molecular weight between 1,15,000 g/mol to 2,44,660 g/mol, I.V. ranging from 1.0 dl/g to 1.3 dl/g and glass transition temperature is between - 58°C to - 60°C and melting point is between 58°C and 60°C. The thickness of PCL coating over the scaffold may range from 5 to 15 µm. Alternately, PLC can be coated on biodegradable scaffold. PLC polymer has a molecular weight of between 1,47,000 dl/g to 2,61,000 dl/g with I.V. ranging from 1.2 to 1.8 dl/g and glass transition temperature is between 18°C to 25°C.
[033] Additionally, the coated scaffold may be subjected to heat curing at a temperature of around 40°C to 80°C, preferably between 40°C to 60°C for time duration of around 4 to 16 hours. Thermal curing may help in expansion of the scaffold and enhances fracture resistance of the scaffold.
[034] In an embodiment, performance of the scaffold is tested by crush recovery analysis of the scaffold. It is found that, the PCL coated scaffold recovers more to 90% of its initial diameter on 50% compression. However, the scaffold without coating shows 80% recovery on 50% compression.
[035] Lastly, the scaffold is coated with an anti-proliferative drug formulation at the step 111. The drug formulation may be coated by means of without limitation, spray coating. The drug may be coated with a carrier for release of the drug in a controlled manner. The drug may include without limitation, sirolimus, everolimus, zotarolimus or taxane derivative such as paclitaxel or its derivatives or docetaxel etc. The carrier may include without limitation, Poly-DL-lactide co-glycolide, Poly-L-lactide, Poly-L-lactide co-glycolide, Polycaprolactone, Poly-DL-lactide or a mixture thereof.
[036] In an exemplary embodiment, the drug formulation consists of carrier and drug in a ratio of approximately 50:50 (w/w). The drug polymer solution is formulated in organic solvents like dichloromethane, acetone, chloroform or methanol or a mixture of solvents. The drug coated scaffolds are vacuum dried by placing them in a vacuum desiccator for a period of 12-14 hours. This process of drying ensures complete removal of any residual solvents present on scaffold.
[037] In an embodiment, the drug coated scaffold may be crimped over an angioplasty balloon. The crimping may facilitate uniform expansion of the scaffold upon deployment and/or provide radial support to the peripheral arteries. In an embodiment, the crimping is performed in 6 to 8 stags at a temperature of around 50°C to 60°C with dwell time between 240 and 310 sec. In an embodiment, profile of the crimped scaffold is in a range of 1.4 mm to 2.2 mm.
[038] In an embodiment, a protective sheath is placed over the crimped scaffold balloon assembly. The protective sheath may be provided in order to maintain the crimped profile, prevent recoil and/or protect the scaffold during storage from moisture and/or shipping. The protective sheath may be made of biodegradable material without limitation, PTFE, ETFE (Ethylene tetrafluoroethylene), FEP (Fluorinated ethylene propylene), PFA (Perfluoroalkoxy) etc. The protective sheath is placed in such manner that it can be easily peeled off before implantation in the body.
[039] The crimped scaffold assembly is placed in a packaging tray and sealed in an aluminum pouch. The aluminum pouch may be provided with a plurality of oxygen absorber. The oxygen absorber may act as an oxygen scavenger and/or protect the scaffold from deterioration during storage. The oxygen absorber may consist of activated iron, diatomaceous earth, calcium chloride. In an embodiment, the oxygen absorbers are placed in the multi-layered aluminum pouch before sterilization. The crimped scaffold assembly may be placed inside the aluminum pouch with at least one oxygen absorber. Additionally, the aluminum pouch is purged with inert gas at an ambient temperature for time duration of 5 to 35 hours in order to replace oxygen present inside the aluminum pouch. The inert gases may include without limitation, such as argon, nitrogen, etc. Following elimination of oxygen from the aluminum pouch, the oxygen absorbers are removed. The crimped scaffold assembly inside the aluminum is subjected to e beam sterilization. In an embodiment, the crimped scaffold assembly is subjected to e beam sterilization a dose of around 15-30 kGy, preferably between 18-23 kGy at a temperature of around 15°C-25°C.
[040] The scaffold may be subjected to several in-vitro experiments in order to test performance of the scaffold. The in-vitro conditions are maintained such that mimicking biochemical forces of the peripheral arteries. The in-vitro experiments may include without limitation, longitudinal compression, radial compression, strain distribution, fatigue resistance, axial compression, torsion angle, bending deformation and/or in-vitro enzymatic degradation, etc.
[041] A wintest tester may be performed to test longitudinal compression of the scaffold. In an embodiment, the scaffold is subjected to 15% longitudinal compression same as present in peripheral arteries. The force required to compress the scaffold to 15% of its original length may be measured. It is observed that the scaffold requires less than 70gF to be compressed to 15% longitudinally which is an indicator of longitudinal flexibility of the scaffold.
[042] In an embodiment, the scaffold may be twisted to 3° per cm of the scaffold by means of without limitation using any torsional device. A fixture may be attached to wintest tester to study the effect of torsion forces on the scaffold. The 3° per cm twist is within in-vivo physiological conditions of the peripheral arteries. The scaffold shows good torsional flexibility with no damage to struts of the scaffold and can withstand biomechanical forces of 3° per cm twist.
[043] In an embodiment, the scaffold is checked for strain distribution and fatigue analysis with the help of fracture analysis. There may be five types of fractures namely Type-I having fracture of single strut of the scaffold, Type-II having multiple single strut fractures at different sites, Type-III having multiple strut fractures with complete transverse linear fracture, Type-IV having complete transverse linear fracture with displacement and Type V having complete transaxial fracture.
[044] The scaffold may be subjected to several degrees of axial deformation and may be checked for the fracture produced on the scaffold. An apparatus for performing fracture analysis may include a silicon tube filled with phosphate buffer. The silicon tube is used so as to perform function of the peripheral arteries. The silicon tube may be initially stretched in the phosphate buffer and the scaffold is deployed in the silicon tube in stretched state. The scaffold placed inside the silicon tube may be exposed to various compression and expansion deformation cycles in order to test its sustainability in different peripheral arteries such as iliac and superficial femoral artery.
[045] In an exemplary embodiment, the scaffold is subjected to a 3% axial deformation load and tested for a minimum of 0.5 million cycles over a period of 06 months. It is observed that the scaffold successfully sustained the 3% axial load without any fracture over a period of 06 months. The radial strength of scaffold measured over various cycles is also found to be as per standards for its intended use in the iliac artery.
[046] In an exemplary embodiment, the scaffold is subjected to 7% axial deformation load and tested for a 0.5 million cycles over a period of 06 months. The scaffold is non-destructively inspected for fractures at various intervals. It is observed that the scaffold sustained the 7% axial load with type-I fracture within a period of 06 months.
[047] In an embodiment, the scaffold is subjected to bending deformation in order to test its durability. An apparatus for bending deformation may include a silicon tube as mock vessel which consists of phosphate buffer solution at an ambient temperature. In an embodiment, the scaffold is exposed to 0.5 million bending cycles simulation roughly 06 months of active ambulation. In another embodiment, the scaffold is exposed to 30° bend angle for 0.5 million of deformation cycles at 01 Hz accelerated speed. The scaffold is observed non-destructively for various intervals. It is concluded that in both the above mentioned conditions, the scaffold is sustained with type I fracture.
[048] In an embodiment, the scaffold is tested for treatment of atherosclerotic disease in the renal arteries. The apparatus used for the test may be same as bending deformation test apparatus. The test may be performed for bending deformation of simulated renal arteries. In an embodiment, the test is performed for 4 million cycles for time duration 06 months. In a preferred embodiment, the test is conducted at an accelerated speed of 01 Hz (60 rpm) bending deformation of the silicon tube. The silicon tube is configured to 30° angle and bending displacement configured to 24mm. The scaffold is inspected non-destructively for fractures at various intervals. It is observed that the scaffold sustained Type-I fracture.
[049] In an embodiment, the scaffold is subjected to in-vitro enzymatic degradation. The enzymatic degradation may be performed in the presence of enzyme without limitation proteinase K, pronase, bromelain, preferably proteinase K enzyme is used which is responsible for degradation of PLLA polymer. In an embodiment, the proteinase K enzyme with phosphate buffer solution of pH 7.4 is used to study enzymatic degradation of PLLA scaffold. In another embodiment, Tris-HCl buffer solution at pH 8.6 is used along with Proteinase K enzyme for the enzymatic degradation study. A comparative analysis of enzymatic degradation between the Proteinase K enzyme in PBS (pH 7.4) and Proteinase K enzyme in Tris-HCl (pH 8.6) showed more degradation with Tris-HCl and alkaline pH then enzyme in PBS and neutral pH.
[050] In another embodiment, the PLLA scaffold subjected to enzymatic degradation at physiological conditions of 37°C in incubator. The enzyme-buffer system in a concentration of 0.2 mg proteinase K enzyme/Tris-HCl buffer with pH 8.6 may be used. A decrease in molar mass of PLLA scaffold is observed.
[051] 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.