WO2019064308A1

WO2019064308A1 - Occluder with a locking system and a method of manufacturing thereof

Info

Publication number: WO2019064308A1
Application number: PCT/IN2017/050524
Authority: WO
Inventors: Deveshkumar Mahendralal KOTHWALA; Rajnikant Gandalal Vyas; Dr. Pramodkumar MINOCHA
Original assignee: Meril Life Sciences Pvt Ltd
Priority date: 2017-09-27
Filing date: 2017-11-11
Publication date: 2019-04-04

Abstract

An occluder is disclosed. The occluder includes a biodegradable frame and a locking system to lock the occluder at the site of treatment. The locking system comprises a suture and an anchor. One of the ends of the suture is attached to one of the ends of the biodegradable frame and other end of the suture passes through other end of the biodegradable occluder. The biodegradable frame is locked once the suture is pulled till the anchor mates with the other end of the biodegradable frame. The occluder is manufactured by braiding of one or more monofilaments made of biodegradable polymer to form a biodegradable frame. The biodegradable frame is annealed one or more time to form an annealed biodegradable occluder/ frame. The annealed biodegradable frame is welded at two ends and is coated with a layer of polymer on its external surface.

Description

OCCLUDER WITH A LOCKING SYSTEM AND A METHOD OF MANUFACTURING THEREOF

FIELD OF INVENTION

[001] The present disclosure relates to an occluder, more specifically to an occluder with enhanced shape memory effect and method of manufacturing thereof. BACKGROUND

[002] Occluders are used to occlude and/or close the space causing congenital heart defects. A congenital heart defect is a problem with the structure of the heart. Congenital heart defects may be a most common type of birth defect. The defects may involve walls of the heart, valves of the heart, arteries and/or veins near the heart. They can disrupt the normal blood flow through the heart. The blood flow may slow down, go in the wrong direction and/or to the wrong place, and may get blocked completely. Symptoms of the congenital heart disease may include shortness of breath, cyanosis, fainting, heart murmur, under-development of limbs and muscles, or respiratory infections, rapid breathing, bluish skin, poor weight gain, etc. Various types of congenital heart defects may include Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Muscular Ventricular Septal Defect (mVSD), Patent Ductus Arteriosus (PDA), Patent Foramen Oval (PFO), etc.

[003] Generally, a metal device may be used to treat such types of defects in the heart. These devices may present significant risks including thrombus formation on the device, metal allergy, tissue erosion, etc. It has been studied that most thromboembolic events and associated neurological disorder may occur within the first year after implantation or in some cases even after five years. These conditions may require removal of the implanted device through an open heart surgery.

[004] A second category of devices - bioresorbable devices - exist. These bioresorbable devices may be made of bioresorbable monofilaments and bioresorbable fabric which degrade completely over a period of time after treating the defect. For example, the structure of the biodegradable device may degrade after 1 to 2 years of implantation overcoming aforesaid disadvantages associated with metal device. However, conventional bioresorbable devices also suffer from low strength and/or low shape memory characteristics upon deployment to the target site.

SUMMARY [005] The present invention discloses an occluder for treatment of congenital heart diseases. The occluder includes a biodegradable frame and a locking system to lock the occluder at the site of treatment. The locking system comprises a suture and an anchor. The anchor is placed at equidistant from two ends of the suture. The first ends of the suture is attached to first end of the biodegradable frame and the second end of the suture passes through the second end of the biodegradable frame. The biodegradable frame is locked once the suture is pulled till the anchor mates with the other end of the biodegradable frame.

[006] The occluder is manufactured by braiding of one or more monofilaments made of biodegradable polymer to form a biodegradable frame. The biodegradable frame is annealed one or more time to enhance the shape memory characteristics of the occluder. The annealed biodegradable frame is welded at two ends and is coated with a layer of polymer on its external surface. One or more annealing of the biodegradable frame includes annealing after braiding of the monofilaments, second annealing is performed after welding of the biodegradable frame and third annealing is performed after coating of the biodegradable frame. BRIEF DESCRIPTION OF THE 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.l illustrates a schematic view of the occluder in accordance with an embodiment of the present invention.

[009] FIG.2 illustrates VSD Occluder device in locked state in accordance with an embodiment of the present invention. [0010] FIG.3 illustrates a flow chart depicting process involved in manufacturing of the occluder in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS [0011] 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 communica ble 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.

[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.

[0013] In accordance with the present disclosure, an occluder for treatment of congenital heart diseases is provided. In an embodiment, the occluder is made of biodegradable monofilaments. In another embodiment, the occluder is manufactured by performing multiple heat treatments in order to provide enhanced shape memory properties to the occlusion device. The apparatus disclosed in the present invention is designed to fill the occlusion of a tissue wall inside a body effectively, hold the device securely at the treatment site and/or impart fast tissue growth leading to treatment of the tissue wall containing the defect.

[0014] Now referring specifically to the drawings, FIG.l represents a schematic view of an occluder 100 in an unlocked state and having a locking system 30 in accordance with an embodiment of the present invention. The occluder 100 is a self-expanding biodegradable apparatus with enhanced shape memory properties. The occluder 100 has a controlled degradation rate inside the body. For example, the occluder 100 may degrade completely over a period of 1 to 2 years following treatment of the targeted defect. The occluder 100 includes a frame 10, a locking system 30 and optionally, a plurality of radiopaque markers 20. The radiopaque markers 20 may be made of without limitation, platinum.

[0015] The frame 10 of the occluder 100 is made of a biodegradable polymer. In an embodiment, the frame 10 of the occluder 100 is made of one or more biodegradable polymer monofilaments. The biodegradable material may include without limitation, Poly-L-Lactic Acid (PLLA), Poly lactic-co-glycolic Acid (PLGA), Poly-D,L-lactic Acid (PDLA), Polydioxanone (PDO) or combination thereof. In an embodiment, the polymer material possesses shape memory properties and/or effect. [0016] In an exemplary embodiment, the frame 10 of the occluder 100 is made of poly(lactic- co-glycolic acid) (PLGA). The poly(lactic-co-glycolic acid) PLGA consist of 85% mol L-Lactide and 15% mol Glycolide. The poly(lactic-co-glycolic acid) PLGA is used for extrusion of polymer into monofilaments. The poly(lactic-co-glycolic acid) PLGA monofilaments may exhibit high strength and modulus. In an embodiment, the poly(lactic-co-glycolic acid) PLGA monofilaments exhibit high strength due to an orientation process followed while extrusion of the monofilament. An exemplary orientation process includes the polymer filaments are placed under high tension in order to stretch the filaments. Molecules of the polymer filaments may straighten out and/or line up parallel to the filament axes. In an embodiment, tensile strength of the oriented polymer filament is 10 times greater than the un-oriented polymer filament. [0017] In an embodiment, in an unlocked state, the occluder has a shape corresponding to for example, the digit '8'. The occluder 100 is a single unit which includes a first end 11, a second end 13, an upper disk 12, a lower disk 14 and a waist 16. The first end 11 and the second end 13 may include respective necks which may be hollow for passage of a suture through them. The diameter of the neck may be sufficient enough to facilitate passage of a suture and/or an anchor as explained below.

[0018] In an embodiment, the occluder 100 includes the upper disk 12 towards the first end 11 and the lower disk 14 towards the second end 13 and a waist 16 in middle. The upper disc 12 and the lower disc 14 of the frame 10 cover and/or occlude a defect (for example, a hole) in a tissue wall. The waist 16 is placed in the defect. In an embodiment, the diameter of the waist 16 is comparable to the diameter of the targeted defect across the tissue wall. The size of the waist 16 may vary depending upon the type of targeted defect. In an embodiment, the size of the waist 16 is in a range of 6mm to 42mm in case of Atrial Septal Defect (ASD) occluder, 4 to 26mm, in case of Ventricular Septal Defect (VSD) occlude and 4mm to 22mm in case of Patent Ductus Arteriosus (PDA) occluder.

[0019] Further, the upper disk 12 and the lower disk 14 may have a diameter distinctly larger compared to the waist 16 enable the occluder to be seated in the defect. In various embodiments, the upper disk 12 and the lower disk 14 may be of same or different diameter.

[0020] In an embodiment, the occluder 100 has a locking system 30. The locking system 30 keeps the upper disc 12 and the lower disc 14 of the occluder 100 anchored to the tissue wall containing an opening and/or defect effectively. The locking system 30 of the occluder 100 includes a suture 32, and an anchor 40 coupled to the suture 32. The suture 32 includes a first end 34 and a second end 36. The first end 34 of the suture 32 may be attached to the neck of the first end 11 of the frame 10. Similarly, the second end 36 of the suture 32 may pass through the neck of the second end 13 of the frame 10. In an embodiment, the first end 34 of the suture 32 is attached to the first end 11 by means of without limitation, welding.

[0021] The anchor 40 may be placed at a predefined distance from both the ends 34 and 36 of the suture 32. In an embodiment, the anchor 40 is equidistant from both the ends 34 and 36 of the suture 32. The anchor 40 may be made of any material known in the art for example, polylactic acid (PLA), polyflactic-co-glycolic acid) (PLGA) etc. The anchor 40 may be of any shape and size for example, a rectangular shape. The dimensions of the anchor 40 may define the diameter of the neck of the first and second ends (11, 13) of the frame 10. In an embodiment, dimensions of the neck of the first and second ends (11, 13) of the frame 10 are made greater than the dimension of the anchor 40 to facilitate passing of the anchor 40. [0022] Alternatively, the locking system 30 may be a uni-knot and/or double uni-knot (not shown). The suture 32 may be attached at one of the disc and knotting is done at the opening of another disc. The anchor 40 is attached above the knot. In an embodiment, when a pulling force is applied to the loose end of the suture, the occluder 100 is locked and provides complete closure at the site of a defect. [0023] Optionally, the frame 10 of the occluder 100 may include a plurality of markers on first end 11 and/or second end 13 of the frame 10. The markers are used to visualize the position of the occluder 100 during fluoroscopy imaging. In an exemplary embodiment, a first marker 20 is positioned on the first end 11 and a second marker 22 is positioned on the second end 13 of the occluder 100. The markers 20 and 22 are attached on the ends 11 and 13 respectively by means of without limitation crimping and/or any other suitable means. In another embodiment, attachment of the markers 20 and 22 on the first end 11 and the second end 13 respectively aids in holding together the open ends of the frame 10 of the occluder 100. The markers 20 and 22 may include without limitation, radiopaque markers Stainless steel, Platinum, Gold, Platinum-lridium, Tantalum, etc.

[0024] The frame 10 of the occluder 100 includes a non-woven fabric (not shown). The fabric may be attached to an external and/or internal surface of the frame 10. The fabric may be made of biodegradable material. The biodegradable material may include without limitation, Poly-L-lactide (PLLA). [0025] The fabric attached to the external and/or internal surface of the frame 10 aids in covering one or more defects inside a body. The fabric may block blood flow for growth of tissue over the frame 10.

[0026] In an embodiment, after successful implantation of the occluder 100 at the site of the defect, a layer of tissue grows over the frame 10 of the occluder 100 over a period of time. The occluder 100 may be resorbed over a period of 1- 2 years following treatment of the targeted defect. In another embodiment, the occluder 100 is resorbed completely inside body except the markers 20 and 22 provided at the ends 11 and 13 of the frame 10. In an embodiment, the markers 20 and 22 are used keep a track of the patient's medical history.

[0027] Fig. 2 depicts the occluder in locked state, namely, the anchor 40 is parked at the end 13. In an embodiment, the suture 32 with anchor 40 is inserted through first end 11 of the frame 10. The second end 36 of the suture 32 is passed along with anchor 40 through the second end 13 of the frame 10. When the second end 36 of the suture 32 is pulled, the anchor 40 is also pulled towards the neck of the second end 13 of the frame 10. Once the anchor 40 reaches the neck of the second end 13 of the frame 10, it flips and gets secured in the neck of the second end 13. Due to this, the upper disc 12 and the lower disc 14 attain a rigid configuration termed as 'locked state' around the tissue wall containing defect and/or opening.

[0028] In an exemplary embodiment, FIG. 3 illustrates a flow chart depicting the process involved in manufacturing of the occluder 100. The process of manufacturing of the occluder 100 commences at the step 301. At this step, monofilaments made of preferably PLGA having thickness ranging from 100 μιη- 200 μιη. The monofilaments are braided together with the help of without limitation a circular braiding machine for example, a mandrel. Diameter of the mandrel and/or angle of braiding may be varied depending upon type of the occluder 100 to be manufactured. In an embodiment, the diameter of the mandrel and angle of braiding is in a range of 4mm to 60 mm and 75°- 150° respectively. In another embodiment, the braiding of the monofilaments is performed at a take-up speed of around 1.0 V/Hz to 5.0 V/Hz, rotational speed of around 20 V/Hz and 50 V/Hz and/or the number of carriers between 32-104.

[0029] At the step 303, the frame 10 is annealed over the mandrel. The process of annealing is performed to change the microstructure of the monofilaments in order to change their mechanical properties. The process of annealing of the frame 10 may be performed by heating the monofilament followed by cooling of the same.

[0030] The annealing of the frame 10 may be performed in a vacuum hot annealing unit. The annealing unit may be designed to ensure uniform heat treatment of the frame 10. The process of annealing may be performed at a first predetermined temperature and time duration. In an embodiment, the annealing is performed at a temperature of around 90°C - 110°C for time duration of approximately 8hrs to 24hrs.

[0031] In an embodiment, the process of annealing of the frame 10 after braiding at the step 301 restores ductility of the monofilaments. The aforesaid process imparts shape memory to filaments and/or frames 10 and/or makes the monofilaments resistive to cracking during course of treatment.

[0032] At the step 305, the frame 10 after annealing at the previous step is welded at the ends 11 and 13. In an embodiment, the welding of the frame 10 is performed with the help of without limitation a laser welding machine. The welding may be performed at laser power of around 1.1W, rotational speed of around 300rpm at a room temperature for time duration of around 9 seconds. The temperature of work floor area of the welding may be maintained at a temperature of around 22°C. The intensity of laser beam radiations facilitates welding of the ends (11,13) of the frame 10. Optionally, at the step 305, a plurality of markers 20 may be attached on the welded ends 11 and 13 of the frame 10. The markers 20 may be attached to the ends 11 and 13 by means of without limitation, crimping. In an embodiment, a sleeve is mounted over both ends 11 and 13 of the frame 10 with a plurality of markers 20 and a stylet is inserted throughout the frame 10.

[0033] The frame 10 may be kept at a collet of the laser welding machine. Positioning and parameter setting of the laser welding machine may be followed by the welding of two ends 11 and 13 of the frame 10. The sleeve is removed after the welding process is completed. The stylet passes throughout the frame 10 and/or radio opaque jacket and/or markers 20 and creates a cavity at the ends 11 and 13 of the frame 10. The cavity may be used for fixing the locking system 30. In an embodiment, the laser welding is performed to hold the monofilaments ends together with the markers 20.

[0034] At the step 307, the frame 10 is molded into a shape of an occlusion device. In an embodiment, the shape setting the frame 10 is performed by using molds similar to the congenital heart defects without limitation, Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Patent Ductus Arteriosus (PDA), Patent Foramen Oval (PFO), etc. The mold may be prepared by using metallic material without limitation, stainless steel.

[0035] In an embodiment, desired shape of the occluder is achieved by inserting frame 10 into the mold. Inside the mold, shape setting may be performed by any method known in the art such as, annealing of the frame 10. The annealing may be performed at a second predetermined temperature and time duration. In an embodiment, the shape setting of the frame 10 is achieved at a temperature of around 90°C to 110°C temperature for time duration of around 4hrs to 24hrs. The shape setting imparts desired shape and shape memory to the occluder 100. [0036] At the optional step 309, following the shape setting procedure at the step 307, the occluder 100 is coated with a biodegradable polymer. The coating of the occluder 100 may be achieved by any method known in the art for example, the spray coating technique. The coating agents may include without limitation, PGS [Poly (glycerol sebacate)], Poly-L-lactide-co- caprolactone (PLCL) or PCL (Poly-Caprolactone) with or without cross linkers. [0037] In an exemplary embodiment, the coating of the occluder 100 is achieved with [Poly (glycerol sebacate)] (PGS). In an embodiment, coating is achieved by means of spray coating technique in an amount ranging between approximately 10ml to 30ml. The Poly (glycerol sebacate)] (PGS) coating may improve elasticity of the occluder 100. [0038] In another embodiment, the occluder 100 is coated with Poly-Caprolactone (PCL). In an embodiment, the coating is achieved by means of spray coating technique in an amount ranging between approximately 10ml to 45ml. The Poly-Caprolactone (PCL) coating may improve strength and binds cross section of the frame 10. In an embodiment, a coating formulation is prepared by Poly-Caprolactone (PCL) in dichloromethane (DCM) solvent in a concentration of around 0.2 % to 1.0 %.

[0039] In an embodiment, the coated occluder 100 is kept in a desiccator for drying for time duration of around 16hrs to 24hrs to evaporate residual solvents. The coated occluder 100 is heat treated in the mold at a temperature of around 40°C - 80°C for time period of around 8hrs to 16hrs. The heated occluder 100 is allowed to cool at ambient temperature. [0040] In an embodiment, the process of coating of the occluder 100 and heat treatment increases strength of the occluder 100 and/or reduces deformation of the occluder 100 upon deployment to the treatment site.

[0041] At the step 311, a non-woven fabric is attached at the external and/or internal surface of the frame 10. The fabric may be made of biodegradable material. The biodegradable may include without limitation, Poly(lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA), poly-D-lactide (PDLA), Polycaprolactone (PCL), etc. The non-woven fabric may be attached by any method known in the art for example, sewing.

[0042] In an exemplary embodiment, the Poly(lactic acid) (PLLA) fabric of thickness around 0.02mm to 0.07mm, preferably around 0.02mm and GSM range of around 5gsm to 30 gsm, preferably around 15gsm is used. In an embodiment, the Poly(lactic acid) (PLLA) fabric is sewn together with metal wire of thickness around 10 to 40 microns. The metal wire may include without limitation, platinum, nitinol or their combination wire etc.

[0043] In an embodiment, the fabric is sewed to the frame 10 by means of a curved needle and/or platinum wire in a manner where one cross section of the filament passes through another cross section by leaving one cross point. In an embodiment, sewing fabric with the frame 10 imparts strengths, elasticity and/or durability to the occluder 100 during loading inside a catheter and/or after deployment to the treatment site.

[0044] At the step 313, the occluder 100 is fitted with fabric in the previous step 311 is further processed with shape setting techniques. The shape setting may be performed at a third predetermined temperature and time duration. In an embodiment, the shape setting is performed by annealing the occluder 100 at a temperature of around 90°C to 110°C for time duration of around 8hrs to 16hrs. The shape setting may be performed in a heating unit, for example a vacuum oven. The shape setting at this step imparts shape memory to the occluder 100. [0045] At the step 315, the occluder 100 is fitted with a locking system 30. The locking system 30 is included to keep the upper disc 12, lower disc 14 and the waist 16 fixed to the site of defect in tissue wall containing the defect. Lastly at the step 317, the occluder 100 is packaged in an aluminum pouch. The packaged device is sterilized with e-beam radiation.

[0046] 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.

Claims

WE CLAIM

1. An occluder comprising: a. a biodegradable frame, the biodegradable frame including a first end, a second end, an internal surface and an external surface; and b. a locking system comprising a suture and an anchor, a first end of the suture is attached to the first end of the biodegradable frame, a second end of the suture passes through the second end of the biodegradable frame such that the suture along with the anchor is held inside the biodegradable frame, the biodegradable frame is locked once the suture is pulled till the anchor mates with the second end.

2. The occluder as claimed in claim 1 wherein at least one of the external surface or the internal surface of the biodegradable frame includes a fabric to facilitate tissue growth.

3. The occluder as claimed in claim 1 wherein at least one of the first end and second end of the biodegradable frame include at least one marker.

4. The occluder as claimed in claim 1 wherein the biodegradable frame comprises at least one of Poly-L-Lactic Acid (PLLA), Poly lactic-co-glycolic Acid (PLGA), Poly-D,L-lactic Acid (PDLA), Polydioxanone (PDO) or combination thereof.

5. The occluder as claimed in claim 1 wherein the marker is a radiopaque marker.

6. The occluder as claimed in claim 1 wherein the biodegradable fabric comprises Poly(lactic acid) (PLLA).

7. The occluder as claimed in claim 1 wherein the anchor comprises at least one of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA).

8. A method for manufacturing of the occluder, the method comprising: a. braiding of one or more monofilaments made of biodegradable polymer to form a biodegradable frame, the biodegradable frame including a first end, a second end, an internal surface and an external surface; b. annealing of the biodegradable frame at a first predetermined temperature and first predetermined time duration one or more time to form an annealed biodegradable frame; c. welding of the biodegradable frame at a room temperature for time duration of 9 seconds to form a first welded end and a second welded end; and d. coating a layer of biodegradable material on the annealed biodegradable frame to form a coated occluder.

9. The method as claimed in claim 8 wherein the first predetermined temperature is 90°C- 110°C and first predetermined time duration is 8hours-24hours.

10. The method as claimed in claim 8 wherein the method comprises mounting at least one marker on at least one of the first welded end and the second welded end of the biodegradable frame.

11. The method as claimed in claim 10 wherein the mounting comprises crimping of at least one marker.

12. The method as claimed in claim 8 wherein the method comprises fitting of a fabric to at least one of the external surface or the internal surface of the coated frame to yield a fabric fitted biodegradable frame.

13. The method as claimed in claim 8 wherein the method comprises shape setting of the fabric fitted biodegradable frame.

14. The method as claimed in claim 8 wherein the method comprises incorporating a locking system in the fabric fitted biodegradable frame.

15. A method for manufacturing a multi-stage annealed occluder, the method comprising: a. a first annealing of a biodegradable frame post braiding of one or more monofilaments at a first predetermined temperature and time duration; b. a second annealing of the biodegradable frame of step (a) after welding the biodegradable frame at one or more of two ends at a second predetermined temperature and time duration; and c. a third annealing of the biodegradable frame of step (b) after attachment of a fabric on at least one of an external surface or an internal surface of the biodegradable frame of step (b) at a third predetermined temperature and time duration to yield a multi-stage annealed occluder.

16. The method as claimed in claim 15 wherein the first predetermined temperature is 90°C- 110°C and first predetermined time duration is 8hours-24hours.

17. The method as claimed in claim 15 wherein the second predetermined temperature is 90°C-110°C and second predetermined time duration is 4hour- 24hours.

18. The method as claimed in claim 15 wherein the third predetermined temperature is 90°C - 110°C and a time duration of around 8hours-16hours.