FIELD OF INVENTION

[001] The present disclosure relates to a biodegradable endoprosthetic device, particularly to a device that can be crimped to a low profile for treatment of congenital heart diseases in paediatric patients.

BACKGROUND

[002] Congenital Heart Disease (CHD) is a condition present at birth due to improper

development of heart or its surrounding blood vessels. CHDs may be identified as coarctation of aorta, ventricular septal defect, ductus arteriosus, pulmonary artery stenosis, atrial septal defect, etc. Some of the congenital heart diseases can be treated with medications, while others may require surgeries or interventions.

[003] The treatment of congenital heart diseases may include surgery and/or balloon dilation. Patients treated with percutaneous balloon angioplasty may have to undergo repeated procedures every few years due to elastic recoil of vessel wall resulting into ineffective relief from obstruction. The treatment can be further associated with complications such as recoarctation, dissection and aneurysm formation.

[004] Therefore, a stent is being used in order to prevent elastic recoil and to keep lumen intact in paediatric patients. However, metal stents used in paediatric cardiology may inhibit vessel growth due to their rigid structure. Due to this, once CHD is treated, physicians may have to surgically remove the stent and re-dilate the vessel. Hence, the principle disadvantage of stent implantation in young children is the need for repeated surgery. Additionally, the presence of metallic stents in the body lumen can lead to complications such as thrombosis, late restenosis and stent fracture.

[005] In order to overcome limitations of metallic stents, bioresorbable stents were used for treatment of congenital heart defects in paediatric patients. However, usage of conventional biodegradable stents may also pose some drawbacks such as higher crimp profile due to for example, high thickness and width of the strut of the stent. The higher crimp profile of the stent may pose difficulty during implantation in paediatric patients. Additionally, higher crimp profile may lead to less flexibility during maneuvering of the device in curved and/or tortuous paths during delivery of the scaffold to a treatment site.

SUMMARY

The present invention discloses a biodegradable endoprosthesis for paediatric patients. A biodegradable stent includes a plurality of struts and an outer surface, each strut having a thickness in the range of 140 pm to 190 pm and width in the range of 90 pm to 190 pm. The biodegradable endoprosthesis includes a biodegradable graft having a thickness in the range of 30 pm to 100 pm. The biodegradable graft is provided on the outer surface of the biodegradable stent to yield a biodegradable endoprosthesis. The biodegradable endoprosthesis has a deployed diameter in the range of 4mm to 10mm. The biodegradable endoprosthesis is crimped over a balloon to yield a crimped biodegradable endoprosthesis. The crimped biodegradable

endoprosthesis has a crimped diameter in the range of 1.3mm to 2.1mm.

BRIEF DESCRIPTION OF THE 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. la illustrates a schematic view of the endoprosthesis in deployed configuration in accordance with an embodiment of the present disclosure.

[008] FIG. lb illustrates a schematic view of stent geometry in accordance with an embodiment of the present disclosure.

[009] FIG. 2 illustrates a flow chart depicting a process involved in manufacturing of the endoprosthesis in accordance with an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE DRAWINGS

[0010] Prior to describing the disclosure 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.

[0011] 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. [0012] 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. [0013] Paediatric patients include neonates with age of less than 1 month, infants between the age group of one month to 02 years, toddlers between the age group of 01 year to 04 years.

[0014] In accordance with the present disclosure, an endoprosthesis for treatment of congenital heart diseases to be delivered in a lumen of smaller dimensions is disclosed. In an embodiment, the endoprosthesis is used for treatment of paediatric patients. In various embodiments, the present disclosure pertains to treatment of aortic coarctation, pulmonary artery stenosis and/or ductus arteriosus by providing a crimp profile which is easy to deploy in paediatric patients. For example, the endoprosthesis having deployed (expanded) diameter of approximately 4mm to 10mm is crimped to a diameter of approximately 1.3 mm to 2.1 mm, more preferably 1.5mm to 1.9mm. The reduced crimp profile (diameter) of the endoprosthesis is achieved due to stent geometry, balloon profile and strut thickness of the stent.

[0015] In paediatric cardiology, the endoprosthesis may be implanted within the body of a patient using femoral approach. The femoral approach may include deployment of the endoprosthesis through the femoral artery in a patient. The femoral artery is usually more visible and easy to access. The path of intervention from the femoral artery to the treatment site in paediatric patients is relatively short as compared to adult patients. Therefore, the endoprosthesis may be

maneuvered to the treatment site using an introducer sheath/delivery catheter of smaller dimensions. The femoral artery for treatment of aortic coarctation may include insertion into transvenous-transeptal antegrade and/or retrograde transfemoral artery. An alternative to the retrograde transfemoral arterial approach may include an antegrade transvenous technique. The antegrade transvenous technique may not require entry into patient's femoral arteries. The implantation of the endoprosthesis using this technique may require a flexible stent. The flexibility of a stent may be increased by lowering the crimp profile.

[0016] The endoprosthesis of the present disclosure may prevent over-dilation and/or under- dilation of tortuous and narrowed blood vessels in paediatric patients. Further, the endoprosthesis of the present disclosure has high radial force to keep tight and/or scarred lesions open, high degree of flexibility for placement around curved structures and low crimp profile to allow a stent to enter into a narrow lumen with ease. The endoprosthesis of the present disclosure can also be used for treatment of stenosed lumen like urethral, pulmonary, airwary and/or tracheal in paediatric patients.

[0017] Now referring specifically to the drawing, FIG. la represents an endoprosthesis 100 in accordance with an exemplary embodiment of the present disclosure. The endoprosthesis 100 may include a stent 10 and a graft 30. In an embodiment, the endoprosthesis 100 is crimped over a surface of a balloon resulting in a low crimp profile. In another embodiment, the endoprosthesis 100 may be implanted in the body of a patient with the help of a delivery sheath of 6F diameter or lower.

[0018] The present disclosure is applicable to, but is not limited to, self-expandable stents, balloon- expandable stents, stent-grafts, and generally tubular medical devices in the treatment of CHD in infants and children.

[0019] The stent 10 may include a plurality of cylindrical rings connected or coupled with struts.

For example, the rings may have an undulating sinusoidal structure. When deployed in a section of a vessel, the cylindrical rings are load bearing and support the vessel wall at an expanded diameter or a diameter range due to cyclical forces in the vessel. Load bearing refers to the supporting of the load imposed by radially inward directed forces. Structural elements, such as the linking elements or struts, are generally non-load bearing, serving to maintain connectivity between the rings. For example, a stent may include a scaffold composed of a pattern or network of interconnecting structural elements or struts as depicted in exemplary diagram Fig 1(b) and described below. In other embodiments, stent designs include without limitation wire structures, and woven mesh structures.

[0020] The stent 10 may be a self- expandable and/or balloon expandable. The self-expandable stent 10 may be restrained in a delivery system and elastically released into the target vessel. The restraining of stent 10 may be achieved by loading the stent 10 into a delivery sheath. The stent 10 may be implanted into the target site by retracting the delivery sheath resulting in release of the stent 10 in a target vessel. The balloon expandable stent 10 may be crimped over a surface of a balloon may be deployed at the target site with the help of a balloon catheter.

[0021] The stent 10 may be made of polyester, polycarbonates, or degradable metals. The polycarbonates material may include without limitation Poly(trimethylene carbonate) (PTMC). The degradable metal may include without limitation magnesium alloy, iron alloy and/or zinc alloy. The polyester material may include without limitation biodegradable material such as Poly-L-lactic acid (PLLA), Poly (D, L-lactide/glycolide) copolymer (PDLA), Polyglycolic acid (PGA), Polycaprolactone (PCL), Poly-L-lactide co-glycolide (PLGA) etc. In an embodiment, the stent 10 is made of Poly-L- lactic acid (PLLA). [0022] The stent 10 may be manufactured via techniques such as without limitation knitting, braiding, weaving, etc. In an exemplary embodiment, monofilaments that are used to make the stent 10 are extruded from biodegradable polymer granules and braided together. The thickness of monofilaments may range from 100 pm to 200 pm, more preferably 120 pm to 180 pm. The braiding of the monofilaments or multi-filaments of the bioresorbable polymer may be performed on a mandrel with the aid of 24 to 96 carrier braiding machine. The braided structure is stabilized by heat treatment, for example above glass transition temperature of polymer and below melting point of polymer in order to impart desired strength suitable for stenting applications. The above method of making a biodegradable stent is exemplary and other method(s) of making the biodegradable stents resulting in biodegradable stents as per the teachings of the present disclosure are within the scope of the present disclosure.

[0023] In accordance with the present disclosure, the endoprosthesis 100 may include a graft 30 on an outer surface of the stent 10. The graft 30 may be made of a biodegradable material. The biodegradable material may include without limitation poly-L-lactide-co-caprolactone,

polycaprolactone, poly glycerol sebacate (PGS) or mixtures thereof. In an embodiment, the graft 30 is made of poly-l-lactide-co-caprolactone (PLCL) comprising of l-lactide and caprolactone in ratio of 70% and 30% respectively. The l-lactide imparts strength while caprolactone imparts flexibility. The molecular weight of the graft 30 may be selected based upon the degradation period of the stent 10. In an embodiment, the molecular weight of graft 30 ranges between 1,47,000 g/mol to 2,61,000 g/mol and degrade over a period of 12 months to 18 months. In an embodiment, the graft 30 is provided on the stent 10 by means of without limitation spray coating.

[0024] The thickness of the graft 30 may range from 30 pm to 100 pm, preferably between 40 pm to 70 pm. In paediatric cardiology, the endoprosthesis 100 must have enough strength and flexibility to keep the scarred lesion open and to pass through the tortuous narrow path of the lumen of patient. The graft 30 over the stent 10 may enhance the radial strength of the stent 10 by 1.2 to 1.8 times. In an embodiment, the graft 30 enhances the radial strength of the stent 10 from 5 N to 15 N. Additionally, aortic coarctation during balloon angioplasty may lead to several complications such as aortic dissection, aortic aneurysm formation or recoarctation. In such cases, the graft 30 may serve to seal ruptured artery adequately with complete dilation of

endoprosthesis. [0025] Additionally or optionally, the stent 10 with the graft 30 may be coated with an antiproliferative drug and/or anti-inflammatory agent. The antiproliferative drug may include without limitation such as rapamycin and/or its derivatives, taxane derivatives, paclitaxel and/or its derivatives. The anti-inflammatory agents may include without imitation agents from a fenac family such as diclofenac, dexamethasone, co-drugs and/or mixtures thereof.

[0026] The endoprosthesis 100 of the present disclosure in coronary application has a deployed diameter of approximately 2mm to 4mm. The length of the endoprosthesis 100 may range between 13mm to 48mm. The deployed diameter of the endoprosthesis 100 in aortic/pulmonary application may range between 4mm to 10mm. The endoprosthesis 100 has a length in a range of approximately 9mm to 30mm. In an embodiment, the crimp diameter of the endoprosthesis 100 in coronary applications is approximately 1.1 mm to 1.4 mm and in aortic/pulmonary application is approximately 1.5mm to 1.9mm.

[0027] The endoprosthesis 100 for paediatric cardiology has high radial strength to keep vessel lumen open for predetermined period of time. In an embodiment, the endoprosthesis 100 possesses radial strength of approximately more than 10 N, more preferably between 10 N to 20 N. Radial strength of the endoprosthesis 100 may be maintained by geometry of the stent 10.

[0028] In an embodiment, the crimp profile of the endoprosthesis 100 may be maintained by altering the geometry of the stent 10 and balloon crossing profile. In accordance with the present disclosure, the crimp profile of the endoprosthesis 100 having larger deployed diameter is reduced to approximately 60 % to 75 % of its initial diameter. In an embodiment, the reduction in the crimp diameter is obtained by optimizing the geometry of the stent 10, thickness of strut 3 of the stent 10 and diameter of the balloon on which the endoprosthesis 100 is crimped.

[0029] The crimped endoprosthesis 100 allows easy access into the small arterial segment. The crimped endoprosthesis 100 may be deployed with the help of a sheath of low diameter. The sheath may include without limitation, 6F (2mm) or lower as per the requirement.

[0030] The deployed endoprosthesis 100 results in opening of aorta and pulmonary artery. The open arterial segment allows increase in blood flow to facilitate normal development of child's aorta and lungs associated with pulmonary artery. [0031] The endoprosthesis 100 supports aorta and pulmonary artery for at least a period of six months and then completely degrades over a period of time. The endoprosthesis 100 may undergo hydrolytic degradation in the body and eventually gets eliminated as carbon di oxide and water.

The degradation of endoprosthesis 100 includes chemical degradation and loss of mechanical properties of the endoprosthesis 100.

[0032] FIG. lb represents an exemplary geometry of the stent 10 in accordance with an embodiment of the present disclosure. In an embodiment, the stent 10 is shaped to a desired geometry by laser cutting. The laser cutting may be performed with the help of a femto seconds equipment having laser beam of 1300-1500 nm wavelength. [0033] The stent has a proximal end 1, a distal end 2. The stent 10 may include a plurality of rings 10a connected or coupled with struts 3 to form a plurality of cells. The rings 10a may be in the form of sinusoidal wave. Each ring 10a includes a plurality of peaks 4 and valleys 5. The rings 10a are aligned in a manner such that peak 4 of one strut face the valley 5 of subsequent strut and vice versa. The stent 10 forms a hybrid design of cells. The hybrid design includes a plurality of rows of open cells 6 and a plurality of rows of closed cells 8. In an embodiment, one row of closed cell 8 is disposed at the proximal end 1 and one row of closed cell 8 is disposed at the distal end 2. The rows of open cells 6 are disposed between the rows of closed cells 8. The structure of the stent 10 distributes stress at peaks 4 during crimping and expansion throughout the whole length and may lead to fracture resistance. [0034] It is to be noted that the teachings of the present invention are not restricted to the hybrid design of cells depicted in Figs la and lb, rather other hybrid design of cells with the width and thickness of struts as claimed in the present invention are also within the teachings of the present disclosure.

[0035] Further, while an exemplary embodiment of stent design described in the present invention includes hybrid cell design, stents employing only open or closed cell design (for example, sinusoidal open ring structure or honeycomb structure) having a width and thickness of struts as claimed in the present invention are also within the teachings of the present disclosure. [0036] The proximal end 1 and the distal end 2 of the stent 10 may have a plurality of markers 7. In an embodiment, the 3 couplet of the markers 7 are affixed at an equi-distant at an angle of 120° to each other.

[0037] The geometry of the stent 10 may be optimized for required crimp profile. The geometry of the stent 10 may be altered by changing length and/or width of the cells. In an embodiment, the length of the closed cells 8 may range between 1.35mm to 1.75 mm and width may range between 0.90mm to 1.10mm. In another embodiment, the length of the open cells 6 may range between 3.10mm to 3.40mm and width may range between 1.70mm to 1.90mm. The stent having greater length and width of the cell may result in lower crimp profile of the stent. [0038] The width and thickness of the struts 3 and rings 10a of the stent 10 directly influence the crimp profile of the endoprosthesis 100. In an embodiment, higher width and lower thickness of the strut 3 as well as rings 10a lead to lower crimp profile of the endoprosthesis 100. For example, the width of the struts 3 and rings 10a is selected from 120 pm to 190 pm and the thickness of the struts 3 and rings 10a is selected from 140 pm to 180 pm resulting in a crimp profile of 1.3mm to 2.1mm.

[0039] Alternatively, lower width and higher thickness of the strut 3 as well as rings 10a may lead to lower crimp profile of the endoprosthesis 100. For example, the width of the struts 3 and rings 10a is selected from 90 pm to 150 pm and the thickness of the struts 3 and rings 10a is selected from 120 pm to 220 pm resulting in a crimp profile of 1.3mm to 2.1mm. The lower width of the strut 3 and rings 10a may result in availability of more free space on the surface of the balloon. The free space on the surface of the balloon causes more crimping of the endoprosthesis 100 which leads to reduced crimp diameter of the endoprosthesis 100. Though the lower width of the struts 3 and rings 10a of the stent 10 may lead to lower strength, the strength of the stent 10 is balanced by selecting struts 3 and rings 10a of higher thickness. [0040] In accordance with an embodiment, the balloon crossing profile directly influences the crimp profile of the endoprosthesis 100. In an exemplary embodiment, the balloon having a low crossing profile, for example 1.6mm to 2.2mm results in a low crimp profile of the endoprosthesis 100. The polymer material may include without limitation nylon, pebax, polyethylene

terephthalate (PET), polyurethane. In an embodiment, the balloon 20 is made of pebax. [0041] In accordance with an embodiment, FIG.2 depicts a flow chart for a process involved in manufacturing of the endoprosthesis 100. The process of manufacturing the endoprosthesis 100 commences at the step 201. At step 201, a stent 10 having sinusoidal wave rings connected by a plurality of struts is provided. The width and thickness of rings and struts is in a range of 90 pm to 190 pm and 140 pm to 190 pm respectively.

[0042] At step 203, the outer surface of the stent 10 is provided with a layer of formulation of a biodegradable polymer resulting in formation of the graft 30. The stent 10 along with the graft 30 form the endoprosthesis 100. The graft 30 may be provided by means of without limitation a spray coating technique. In an embodiment, the concentration of the biodegradable polymer is maintained between 0.5 % w/v to 1.0 % w/v.

[0043] At step 205, the stent 10 with the graft 30 obtained at previous step is subjected to a process of annealing. In an embodiment, the endoprosthesis 100 is annealed at an annealing temperature of around 70°C to 140 °C, preferably between 90°C to 120°C for a time period of around 10-24 hours, preferably 12-20 hours in a vacuum of around -700mmHg to -750mmHg in order to impart stability to the endoprosthesis 100.

[0044] Further, at step 207, the endoprosthesis 100 is mounted on an outer surface of a balloon and is subjected to a process of crimping. In an embodiment, crimping is performed in 6 to 8 stages. The crimping temperature of each stage may vary between 25°C and 60°C, preferably between 45°C to 55°C for time duration of approximately 200 seconds to 310 seconds. [0045] At step 209, the endoprosthesis 100 in crimped state over the balloon is sealed in an aluminium pouch with inert gas to prevent polymer degradation and maintain structural integrity. The inert gas may include nitrogen, argon or helium. Additionally and optionally, the

endoprosthesis 100 is subjected to a process of radiation sterilization with e-beam radiations. In an embodiment, dose of e-beam radiation is maintained between 15-30 kGy, preferably between 18-23 kGy. The sterilization is performed at a temperature of 15°C-25°C. Lastly, the endoprosthesis 100 is implanted in the body of a patient with the help of a delivery sheath of low diameter at step 211. The sheath may include without limitation, 6F (2mm) or lower as per the requirement.

[0046] The low crimp profile of the endoprosthesis 100 may impart flexibility for easy movement of the endoprosthesis 100 in curved and small lumen of the body of the patient. It may also provide small puncture site for implantation in the body which is a crucial requirement for treatment of paediatric patients.

[0047] The crimped endoprosthesis 100 allows easy access into the small arterial segment. The crimped endoprosthesis 100 may be deployed with the help of a sheath of low diameter. The sheath may include without limitation, 6F (2mm) or lower as per the requirement.

[0048] The deployed endoprosthesis 100 results in opening of aorta and pulmonary artery. The open arterial segment allows increase in blood flow to facilitate normal development of child's aorta and lungs associated with pulmonary artery.

[0049] The endoprosthesis 100 supports aorta and pulmonary artery for at least a period of six months and then completely degrades over a period of time. The endoprosthesis 100 may undergo hydrolytic degradation in the body and eventually gets eliminated as carbon di oxide and water. The degradation of endoprosthesis 100 includes chemical degradation and loss of mechanical properties of the endoprosthesis 100.

[0050] Various crimping trials are performed by varying balloon crossing profile, stent diameter and stent thickness.

[0051] In an exemplary embodiment, the stent 10 of diameter 5mm and length 15 mm is used for crimping process. The balloon crossing profile is in a range of 2.1 mm to 2.2 mm. The thickness of the stent is varied in a range of 150 to 180 pm and 170 to 200 pm. The dislodgement force is maintained at around 3.5N. [0052] As per the teachings of the present invention, during experimental trials, it is observed that stent with thickness 170 to 200 pm is crimped to a profile of 2.0mm to 2.1 mm. The stent with thickness of 150 to 180 pm is crimped to a lower profile of 1.9mm to 2.0mm. The stent with lower thickness is crimped to a slightly lower profile as compared to the stent with higher thickness.

[0053] In another experimental trial, the balloon crossing profile is in a range of 1.6mm to 1.9mm. The stent diameter is 5mm and length is 15mm. The thickness of the stent is in a range of 130 to 160 pm and 170 to 200 pm. The stent 10 having thickness 170 to 200 pm is crimped to a profile in a range of 1.9mm to 2.0mm. The stent 10 having thickness in a range of 130 to 160 pm is crimped to a diameter of 1.55 mm to 1.75 mm. [0054] The stent 10 with crimped diameter of 1.55 mm to 1.75 mm is suitable to be delivered with 6F (2mm) sheath. The stent 10 is uniformly crimped over the balloon 20. The dislodgement force is maintained same as the previous example.

[0055] 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.