Polymeric venous valve systems and methods of making and using thereof

Abstract

Polymeric venous valve systems having a supportive frame embedded in a polymeric sleeve and a plurality of polymeric leaflets forming a continuum with the polymeric sleeve are described herein. Methods of making and using such polymeric venous valve systems are also described. The polymeric venous valve systems are well-suited for use in low pressure and low shear venous environments.

Description

[0001] POLYMERIC VENOUS VALVE SYSTEMS AND METHODS OF MAKING AND USING THEREOF

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under HL134418 and EB026414 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0004] CROSS REFERENCE TO RELATED APPLICATION

[0005] This application claims priority to U.S. Provisional Patent Application No. 63 / 580,859 filed September 6, 2023, the disclosure of which is incorporated herein by reference.

[0006] FIELD OF THE INVENTION

[0007] The invention is generally in the field polymeric venous valve systems and methods of making and using thereof.

[0008] BACKGROUND OF THE INVENTION

[0009] Valves are structures within the body that serve to partition fluid flow. In the cardiovascular system valves exist both in the heart and the vasculature. A typical valve structure consists of a fibrous ring structure and component leaflets, examples being the aortic and pulmonic valve. Beyond these simple valves, specific valves, such as the mitral and tricuspid valves are complex multi-part structures involving leaflets, a valve ring, chordae tendinae and papillary muscles all of which act in temporal and functional harmony to control fluid flow.

[0010] With the passage of time, repeated duty cycling of such native valves, as well as the onset of disease-related pathological changes and aging, native valves can deteriorate. A range of valvular maladies typically occur including the development of valvular stenosis, i.e. narrowing of the valve, or the development of valvular regurgitation or insufficiency with progressive incompetence of the native valve. Beyond these, other specific changes may occur including enlargement of the valve orifice, calcification of the valve, inflammatory changes of the valve, infection developing on the valve or valve ring, or underlying tissue changes in the organ, e.g. heart or artery, or organ component in which the valve resides. All of these lead to geometric and mechanical alteration of the overall native valve resulting in dysfunction and consequent organ and system sequelae.

[0011] For complex valves, such as the mitral and tricuspid valve, derangement or dysfunction of any of the additional elements, e.g. chordae or tethering papillary muscles, will also lead to valvular dysfunction. In addition, ischemic changes related to muscle or associated wall function will similarly lead to dysfunction of native valves.

[0012] Accordingly, a major focus of technology development for the treatment of valvular disorders has been the development of replacement valves which can be utilized on the left heart and arterial side of the cardiovascular system. Typically, such prosthetic valves have been developed for treatment of aortic stenosis - either surgical prosthetic valves, or percutaneous bioprosthetic valves, such as employed in TAVR, or mitral valve repair and replacement technologies. A common feature of these replacement valve systems is that they are subjected to significant pressures, such as the left ventricular end systolic pressure - typically in the range of 80 to 220 mm Hg, or aortic arterial pressures ranging from pressures within the range of about 80 / 50 to 240 / 140. As such, these valvular replacement systems are robust and have stiff bodies, components, and leaflets, which designed specifically to handle the significant impulse pressures, dp / dt, flows, shear stress, and reflected oscillatory waves associated with the high pressure side of the cardiovascular system.

[0013] Beyond high pressure systems, however, a growing need exists for valvular solutions for low pressure systems, as well. These are common on the right side of the cardiovascular system with the right heart and venous aspects of the vascular tree. On the right side, the pressures are much lower, typically ranging from 0 - 20 mm Hg, with occasional short impulses in the right ventricle (RV) with RV end diastolic pressure (RVEDP) up to about 40-50 mm Hg. On the right side significant diseases exist such as tricuspid regurgitation, or venous incompetence in the great veins and lower extremity veins, e.g. the greater saphenous vein.

[0014] Beyond the pressure differences, on the right side flow differences exist between veins and arteries. For example, in healthy individuals the peak systolic velocity (PSV) of the aorta and of the iliac arteries is 90+20 cm / sec (mean+SD), with a gradual decrease in PSV being observed moving from the iliac to the popliteal arteries. In contrast, normal main portal vein (MPV) (a medium to large sized vein) peak systolic velocities are lower, typically ranging between 20 cm / sec and 40 cm / sec. Similarly, a recent study of finger blood flow the arterial blood flow velocities were measured to range from 4.9-19 cm / sec, while venous blood flow was significantly slower at 1.5-7.1 cm / sec. Taking into account the corresponding vessel diameters ranging from 800 micron to 1.8 mm, blood flow rates of 3.0-26 ml / min in arteries and 1.2-4.8 ml / min in veins were obtained. See Klarhbfer, M., Csapo, B., Balassy, C., Szeles, J. C., & Moser, E. (2001). High-resolution blood flow velocity measurements in the human finger. Magnetic Resonance in Medicine, 45(4), 716-719. These flow differences often account, particularly in the case of disease states, for venous pooling and stagnation which is a primary driver of thrombosis. As such a major limitation of venous and right-sided disease, as well as of therapeutic technologies, remains the risk for venous thrombosis and venous thromboembolism (VTE), all of which carry significant morbidity and mortality.

[0015] Accordingly, there remains a need for valve replacements that can address the issues identified above.

[0016] Therefore, it is the object of the present invention to provide valve replacements with performance characteristics selected for venous applications.

[0017] It is a further object of the present invention to provide methods of making such valve replacements.

[0018] It is still a further object of the present invention to provide valve replacement devices for use in venous valve replacements in subjects in need thereof.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1A shows a non- limiting illustration of a polymeric venous valve system 100 having a supportive frame 110 embedded in a polymeric matrix forming a polymeric sleeve 120, three polymeric leaflets 130 each being a continuum of the polymeric sleeve without sutures where each of the polymeric leaflets is connected to the polymeric sleeve at an attachment end, an anti-leak flap 135, three crown supporting struts 140, three axial leaflet locking struts 150, and a plurality of optional anchors 160.

[0021] Figure IB shows a non-limiting illustration of a polymeric venous valve system 100 having three levels: a crown level 170, a calcific leaflet level 180, and an optional outflow track (OT) level 190.

[0022] Figure 1C shows a non-limiting illustration of a polymeric venous valve system where an anti-leak flap 135 is located adjacent to the sinus 200, native leaflets 210, and an optional outflow track (OT) level 220 of a venous valve. Figure ID shows a non-limiting illustration of a top view of the polymeric venous valve system with supportive frame 110, polymeric sleeve 120, polymeric leaflets 130, and anti-leak flap 135.

[0023] Figure IE shows a non- limiting illustration of a top view of the polymeric venous valve system where the anti-leak flap 135 includes a plurality of optional slits 138.

[0024] Figure 2A shows a non-limiting illustration of a top view of three polymeric leaflets 130 of the polymeric venous valve system where each of the polymeric leaflets has variable thickness along the length of the polymeric leaflet.

[0025] Figure 2B shows a non-limiting illustration of thickness variability across an exemplary polymeric leaflet.

[0026] Figure 3A shows a non-limiting illustration of indentation(s) on the edge 310 or in the middle 320 of portions of the struts of the supportive frame.

[0027] Figure 3B shows a non-limiting illustration of an indentation 330 on a joint of the supportive frame 110.

[0028] Figure 4A shows a non-limiting illustration of a partial section of the polymeric venous valve system with supportive frame 110, polymeric sleeve 120, a polymeric leaflet 130, and anti-leak flap 135 against a native leaflet of a venous valve.

[0029] Figure 4B shows a non-limiting illustration of a partial section of the polymeric venous valve system where the anti-leak flap 135 is placed in partial supra-annular position against a native leaflet of a venous valve.

[0030] Figure 4C shows a non- limiting illustration of a partial section of the polymeric venous valve system where the anti-leak flap 135 is placed in supra-annular position against a native leaflet of a venous valve.

[0031] Figure 5A shows a non- limiting representation of a mold 300 having a base core 310, encasement components 320, a top core 330 having multiple axial leaflet lock registrations 340 which are placed around a supportive frame 110.

[0032] Figure 5B shows a non-limiting representation of a base core 310, encasement component 320, a top core 330 having multiple axial leaflet lock registrations 340 after formation of a polymeric venous have system 100 therein.

[0033] Figure 5C shows a non-limiting cross-sectional representation of a closed mold having a base core 310, a top core 330, and encasement component 320 where a polymer is introduced by pressure using a plunger 350 and the polymer flows throughout the mold (white arrows). Figure 5D shows a non-limiting cross-sectional representation of a portion of a mold around where a polymer 360 is flowing around a supportive frame 110 to form a polymeric sleeve thereon.

[0034] Figure 5E shows a non- limiting representation of a base core 310 and a top core 330 where the core components are designed to produce polymeric leaflets having a closed position.

[0035] Figure 5F shows a non-limiting representation of a base core 310 and a top core 330 where the core components are designed to produce polymeric leaflets having a semi-open position.

[0036] Figure 6A shows a non-limiting representation of a polymeric leaflet having a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve.

[0037] Figure 6B shows a non-limiting representation of a curved polymeric valve (bottom left) and a planar polymeric valve (bottom right).

[0038] DETAILED DESCRIPTION OF THE INVENTION

[0039] Polymeric venous valve systems and methods of making and using thereof are described below.

[0040] I. Definitions

[0041] The term “biocompatible,” as used herein, refers to a material, such as a polymer, which performs its desired function when introduced into an organism without inducing significant inflammatory response, immunogenicity, or cytotoxicity to native cells, tissues, or organs.

[0042] The term “hemocompatible” refers to a set of properties of a material that allow for contact with flowing blood without causing adverse reactions such as thrombosis, hemolysis, complement activation, bleeding, or inflammation.

[0043] The term “mechanically stable” refers to the ability of a material to maintain its integrity over time when subjected to one or more external stresses.

[0044] The terms “conformal,” or “conformally coated,” as used herein typically refer to covering a surface topography of an object with a material such that it is completely or effectively covered up to at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% of the surface area which is intended to be covered by the material without exposure of the underlying material of the object where covered. The conformal coating is considered to be in direct contact, in intimate contiguity, and matches the geometry and contour to the surface the coating is applied to, so as to act as a cover, barrier, or shield or otherwise form a barrier layer preventing exposure of the underlying surface to exogenous contact by at least about 50 to 100%, as compared with no conformal coating.

[0045] The term "subject" refers to either a human or non-human animal.

[0046] The term “treating” refers to inhibiting, ameliorating, impeding, alleviating, or relieving a disease, disorder, or condition from occurring in a subject or causing regression of the disease, disorder, and / or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0047] The term “venous,” refers to the vasculature or vascular region originating from the postcapillary space throughout the venous system including, but not limited to, venules, veins, vena cava, pulmonary vein, coronary sinus, and the right heart and its valves.

[0048] The term “venous environment,” refers to space where blood flows within the vasculature originating from the post-capillary space throughout the venous system including, but not limited to, venules, veins, vena cava, pulmonary vein, coronary sinus, and the right heart and its valves.

[0049] Numerical ranges disclosed in the present application include, but are not limited to, ranges of temperatures, ranges of pressures, ranges of integers, ranges of times, and ranges of thicknesses, etc. The disclosed ranges of any type, disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein. For example, disclosure of a thickness range is intended to disclose individually every possible thickness value that such a range could encompass, consistent with the disclosure herein.

[0050] Use of the term “about” is intended to describe values either above or below the stated value, which the term “about” modifies, in a range of approx. + / - 10%; in other instances the values may range in value either above or below the stated value in a range of approx. + / - 5%. When the term “about” is used before a range of numbers (i.e., about 1-5) or before a series of numbers (i.e., about 1, 2, 3, 4, etc.) it is intended to modify both ends of the range of numbers or each of the numbers in the series, unless specified otherwise.

[0051] IL Polymeric Venous Valve Systems

[0052] Valve systems specifically designed for use and implantation in low flow, low shear, venous cardiovascular structures are primarily designed to function as valves or flow regulators. The valves are fabricated from a combination of metallic and polymeric materials, where the polymer has been specifically engineered and formed to reduce stress on the implant structure, as well as to reduce and minimize stress imparted on overflowing fluid, such as blood to reduce stresses on the valve’s leaflets and enhance the valve durability, to improve the blood flow and keep it unidirectional, such as to prevent backflow (regurgitation through the closed valve), and reduce thrombogenicity. The polymeric material forming the leaflets has further been selected and designed to be maximally compatible with a venous environment to impart thrombo- resistance. The polymeric materials are chosen and fabricated to reduce the negative contributions of Virchow's triad, i.e. inflammatory drive, poor flow, and rheological properties and underlying tissue disruption.

[0053] A non-limiting example of such a polymeric venous valve system is shown in Figure 1A, where a polymeric venous valve system 100 includes a supportive frame 110 embedded in a polymeric matrix forming polymeric sleeve 120, a plurality of polymeric leaflets 130 each being a continuum of the polymeric sleeve without sutures where each of the polymeric leaflets is connected to the polymeric sleeve at an attachment end, an anti-leak flap 135, a plurality of crown supporting struts 140, a plurality of axial leaflet locking struts 150, and a plurality of optional anchors 160. Moreover, as shown in Figure IB, the polymeric venous valve system 100 having three levels: a crown level 170, a calcific leaflet level 180, and an optional outflow track (OT) level 190. The crown supporting struts and axial leaflet locking struts are preferably not embedded in the polymeric matrix forming the polymeric sleeve. Further, the plurality of leaflets are able to open and close at an operative end, wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

[0054] In one non-limiting instance, a polymeric venous valve system includes: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame includes a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve; wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa (including sub-ranges or individual values of the aforementioned pressure and shear ranges); wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

[0055] Typically, the polymeric venous valve system also includes at least one feature selected from the following list:

[0056] (a) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;

[0057] (b) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic polymers therein and / or coated thereon, wherein the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment;

[0058] (c) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more surfactant safe lipids therein and / or coated thereon;

[0059] (d) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more pharmaceutically acceptable surfactants therein and / or coated thereon;

[0060] (e) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more fluorocarbon polymers and / or perlluoroalkyl substances (PFAS) therein and / or coated thereon;

[0061] (f) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more carbon-based structures therein and / or coated thereon;

[0062] (g) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more buffering agents therein and / or coated thereon;

[0063] (h) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more anticoagulant agents therein and / or coated thereon;

[0064] (i) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more inhibitor agents coated thereon; j) the plurality of polymeric leaflets, and optionally the polymeric matrix, have an elastic modulus in a range of between about 1 -20 MPa;

[0065] (k) the plurality of polymeric leaflets, and optionally the polymeric matrix, have a Young’s modulus in a range of between about 1-20 MPa;

[0066] (l) the plurality of polymeric leaflets, and optionally the polymeric matrix, are free of crystallinity or are substantially free of crystallinity;

[0067] (m) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of polymer(s) having a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons;

[0068] (n) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of uncrosslinked polymer(s) or the plurality of polymeric leaflets and / or the polymeric matrix are formed of crosslinked polymer(s) having a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;

[0069] (o) the plurality of polymeric leaflets each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar; and

[0070] (p) the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size. “Substantially free of surface asperities,” refers to surfaces that are at least 95%, 96%, 97%, 98%, 99%, or greater free of any asperities greater than about 1, 2, 3, 4, or 5 nm in size.

[0071] Any combination or sub-combination of the above-listed features, (a)- (p), may be present in a valve system, including having a combination of all the aforementioned features.

[0072] As described in detail further below, the polymeric venous valve system can be formed by placing a supportive frame in a mold and a suitable polymer can be used to form or cast to the plurality of leaflets of a given design and polymeric sleeve which around or embed a supportive frame which can be, for example, an expandable stent.

[0073] Current tissue valve manufacturing techniques involve manual suturing of the biologic valve tissue onto a stent which causes the possibility of damage to the tissue and where the suturing holes generate stress concentrations that adversely affect the structural integrity and durability of the valve and may also generate loci for thrombus formation. Without wishing to be bound by any particular theory, a suture-less over molding approach to create the leaflets and polymeric sleeve of the venous valve systems described, as part of a single manufacturing step, reduces the risk of calcifications and thrombus formation, biofouling, and infection potential at focal points that may occur in venous valve systems that contain sutures. Moreover, continuous wrapping of the polymeric sleeve around the supportive frame and the adhesion of the polymer to the supportive frame allows even distribution of the leaflet forces and stresses during operation. Polymeric components of the system can address or overcome known clinical complications of persistent thrombosis events, such as hypo-attenuated leaflet thickening (HALT) and stroke. Polymeric materials also offer reduced platelet response and adhesion with smoother, less-fibrous surfaces and hemocompatible surface chemistries.

[0074] Additionally, the design of the polymeric venous valve systems described herein achieves variable radial force over the length of the system with higher force aiding in anchoring against the venous annulus and leaflets.

[0075] In some instances, the polymeric venous valve system is a transcatheter tricuspid valve replacement device, which is designed to replace a tricuspid valve in a subject, and includes: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame comprises a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve; wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

[0076] The transcatheter tricuspid valve replacement device may include any of the aforementioned features (a)-(p) of the polymeric venous valve systems described herein.

[0077] In some instances, the supportive frame of the transcatheter tricuspid valve replacement device is a nitinol stent which has a distal end and a proximal end adapted for deployment within a tricuspid valve annulus. In some instances, the plurality of polymeric leaflets each have a variable thickness in the leaflets (variable thickness in polymeric leaflets is detailed below). Variable thickness of the polymeric leaflets can minimize flexural stresses of the polymeric leaflets during their opening and closing providing enhanced durability. Variable thickness of the polymeric leaflets can also improved hemodynamic performance resulting in increased blood flow and reduced regurgitation, as compared to hemodynamic performance of a native (defective) tricuspid valve which is replaced with a transcatheter tricuspid valve replacement device. The transcatheter tricuspid valve replacement device can be used to restore or improve the Coanda flow effect, which helps prevent the polymeric leaflets from prolapsing into the atrium of the tricuspid valve.

[0078] A. Components of Polymeric Venous Valve System

[0079] The various components of the polymeric venous valve system are described in detail below.

[0080] 1. Supportive Frame

[0081] In some instances, the supportive frame is formed of an armature or scaffold-like construct including a plurality of openings and formed from a plurality of connected struts or wire-like elements, wherein each strut or wire-like element is connected to one or more other struts or wire- like elements via a joint. In some other instances, the armature or scaffold-like construct may be in the form of a cage having tubular or wire-like elements configured in a stent-like configuration. In some instances, the armature or scaffold-like construct is formed having a compressed circumferential / axial profile or can otherwise be formed and subsequently crimped, compacted, or collapsed from its size, as formed, into a smaller circumferential / axial profile suitable for implantation, such as through a delivery catheter. The armature or scaffoldlike construct is expandable from its crimped, compacted, or collapsed back up to its size, as formed, or any desired size in between. Preferably, the armature or scaffold-like construct is an expandable stent which is self-expandable or otherwise requires active expansion by balloon expansion or heat expansion. Expandable stents are plastically deformed with mechanical energy, such as by balloon expansion, into an “opened” or deployed shape. Self-expandable stents can be thermally fixed or shape-set after expansion. Such expandable stents and materials for making such stents are known in the art.

[0082] In some instances, the total diameter of the supportive frame embedded in the polymeric sleeve, when crimped, compacted, or collapsed is about 4, 5, 6, or 7 mm and can be delivered through an artery, such as the femoral artery. The polymeric sleeve embedded supportive frame once crimped, compacted, or collapsed can be expanded or returned back to its original size or to a total diameter size ranging from about 15 to 30 mm, 20 to 30 mm, 25 to 30 mm, or to a total diameter size of about 25, 26, 27, 28, 29, or 30 mm in (re)expanded form. In some instances, it is better to avoid crimping of the as-formed polymeric venous valve system until it is time to load it into a delivery catheter, such that the first crimping, compacting, or collapsing of the polymeric venous valve system is during loading into a catheter, or placement or affixing onto a delivery deployment device.

[0083] In some cases, once the polymeric venous valve system is inserted / deployed into a body valve and fully expanded so there is oversizing, which refers to how much the expanded supportive frame of the polymeric venous valve system is constricted by the surrounding anatomy (i.e., diameter of valve orifice). Oversizing can be used to produce a radial force in order to keep the polymeric venous valve system in a desired position in situ, such as by frictional fit or similar mechanical locking in place. Such constriction is usually proportional to how much radial force the expanded supportive frame of the polymeric venous valve system can exert on the anatomy to keep the system in place and avoid migration of the polymeric venous valve system. For the supportive frame, oversizing of about 0 to 40%, about 0 to 30%, about 0 to 20%, about 0 to 15%, about 0 to 10%, or about 0 to 5% and sub-ranges within are acceptable. In some instances, oversizing can be dependent on the radial force that the supportive frame of the system can exert. For example, oversizing of the supportive frame in a relaxed state is considered to be 0%. Oversizing of the supportive frame in the mold can range from about 0 to 8%. Finally, oversizing of the supportive frame, as part of the system, when used in vivo can range from about 5 to 50%, about 5 to 40%, about 5 to 30%, about 5 to 20%, about 5to 10%, or about 10 to 15%, as well as sub-ranges within. The extent of oversizing can also depend on the anatomical location of implantation of the polymeric venous valve system.

[0084] In some instances, the supportive frame is made of a metal or metal alloy which is known to be suitable for medical implantation. Without limitation, the supportive frame can be formed of self-expanding memory metal alloys, such as NiTiCo, NiTiCr, NiTiCu, NiTiNb, or NiTi (Nitinol) or other known expandable metal / metal alloys, such as spring steels, stainless steel, platinum, tantalum alloys, or cobalt chromium. If actively expandable, the supportive frame can be made of biocompatible metals of particular types, including stainless steel (316L, 304L), cobalt-chromium alloys (L605), nickel-titanium alloy (Nitinol), platinum, and tantalum alloys. In some instances, the struts or wire-like elements forming the supportive frame can have any suitable dimensions (i.e., length, thickness, radial diameter, etc.). In some cases, the struts or wire-like elements have a tubular shape with a uniform radial tube diameter and the radial thickness ranges from between about 0.2 to 0.6 mm. In some instances, the radial thickness is about 0.3 mm. In some other cases, the struts or wire-like elements are not tubular but have a uniform thickness throughout the struts or wire-like elements and the thickness ranges from between about 0.2 to 0.6 mm. In some other instances, the strut or wire-like elements are curvilinear and can have a variable circumferential thickness along the length of the strut or wire-like element where the thickness of the strut or wire-like element has a 150-250 m circumferential size and a 250-350 pm radial size, and any sub-ranges or individual values disclosed therein.

[0085] In some instances, the struts or wire-like elements of the supportive frame, regardless of shape, are (electro)polished which reduces their thickness prior to the supportive frame being embedded in the polymeric sleeve. Further, (electro)polishing can be performed to remove sharp features that would add stress concentrations, to aid in reducing crimping, compacting, or collapsing strain and resisting plastic deformation during crimping, compacting, or collapsing, as well as increasing the fatigue life / resistance of the formed supportive frame. Additionally, polishing can prepare blood contacting surfaces for better hemocompatibility or provides a more favorable surface morphology to resist thrombus development. In some instances, prior to or following (electro)polishing, the supportive frame may be subjected to sand blasting or chemical etching or other surface modifying method to generate texture and asperities, to the frame surface which can aid in adhesion of the polymer matrix during coating and formation of the polymeric sleeve on the frame; and / or aid in enhancing the durability of adhesion to the frame over use life. In some cases, the supportive frame can be masked before chemical etching or sand blasting to ensure only (electro)polished surface(s) are exposed to blood flow.

[0086] The supportive frame may be formed by any suitable method known in the art. Methods of fabrication can include, but are not limited to, laser cutting or etching, laser forming, wire braiding or bending, metal etching, metal vapor deposition, 3-D metal printing, precision machining / CNC, chemical etching, spray coating, sputter coating, powder coating, additive manufacturing, and other art known techniques used to form a stent-like armature or scaffoldlike construct suitable for implantation in a subject. As an example, in some instances, a stock material maybe extruded into a cylinder or generated by art known vapor deposition methods for controlled alloy / composite structuring. The cylinder can be, for example, cut with a laser or lathe into a desired shape having a compressed 2D circumferential / axial profile. The compressed profile and stock tube size dictates the minimum compressed size of the supportive frame. In such non-limiting instances, the initial supportive frame can be shape set with expanding or step- wise increasing with a mandrel or jig. The shape setting process can include a single or multiple steps to avoid damaging the structural integrity of the supportive frame. In one non-limiting instance, the supportive frame is made by laser cutting from nitinol tubes and then performing thermal shape-setting that includes expansion of the supportive frame using dedicated jig(s) and temporal exposure to elevated temperature (e.g., about

[0087] 450 °C to 550 °C, or, in some instances, about 520 °C). In forming such supportive frames, shape-setting can be performed in single step or in multiple steps (where in each step the supportive frame is incrementally expanded to the desired size) and full or partial electropolishing may optionally be performed during these shape-setting steps. Sandblasting and / or electropolishing may be performed after all shape-setting steps are completed. Other methods of making implantable stents are described in U.S. Patent 8,715,335; 10,729,824; 10,806614; 10,874,532; 11,045,297; 11,058,564. In less preferred instances, the supportive frame may be formed of polymer(s), such bio-degradable polymers known in the art.

[0088] In some instances, at least some or all of the surfaces of components (i.e., struts) forming the supportive frame include surface texture features, such as micro and / or macro asperities, which impart surface roughness thereon. The surfaces may have morphologies ranging from fully smooth and featureless (e.g. on once face - i.e. adluminal) to others having micro and / or macro asperities (e.g. abluminal face). However, such surface morphologies having asperities are found only on one or more surfaces that are not exposed, for example, to blood flow in order to prevent risk of thrombus formation. Such surface roughness may be imparted by various methods including, but not limited to, plasma etching or chemically etching the supportive frame prior to embedding the frame in a polymeric matrix. Methods and conditions for plasma and chemical etching are known to those skilled in the art. In some other instances, the surfaces of components (i.e., struts) forming the supportive frame can have a suitable primer coating that can chemically bind polymer(s) applied thereto. In one non-limiting example, one or more primer coatings may include a first coat of identical or similar polymer as in the final polymeric sleeve, or other polymers providing adhesive properties, increased durability properties, or additional functionalities, such as providing device radiographic opacity. In some instances, a primer coating may be made of or include silicone polymers.

[0089] The supportive frame and struts or wire-like elements can be designed to selectively produce a radial force within a portion or segment of the polymeric venous valve system (such as at the calcific leaflet level; see Figure IB) or a lowest or minimal crimping, compacting, or collapsing strain, while maintaining the lowest surface area or volume, when embedded in the polymeric sleeve.

[0090] As noted above, in some instances, the supportive frame and the strut or wire-like elements from which it is formed are curvilinear where the curved shape allows for bending motion during crimping, compacting, or collapsing occur over the length of the strut or wire-like element and is not constrained to a joint region between the strut or wire-like elements. Without wishing to be bound by any particular theory the larger bending curvature can allow more polymeric matrix material to be cast during molding to embed the joint regions without risking increased shearing stresses against the polymeric matrix material that may lead to damage during crimping, compacting, or collapsing of the supportive frame. a. Optional Supportive Frame Components

[0091] The supportive frame may include optional components including one or more anchors, one or more indentations, and / or one or more openings, and these are preferably not covered / coated by any polymer or polymeric matrix. See Figure 1 A for exemplary non-limiting examples of anchors (160) and Figures 3 A and 3B for exemplary non-limiting examples of indentations which may form part of the strut or wire-like elements of the supportive frame.

[0092] In some instances, one or more anchors which may form part of the strut or wire-like elements of the supportive frame are located on extreme ends of struts the supportive frame. For example, anchors may be placed on the crown supporting struts (140) or wire-like elements of the crown level and / or supporting frame at the OT level of the frame. The anchors form part of the supportive frame and can be formed during the manufacture of the frame.

[0093] The anchors may have any suitable size and shape. In some instances, the anchors form square, rectangular, circular, or oval ring shapes. The anchors, in some instances, are designed to interface the supportive frame into a mold and hold it and constrain the supportive frame during the molding process to embed it in the polymeric sleeve. The anchors, in some other instances, can serve as imaging marks during deployment of the polymeric venous valve system when the anchors are marked with a radiopaque material or metal. Exemplary imaging marker materials can include, but are not limited to, gold, tantalum, or platinum-iridium. It is possible to mechanically connect a piece of the imaging marker material to specific regions in the supportive frame, which can be designed specifically for that purpose (e.g. leaving a void for placing the marker). In such instances, when used as imaging marks, the anchors designate the top and bottom of the polymeric venous valve system and can be used to find the location of leaflets.

[0094] In some instances, one or more indentations and / or one or more openings may form part of the strut or wire-like elements of the supportive frame, as shown in Figures 3 A and 3B. The indentations can be used for mechanically locking the polymeric sleeve to the supportive frame. Such indentation or openings can be spread along the supportive frame so as to minimize separation and sliding of the polymer on the struts or wire-like elements of the supportive frame during crimping / compacting / collapsing of the embedded supportive frame, as well as during deployment (i.e., implantation in a subject) and expanding the supportive frame of the system to localize / implant it in a valve. The indentations or openings can be placed in the middle of the struts or wire- like elements of the supportive frame, a region where deformation of the strut is believed to be relatively small, such that the indentation would not impair the mechanical stability of the stent. The indentations or openings can be formed during or following the manufacture of the supportive frame and prior to embedding the frame in the polymeric sleeve. In some instances, the indentations can have a depth of about 10 to 100 pm or a depth of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 pm, in relation to a non-indented portion of the struts or wire-like elements.

[0095] 2. Polymeric Sleeve

[0096] As described above, the supportive frame is embedded in a polymeric matrix that forms a polymeric sleeve which enmeshes and encases all or at least a large portion (i.e., greater than 90% of the surface) of the supportive frame at least at the calcific leaflet and OT levels. See Figure IB. In some instances, portions of the supportive frame, such as the axial leaflet locking struts (150) at the calcific leaflet level (180), are not embedded or otherwise coated with any polymeric matrix or sleeve.

[0097] In some instances, the thickness of the embedding polymeric matrix forming the polymeric sleeve can have any suitable thickness thereon. The thickness of the extraluminal polymeric matrix material covering the supportive frame can, for example, when formed by compression molding or other molding techniques have a thickness in a range from about 0 to 500 microns in the circumferential direction and / or a thickness ranging from about 0 to 400 microns in the radial direction of the struts or wire-like elements of the supportive frame. In some instances, an average thickness of about 400 microns in the circumferential direction (i.e. about 200 microns are on each side of the strut) is present. A thickness value of zero, as noted above, can occur in certain cases where the supportive frame is in contact with a mold surface during the embedding of the frame in the polymeric supportive sleeve and some regions of exposed supportive frame could have no or about zero thickness of polymeric matrix thereon. In other instances, where the supportive frame is embedded in a polymeric matrix material by, for example, dip coating the frame into polymer solution, the encapsulation thickness of the struts or wire-like elements of the supportive frame is expected to be smaller with a thickness ranging from about 0 to 200 microns in the circumferential and / or radial directions.

[0098] The polymeric sleeve can be formed of any suitable biocompatible, hemocompatible, and mechanically-stable polymer. In preferred instances, the polymeric material will have elastomeric properties allowing for expansion and reconfiguration following deployment, once situated in its deployment location. The polymeric sleeve should not separate from the supportive frame in use and over time. Such suitable polymers are art known for use in medical implants, and blends of such polymers are also contemplated. In some instances, the polymers used to form the polymeric sleeve are materials which can also offer reduced platelet response and adhesion with smoother, less-fibrous surfaces and hemocompatible surface chemistries.

[0099] In some instances, the surface(s) on the outer face of the polymeric sleeve can be made rougher than the surface of the inner surface of the polymeric sleeve (valve lumen) in order to allow for better adhesion and integration of the outer, i.e. ectoluminal surface, to the native tissue in which the valve system is being implanted on.

[0100] Without particular limitation, exemplary polymers which can be used to form the polymeric sleeve during molding include thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), polyurethanes, silicones, PTFE, crosslinked poly(styrene- isobutylenese-styrene) (xSIBS), and poly(styrene-isobutylene-styrene) (SIBS). Thermoplastic elastomers (TPEs) can be formed of or contain polymyrcene, polymenthide, and poly(e- decalactone). Elastomeric biomaterials can include, for example, silicones, thermoplastic elastomers, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes. As appropriate, the skilled person would be able to select conditions (i.e., temperatures, solvent(s), etc.) needed to form polymer melts or form polymer solutions of the aforementioned to be able to embed the supportive frame during molding, as detailed further below. The polymers named herein can have any suitable weight average molecular weight that allows for a low level of stiffness for use in a low pressure and low shear venous environment. In some instances, the weight average molecular weight is in a range of between about 10,000 to about 50,000 Daltons, as well as sub-ranges or individual values contained within the aforementioned range.

[0101] In some instances, the polymeric matrix forming the polymeric sleeve is formed of at least one of the polymers named above, which includes one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment. The one or more hydrophilic groups are typically functionalized on the one or more surfaces of the polymeric matrix and at least partially exposed on the one or more surfaces. In some instances, the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. In some instances, the polymeric matrix is formed of at least one polymer which was modified to include such hydrophilic groups. Methods of modifying polymers to add hydrophilic functional groups are known in the art. These can exclude, without limitation, exposure to a plasma with one or more gases selected, for example, from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof. The person of ordinary skill is familiar with other conditions and gases which can be used to functionalize polymers with hydrophilic functional groups.

[0102] In still other instances, the polymeric matrix forming the polymeric sleeve is formed of at least one of the polymers named above, which is mixed, admixed, or blended with one or more suitable hydrophilic polymers known to the person of ordinary skill in the art which are suitable for pharmaceutical use in the body and where the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment. In some instances, the one or more hydrophilic polymers include hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. In some instances, the one or more hydrophilic polymers are bloomed on the one or more surfaces of the polymeric matrix. “Blooming” or “bloomed,” as used herein, refers to the effect of creating mixtures / admixtures with hydrophilic polymer(s) that when blended (for example via solvent mixing, physical blending, slurry dispersion, or other means) the hydrophilic polymers contained within the mixture become at least partially exposed on the surface(s) when the mixture is cast. The hydrophilic polymers migrate to create a hydrophilic surface, typically with hydrophobic layer underneath. For example, bulk SIBS can be blended with PEO, PVA, or PVP and then blend, either from a solvent or from bulk, can be cast and the hydrophilic polymer(s) will bloom to the surface.

[0103] Typically, the inclusion of hydrophilic groups and / or hydrophilic polymers in the polymeric matrix reduce surface free energy of the matrix which can limit denaturation of proteins, such as thrombotic proteins, and their rates of deposition onto the polymeric matrix (such as the polymeric sleeve). In some instances, the protein deposition rate is reduced by at least about 1 to 99%, as well as sub-ranges or individual values contained within, relative to the rate of deposition of a selected protein in the absence of such hydrophilic groups and / or hydrophilic polymers. The reduction of surface free energy can increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric matrix.

[0104] In some instances, the inclusion of hydrophilic groups and / or hydrophilic polymers can alter surface charge of the polymeric matrix to render it neutral or electrically repulsive to one or more thrombotic proteins present in a venous environment. Such thrombotic proteins can include, without limitation, fibrinogen, phosphorylcholine, and combination thereof. The person of ordinary skill is familiar with the surface charges of known thrombotic proteins and can select suitable hydrophilic groups and / or hydrophilic polymers to render the polymeric matrix electrically repulsive to the one or more thrombotic proteins present in a venous environment. In some instances, thrombotic proteins may have negative or positive charges, or be zwitterionic.

[0105] In some instances, the polymeric matrix can include one or more surfactant safe lipids therein, where the surfactant safe lipids can be selected, without limitation, from glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0106] In some instances, the polymeric matrix can include one or more pharmaceutically acceptable surfactants therein, where the one or more pharmaceutically acceptable surfactants are selected from, without limitation, polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-114), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof. Other pharmaceutical surfactants, including nonionic, anionic, cationic, and amphoteric are known in the art and may be suitable.

[0107] In some instances, the polymeric matrix can include one or more fluorocarbon polymers and / or perfluoroalkyl substances (PF AS) therein, where the one or more fluorocarbon polymers are selected from, without limitation, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PF A), pluorinated ethylene propylene (FEP), poly vinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and the one or more perfluoroalkyl substances (PFAS) are selected from, without limitation, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof. In some instances, the one or more fluorocarbon polymers and the one or more perfluoroalkyl substances are present at concentrations, of less than about 100 micromolar (pM) or less than about 10 wt.%, of the polymeric matrix.

[0108] In some instances, the polymeric matrix can include one or more carbon-based structures therein, where the one or more carbon-based structures are selected from, without limitation, carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0109] In some instances, the polymeric matrix can include one or more buffering agents therein, where the one or more buffering agents are selected from, without limitation, acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof. In some instances, the polymeric matrix can include one or more anticoagulant agents therein, where the one or more anticoagulant agents are selected from, without limitation, heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0110] In some instances, the polymeric matrix can include one or more inhibitor agents therein, where the one or more inhibitor agents are selected from, without limitation, CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0111] In some instances, the inclusion of agents, such as those named above, can reduce surface free energy to increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric matrix.

[0112] In some instances, the polymer material which forms the polymeric sleeve may include one or more fiber reinforcement materials. Such fiber reinforcement materials can be formed of or contain, but are not limited to, poly-alkanes, polyethylene, polytetrafluoroethylene, polyamide, polypropylene, polyethyleneterephthalate, polydimethylsiloxane, polyhydroxy alkanoates, polymethylmethacrylate, silicone, parylene, polydimethylsiloxane, SU- 8, liquid crystal polymers, polyurethane, polyetherketones, biodegradable polymers. Exemplary biodegradable polymers can include, without limitation, polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), and copolymers or blends thereof.

[0113] In some instances, the polymeric sleeve may include or be marked with one or more radiopaque materials. Exemplary radiopaque materials which can be added to the above polymers forming the sleeve can include, but are not limited to, stainless steel, gold, tantalum, or platinum-iridium, barium, iodine, and alloys, blends, and mixtures thereof.

[0114] In some instances, the polymeric matrix has an elastic modulus in a range of between about 1-20 MPa, or a sub-range of individual value contained within the range. In some instances, the polymeric matrix has a Young’s modulus in a range of between about 1-20 MPa, or a sub-range of individual value contained within the range. The polymeric matrix, and polymeric sleeve formed thereof, may be selected to have low stiffness based on its use in lower pressure venous environment, as opposed a higher stiffness needed to operate in a higher pressure arterial environment. In some instances, the polymer(s) forming the polymeric matrix may he chosen to he free of any crystallinity (i.e., crystalline phases or regions within) or substantially free of crystallinity, where “substantially free of crystallinity” refers to there being less than 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% crystalline phases or regions within the polymer forming the polymeric matrix. The person of ordinary skill in the art is familiar with techniques for quantifying crystallinity in polymers.

[0115] In some instances, the polymeric matrix can be formed of uncrosslinked polymer(s), such as those named herein. In some other instances, the polymeric matrix is formed of crosslinked polymer(s) having a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%. The person of ordinary skill in the art is familiar with techniques for crosslinking polymer(s) and controlling the extent of crosslinking.

[0116] In some instances, the surfaces of the polymeric matrix are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the polymeric matrix contain asperities which are no greater (on average) than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size. “Substantially free of surface asperities,” refers to surfaces that are at least 95%, 96%, 97%, 98%, 99%, or greater free of any asperities greater than about 1, 2, 3, 4, or 5 nm in size. In a low shear venous environment with greater pooling and time for deposition, low surface roughness (high smoothness) is desirable. The person of ordinary skill in the art is familiar with methods for measuring surface smoothness and the average size of asperities contained on a given total surface area, or portion thereof. Such methods can include (optical) profilometry and electron microscopy methods (AFM, SEM). a. Optional Coatings on the Polymeric Sleeve

[0117] In some instances, the outer surface of the polymeric sleeve may be at least partially or completely covered with a conformal gel, i.e. what has been termed ectoluminal gel paving, which can seal gaps that may form around the outer sleeve of the polymeric venous valve system, post deployment into a valve, and can serve to minimize the risk of paravalvular leak (PVL).

[0118] In some instances, the outer surface of the polymeric sleeve is enveloped with a desiccated hydrogel coating. Post-deployment into a defective valve in a subject, the desiccated gel is subject to rehydration in situ which will result in gradual swelling of the gel which will form a thicker, outer facing, gel layer, which is free to swell filling any irregular gaps between the polymeric venous valve system and valve wall. Endoluminal gel swelling may be limited by: constraint of the gel by the supportive frame, the underlying polymeric sleeve and the minimal swollen thickness of the desiccated hydrogel layer. However, it is believed that sealing and regional efficacy of leak resistance will be increased following by using such conformal gel paving on the polymeric sleeve of the system.

[0119] Exemplary gel paving materials can include, but are not limited to, polymeric hydrogels derived from diacrylate poly(ethylene) glycol (PEG) macromers, which can serve as hemocompatible hydrogel networks, along with macromers incorporating oligocarbonate units. Incorporation of oligocarbonate flanks on PEG before acrylation are able to extend gel durability. In some other instances, non-degradable hydrogel alternatives can be employed, which do not contain degradable units in the copolymer.

[0120] Gel paving hydrogels can be desiccated, with gels shrinking to an extremely low profile (being 90% water) to allow crimping and compaction for valve system deployment. Once deployed, with unsheathing, the hydrogels will gradually re-swell (typically in about 2 to 10 min, with up to a 2 to 9-fold increase in volume), regenerating the hydrogel network to efficiently fill-in irregular-shaped gaps and seal the polymeric heat valve system to the surrounding valve preventing leakage.

[0121] In some cases, a hydrogel paving material is placed on the outer surface of the polymeric sleeve by first enveloping a mesh with the material that will be integral to the polymeric sleeve. This enmeshment facilitates durable bonding, adhesion and resistance to peel, despite crimping and re-expansion of the valve system during deployment.

[0122] In some instances, dessicated hydrogel is applied on the outer surface of the polymeric sleeve to form polymeric sleeve having a thickness in a range from between about 0.5 to 5 mm. The gel paving material will swell to fill gaps in the polymeric matrix forming the polymeric sleeve, which may have varying sizes and shapes.

[0123] In still other instances, the polymeric matrix forming the polymeric sleeve is coated with one or more suitable hydrophilic polymers known to the person of ordinary skill in the art which are suitable for pharmaceutical use in the body and where the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment. In some instances, the one or more hydrophilic polymers include hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. Typically, the inclusion of hydrophilic polymers coated onto the polymeric matrix reduces surface free energy of the matrix which can limit denaturation of proteins, such as thrombotic proteins, and their rates of deposition onto the polymeric matrix (such as the polymeric sleeve). In some instances, the protein deposition rate is reduced by at least about 1 to 99%, as well as sub-ranges or individual values contained within, such as by at least about 1 to 50%, at least about 5 to 50%, at least about 5 to 60%, at least about 10 to 50%, at least about 20 to 50%, at least about 30 to 50%, at least about 40 to 50%, at least about 10 to 60%, at least about 20 to 60%, at least about 1 to 50%relative to the rate of deposition of a selected protein in the absence of such hydrophilic groups and / or hydrophilic polymers. The reduction of surface free energy can increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric matrix.

[0124] In some instances, the inclusion of hydrophilic groups and / or hydrophilic polymer coatings can alter surface charge of the polymeric matrix to render it neutral or electrically repulsive to one or more thrombotic proteins present in a venous environment. Such thrombotic proteins can include, without limitation, fibrinogen, phosphorylcholine, and combination thereof. The person of ordinary skill is familiar with the surface charges of known thrombotic proteins and can select suitable hydrophilic groups and / or hydrophilic polymers to render the polymeric matrix electrically repulsive to the one or more thrombotic proteins present in a venous environment. In some instances, thrombotic proteins may have negative or positive charges, or be zwitterionic.

[0125] In some instances, the polymeric matrix can include one or more surfactant safe lipids coated thereon, where the surfactant safe lipids can be selected, without limitation, from glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0126] In some instances, the polymeric matrix can include one or more pharmaceutically acceptable surfactants coated thereon, where the one or more pharmaceutically acceptable surfactants are selected from, without limitation, polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof. Other pharmaceutical surfactants, including nonionic, anionic, cationic, and amphoteric are known in the art and may be suitable.

[0127] In some instances, the polymeric matrix can include one or more fluorocarbon polymers and / or perfluoroalkyl substances (PF AS) coated thereon, where the one or more fluorocarbon polymers are selected from, without limitation, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), pluorinated ethylene propylene (FEP), poly vinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and the one or more perfluoroalkyl substances (PFAS) are selected from, without limitation, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

[0128] In some instances, the polymeric matrix can include one or more carbon-based structures coated thereon, where the one or more carbon-based structures are selected from, without limitation, carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0129] In some instances, the polymeric matrix can include one or more buffering agents coated thereon, where the one or more buffering agents are selected from, without limitation, acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

[0130] In some instances, the polymeric matrix can include one or more anticoagulant agents coated thereon, where the one or more anticoagulant agents are selected from, without limitation, heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0131] In some instances, the polymeric matrix can include one or more inhibitor agents coated thereon, where the one or more inhibitor agents are selected from, without limitation, CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0132] In some instances, the inclusion of agents, such as those named above, can reduce surface free energy to increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric matrix.

[0133] 3. Polymeric Leaflets

[0134] The valve mechanism of the polymeric venous valve system includes a plurality of individual polymeric leaflets, where the polymeric leaflets form a continuum with the polymeric sleeve. See Figure 1 A. In other words, the polymeric leaflets are connected directly to the polymeric sleeve and are not separately attached to the sleeve, such as by suturing or other attachment means, where the leaflets and the sleeve are continuous and do not ever form discrete components from one another.

[0135] The suture-less feature of the polymeric leaflets of the system can be achieved, for example, by forming the polymeric leaflets and polymeric sleeve (onto the supportive frame) at the same time during the molding process (i.e., single manufacturing step) whereby they form a single polymeric component containing both the polymeric leaflets and polymeric sleeve. In less preferred instances, polymeric leaflets may be formed / molded as a first component and then the leaflets and a supportive frame are dip coated into a suitable polymer melt or solution to form the polymeric sleeve. During such instances, the polymer melt or solution forms the polymeric sleeve over the supportive frame and simultaneously attaches to the polymeric leaflets in the mold. Thus, the leaflets become a continuous inseparable part of the formed polymeric sleeve with smooth transitions forming a “continuum.”

[0136] The plurality of polymeric leaflets which can be formed by molding can be made of the same or a different polymer from which the polymeric sleeve is formed. In most instances, the polymeric leaflets and polymeric sleeve are formed of the same polymer / polymeric matrix. Exemplary polymers which can be used to form the polymeric leaflets include, but are not limited to, thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), polyurethanes, silicones, PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), and poly(styrene- isobutylene-styrene) (SIBS). Thermoplastic elastomers (TPEs) can be formed of or contain polymyrcene, polymenthide, and poly(s-decalactone). Elastomeric biomaterials can include, for example, silicones, thermoplastic elastomers, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes. As appropriate, the skilled person would be able to select conditions (i.e., temperatures, solvent(s), etc.) needed to form polymer melts or form polymer solutions of the aforementioned to be able to form the plurality of leaflets during molding, as detailed further below. The polymers named herein can have any suitable weight average molecular weight that allows for a low level of stiffness for use in a low pressure and low shear venous environment. In some instances, the weight average molecular weight is in a range of between about 10,000 to about 50,000 Daltons, as well as sub-ranges or individual values contained within the aforementioned range. In some instances, thermoplastic polymers can be chosen when instances of dip coating are used to form the systems described and thermoset polymers can be chosen when instances of molding are used to form the systems described. In still other instances, a combination of both dip coating of the polymeric sleeve and to attach them to previously molded polymeric leaflets can be used.

[0137] In some instances, the plurality of polymeric leaflets are formed from at least one of the polymers named above, which includes one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment. The one or more hydrophilic groups are typically functionalized on the one or more surfaces of the polymeric leaflets and at least partially exposed on the one or more surfaces. In some instances, the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. In some instances, the plurality of polymeric leaflets are formed of at least one polymer which was modified to include such hydrophilic groups. Methods of modifying polymers to add hydrophilic functional groups are known in the art. These can exclude, without limitation, exposure to a plasma with one or more gases selected, for example, from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof. The person of ordinary skill is familiar with other conditions and gases which can be used to functionalize polymers with hydrophilic functional groups.

[0138] In still other instances, the plurality of polymeric leaflets are formed of at least one of the polymers named above, which is mixed, admixed, or blended with one or more suitable hydrophilic polymers known to the person of ordinary skill in the art which are suitable for pharmaceutical use in the body and where the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment. Tn some instances, the one or more hydrophilic polymers include hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3), sulfonates (RSO ), carboxylates (RCOO ), phosphates (RPO4), and combinations thereof. In some instances, the one or more hydrophilic polymers are bloomed on the one or more surfaces of the polymeric leaflets. “Blooming” or “bloomed,” as used herein, refers to the effect of creating mixtures / admixtures with hydrophilic polymer(s) that when blended (for example via solvent mixing, physical blending, slurry dispersion, or other means) the hydrophilic polymers contained within the mixture become at least partially exposed on the surface(s) when the mixture is cast. The hydrophilic polymers migrate to create a hydrophilic surface, typically with hydrophobic layer underneath. For example, bulk SIBS can be blended with PEO, PVA, or PVP and then blend, either from a solvent or from bulk, can be cast and the hydrophilic polymer(s) will bloom to the surface.

[0139] Typically, the inclusion of hydrophilic groups and / or hydrophilic polymers included in the plurality of polymeric leaflets reduces surface free energy of the leaflets which can limit denaturation of proteins, such as thrombotic proteins, and their rates of deposition onto the polymeric leaflets (such as the polymeric sleeve). In some instances, the protein deposition rate is reduced by at least about 1 to 99%, as well as sub-ranges or individual values contained within, relative to the rate of deposition of a selected protein in the absence of such hydrophilic groups and / or hydrophilic polymers. The reduction of surface free energy can increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric leaflets.

[0140] In some instances, the inclusion of hydrophilic groups and / or hydrophilic polymers can alter surface charge of the polymeric leaflets to render them neutral or electrically repulsive to one or more thrombotic proteins present in a venous environment. Such thrombotic proteins can include, without limitation, fibrinogen, phosphorylcholine, and combination thereof. The person of ordinary skill is familiar with the surface charges of known thrombotic proteins and can select suitable hydrophilic groups and / or hydrophilic polymers to render the polymeric matrix electrically repulsive to the one or more thrombotic proteins present in a venous environment. In some instances, thrombotic proteins may have negative or positive charges, or be zwitterionic.

[0141] In some instances, the polymeric leaflets can include one or more surfactant safe lipids therein, where the surfactant safe lipids can be selected, without limitation, from glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0142] In some instances, the polymeric leaflets can include one or more pharmaceutically acceptable surfactants therein, where the one or more pharmaceutically acceptable surfactants are selected from, without limitation, polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-114), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof. Other pharmaceutical surfactants, including nonionic, anionic, cationic, and amphoteric are known in the art and may be suitable.

[0143] In some instances, the polymeric leaflets can include one or more fluorocarbon polymers and / or perfluoroalkyl substances (PF AS) therein, where the one or more fluorocarbon polymers are selected from, without limitation, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), pluorinated ethylene propylene (FEP), poly vinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and the one or more perfluoroalkyl substances (PFAS) are selected from, without limitation, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof. In some instances, the one or more fluorocarbon polymers and the one or more perfluoroalkyl substances are present at concentrations, of less than about 100 micromolar (pM) or less than about 10 wt.%, in the polymeric matrix.

[0144] In some instances, the polymeric leaflets can include one or more carbon-based structures therein, where the one or more carbon-based structures are selected from, without limitation, carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof. In some instances, the polymeric leaflets can include one or more buffering agents therein, where the one or more buffering agents are selected from, without limitation, acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

[0145] In some instances, the polymeric leaflets can include one or more anticoagulant agents therein, where the one or more anticoagulant agents are selected from, without limitation, heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0146] In some instances, the polymeric leaflets can include one or more inhibitor agents therein, where the one or more inhibitor agents are selected from, without limitation, CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0147] In some instances, the inclusion of agents, such as those named above, can reduce surface free energy to increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric leaflets.

[0148] In some instances, the polymeric leaflets may include or be marked with one or more radiopaque materials. Exemplary radiopaque materials which can be added to the above polymers forming the polymeric leaflets can include, but are not limited to stainless steel, gold, tantalum, or platinum-iridium, barium, iodine, and alloys, blends, and mixtures thereof.

[0149] The polymeric leaflets forming the valve can have any suitable dimension, shape, or size needed for purposes of replacing a valve in a subject. Typically, the design dimensions of the valve and polymeric leaflets therein are based on the free or open deployed diameter of the supportive frame when implanted in a subject. In some cases, the valve height and leaflet height can range from about 0.5 to 2 times the diameter of the free or open deployed diameter of the supportive frame when implanted in a subject. The valve or leaflet height can tailored and selected for individualized sizes based on a subject’s valve size.

[0150] In most instances, the valve system includes three polymeric leaflets (130) which each have a curvilinear or wavy profile in a circumferential axis and are preferably formed / molded in a semi-open conformation. See Figure 2. Without wishing to be bound by any particular theory, the semi-open profile aids in minimizing both overall stresses (i.e., flexural stresses) in the valve and during formation of the valve in molding. Further, a semi-open profile can lower the stresses in the polymeric leaflets during systole when the valve’s leaflets are fully open, as well as lowering the typical increased stresses acting on the closed leaflets during diastole.

[0151] Nevertheless, other leaflet conformations ranging from fully open to fully closed conformations can also be formed / molded. Selection of a particular configuration (i.e., open, semi-open, closed, and variations therein) can be based on the ease of molding the desired profile and / or to provide a balance between lower systolic and lower diastolic stresses when the valve is in use, preferably to keep the stresses throughout the valve cycle lower and below the fatigue limit of the polymer forming the polymeric sleeves and leaflets.

[0152] In some instances, the polymeric leaflets have an elastic modulus in a range of between about 1-20 MPa, or a sub-range of individual value contained within the range. In some instances, the polymeric leaflets have a Young’s modulus in a range of between about 1-20 MPa, or a sub-range of individual value contained within the range. The polymeric leaflets may be selected to have low stiffness based on its use in lower pressure venous environment, as opposed a higher stiffness needed to operate in a higher pressure arterial environment.

[0153] In some instances, the polymer(s) forming the polymeric leaflets may be chosen to be free of any crystallinity (i.e., crystalline phases or regions within) or substantially free of crystallinity, where “substantially free of crystallinity” refers to there being less than 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% crystalline phases or regions within the polymer forming the polymeric leaflets. The person of ordinary skill in the art is familiar with techniques for quantifying crystallinity in polymers.

[0154] In some instances, the plurality of polymeric leaflets can be formed of uncrosslinked polymer(s), such as those named herein. In some other instances, the plurality of polymeric leaflets are formed of crosslinked polymer(s) having a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%. The person of ordinary skill in the art is familiar with techniques for crosslinking polymer(s) and controlling the extent of crosslinking.

[0155] In some instances, the surfaces of the plurality of polymeric leaflets are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets contain asperities which are (on average) no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size. “Substantially free of surface asperities,” refers to surfaces that are at least 95%, 96%, 97%, 98%, 99%, or greater free of any asperities greater than about 1, 2, 3, 4, or 5 nm in size. In a low shear venous environment with greater pooling and time for deposition, low surface roughness (high smoothness) is desirable. The person of ordinary skill in the art is familiar with methods for measuring surface smoothness and the average size of asperities contained on a given total surface area, or portion thereof. Such methods can include (optical) profilometry and electron microscopy methods (AFM, SEM). a. Variable Thickness

[0156] Without being bound to any particular theory, the use of variable thickness polymeric leaflets in the valve system can achieve lower stresses within the polymeric leaflets and reduce peak stresses at critical cycle time points during operation of the valve.

[0157] The particular pattern of thicknesses within each leaflet can be determined by mapping the time-dependent principal stress distribution of a model of the polymeric leaflets over the duration of a typical cardiac cycle. In a first step, a model thereof is formed and moved through a typical cycle to determine or estimate the locations and relative amounts, e.g. high versus low, of stress in each location throughout a typical cycle for all or one or more regions within the polymeric leaflet. The relative amounts of stress that can be analyzed correspond with the bending, twisting, stretching, or other motions which can occur during a typical diastole and systole cardiac cycle. Based on the mapping of such stresses, the particular locations and relative thicknesses for the leaflets are selected to reduce or minimize stress during cycles of use. Interactive finite element analysis (FEA) can be used to produce / model the aforementioned the time-dependent principal stress distribution. A model of the polymeric leaflets can refer to a physical model formed from a material that is the same as or different from the material of the final leaflets. Optionally, the model is a digital model, such as one created using software, which can be digitally manipulated to determine or estimate the relative stresses and their locations during a typical diastole and systole cardiac cycle.

[0158] Thus, the polymeric leaflets each independently have preferably non-uniform thicknesses throughout. In some instances, the variable thickness is understood by considering a center line of symmetry of each of the polymeric leaflets, where in a given cross-section each of the leaflets has at least two or more thicknesses. In some instances, the polymeric leaflets each independently have a non-uniform (i.e., variable) thickness across any cross-sectional direction of the leaflet. In other words, the polymeric leaflets have a variable thickness profile which is not uniform across any of the leaflet’s circumferential cross- sections, and without any preferential directionality in the thickness within such cross-sections. Such variable thickness profiles of the leaflets can lead to improved hemodynamics, flexibility, and enhanced or high durability of the polymeric valve. In some instances, enhanced or high durability can be defined based on the FDA ISO 5840 (2013) guidelines which defines that such a valve system, as described herein, would survive at least 200 million cycles or more of rapid valve opening and closing (in a special durability tester)- equivalent to about 5 years operation in a subject (patient). In some instances, the polymeric valve system described can perform up to or at least 1 billion cycles, and potentially more cycles going on (equivalent to about 25 years in a subject). The polymeric venous valve systems described, and methods of use thereof, can provide valve replacements with durability exceeding current standards for valve testing and durability.

[0159] In some non-limiting instances, the thickness at one position of a polymeric leaflet will differ from the thickness at another / different position on the same leaflet. The thicknesses across a longitudinal cross-section of the leaflet may vary with a specified slope, such that the thickness decreases or increases in a given direction of the cross-section. For example, as shown in Figure 2A, thickness “x” at a first position of a cross-section of an exemplary leaflet is greater than the thickness “y” at a second position. Figure 2B shows a representation of thickness variability present in an exemplary polymeric leaflet. In still other instances, the thickness from any given position on the polymeric leaflets varies as one moves radially out in any direction to another position.

[0160] In some instances, the polymeric leaflets, which are connected to the polymeric sleeve at an attachment end, have a thickness which is greatest at the attachment end to the sleeve and which decreases with distance away from the attachment end in any direction taken until a terminal edge of the leaflet is reached. In other words, the polymeric leaflets may have thicknesses that become thinner moving out from the attachment edge. In some instances, a maximum thickness of any portion of the polymeric leaflets can range from between about 200 to 600 pm or about 400 to 500 pm, as well as sub-ranges within. The maximum thickness may be dictated by the volume of the leaflets which should be reduced for ease of crimping / compacting / collapsing the formed valve system and for effective reduction of the overall stresses on the system. In some instances, a minimum thickness of any portion of the polymeric leaflets can range from between about 50 to 200 pm , about 50 to 150 pm, or about 50 to 100 pm, as well as sub-ranges within. In still other instances, any portion of the polymeric leaflets have a variable and non-uniform thickness can have thickness ranging from between about 50 to 600 pm. . The desired thicknesses of any part or portion of each of the respective leaflets can be controlled by way of the molding technique and the lowest limit of capable thickness which can be achieved.

[0161] Without wishing to be bound by any particular theory a benefit of variable thickness in the polymeric leaflets is in achieving a maximum peak von Mises stress which is at or below about 30%, 35%, 25%, 20%, 15%, or 10% of the yield stress of the polymer it is composed from, as well as to provide lower and more uniform stress distribution during peak diastole and can reduce bending stresses during systole which reduces the average stresses throughout the entire cardiac cycle. Thus, polymeric leaflets with variable thickness can exhibit lower overall stresses while also providing an overall reduction in the volume of material used in forming the leaflets. This can also benefit the ability to crimp / compact / collapse the polymeric venous valve system due to the decreased volume. Reduction in the polymer volume within the polymeric leaflets can help reduce the size of the valve system for easing delivery of the valve to a subject. In some instances, use of variable thickness polymeric leaflets includes a reduction in peak principal stress (absolute) at or below about +1.2MPa and above about -l.OMPa and a reduction in von Mises stresses at below about 1 MPa, with a lower, more uniform stress distribution during peak diastole.

[0162] The variable thickness in the polymeric leaflets can be achieved by way of compression or injection molding, where two mating mold parts define the variable thickness throughout the entire leaflet surface being molded. Details of the manufacture of such variable thickness polymeric leaflets is detailed below.

[0163] Lastly, it is noted that all tissue-based valves, which are used in current valve replacements have a roughly uniform thickness because these tissues are harvested from animals and cannot incorporate variable thickness therein.

[0164] 4. Anti-Leak Flap

[0165] The polymeric venous valve systems described may optionally contain one or more antileak flaps (135), as shown in Figures 1 A, 1C-1E, and 4A-4C. The one or more anti-leak flaps encircle the defective leaflet level of the system. When the polymeric venous valve system is implanted in a venous valve the anti-leak flap can be located adjacent to the defective leaflets. In some instances, the one or more anti-leak flaps include a plurality of optional slits which can improve flexibility and the ability of the anti-leak flap to cover or abut against the native calcific, or otherwise defective, leaflets of the valve.

[0166] The one or more anti-leak flaps can be formed by molding and can be made of the same or a different polymer from which the polymeric sleeve and / or leaflets is formed. In most instances, the one or more anti-leak flaps, polymeric leaflets, and polymeric sleeve are formed of the same polymer / polymeric matrix. Exemplary polymers which can be used to form the one or more anti-leak flaps include, but are not limited to, thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), polyurethanes, silicones, PTFE, crosslinked poly(styrene- isobutylenese-styrene) (xSIBS), and poly(styrene-isobutylene-styrene) (SIBS). Thermoplastic elastomers (TPEs) can be formed of or contain polymyrcene, polymenthide, and poly(e- decalactone). Elastomeric biomaterials can include, for example, silicones, thermoplastic elastomers, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes. As appropriate, the skilled person would be able to select conditions (i.e., temperatures, solvent(s), etc.) needed to form polymer melts or form polymer solutions of the aforementioned to be able to form the one or more anti-leak flaps during molding, as detailed further below. Typically, the one or more anti-leak flaps are molded together with the polymeric leaflets and polymeric sleeve onto the supportive frame in a single step.

[0167] The one or more anti-leak flaps can have any suitable dimension, shape, or size needed. The length of the flap extending from the surface of the polymeric sleeve can range from about 1 to 5 mm. In some instances, the thickness of any portion of the one or more anti-leak flaps can range from between about 0.01 to 100 m, 30 to 350 pm, or about 30 to 300 pm, where the thickness can be dictated by the molding technique and the lowest limit of capable thickness which can be achieved.

[0168] The anti-leak flaps are believed to have the ability to block PVL channels by either covering the entrance to the channel, as it covers or seals gaps between the valve system and the native calcific leaflets or by filling the gaps between the valve system and the native calcific leaflets. The anti-leak flaps can seal the gaps in response to backward pressure during diastole. During systole the forward pressure is negligible, as the valve system is open, therefore the antileak flaps will remain stationary. As shown in Figures 4A-4C, the anti-leak flap is placed against the native calcific leaflets of the venous valve. The anti-leak flap may be placed in partial supraannular position against the native calcific leaflets or in supra-annular position against native calcific leaflets of the venous valve. The anti-leak flaps can be useful in minimizing or preventing the risk of intra and / or paravalvular leaks.

[0169] 5. Polymeric Leaflet Planarity

[0170] The polymeric leaflets described herein typically demonstrate planarity and reduced concavity to prevent or limit the possibility of stagnation, separation, puddling, and / or pooling of fluids, such as blood, thereon.

[0171] In most instances, at least a portion of the aforementioned surface of each polymeric leaflet is planar. In some instances, the surface is at least about 1 -99% planar based on the total surface area of the surface. In some instances, the surface is at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface. “Total surface area” of the surface, refers to the entire planar area of a polymeric leaflet regardless of any curvature which may be present thereon. Total surface area may be calculated using any suitable method known to the skilled artisan, such as by visual image capture.

[0172] 6. Optional Coatings on the Polymeric Leaflets

[0173] In still other instances, the polymeric leaflets are coated with one or more suitable hydrophilic polymers known to the person of ordinary skill in the art which are suitable for pharmaceutical use in the body and where the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment. In some instances, the one or more hydrophilic polymers include hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO“), phosphates (RPO4-), and combinations thereof.

[0174] Typically, the inclusion of hydrophilic polymers coated onto the polymeric leaflets reduces surface free energy of the matrix which can limit denaturation of proteins, such as thrombotic proteins, and their rates of deposition onto the polymeric matrix (such as the polymeric sleeve). In some instances, the protein deposition rate is reduced by at least about 1 to 99%, as well as sub-ranges or individual values contained within, relative to the rate of deposition of a selected protein in the absence of such hydrophilic groups and / or hydrophilic polymers. The reduction of surface free energy can increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric leaflets. In some instances, the inclusion of hydrophilic groups and / or hydrophilic polymer coatings can alter surface charge of the polymeric leaflets to render them neutral or electrically repulsive to one or more thrombotic proteins present in a venous environment. Such thrombotic proteins can include, without limitation, fibrinogen, phosphorylcholine, and combination thereof. The person of ordinary skill is familiar with the surface charges of known thrombotic proteins and can select suitable hydrophilic groups and / or hydrophilic polymers to render the polymeric matrix electrically repulsive to the one or more thrombotic proteins present in a venous environment. In some instances, thrombotic proteins may have negative or positive charges, or be zwitterionic.

[0175] In some instances, the polymeric leaflets can include one or more surfactant safe lipids coated thereon, where the surfactant safe lipids can be selected, without limitation, from glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0176] In some instances, the polymeric leaflets can include one or more pharmaceutically acceptable surfactants coated thereon, where the one or more pharmaceutically acceptable surfactants are selected from, without limitation, polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myij 59), and combinations thereof. Other pharmaceutical surfactants, including nonionic, anionic, cationic, and amphoteric are known in the art and may be suitable.

[0177] In some instances, the polymeric leaflets can include one or more fluorocarbon polymers and / or perfluoroalkyl substances (PF AS) coated thereon, where the one or more fluorocarbon polymers are selected from, without limitation, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), pluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and the one or more perfluoroalkyl substances (PFAS) are selected from, without limitation, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

[0178] In some instances, the polymeric leaflets can include one or more carbon-based structures coated thereon, where the one or more carbon-based structures are selected from, without limitation, carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0179] In some instances, the polymeric leaflets can include one or more buffering agents coated thereon, where the one or more buffering agents are selected from, without limitation, acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

[0180] In some instances, the polymeric leaflets can include one or more anticoagulant agents coated thereon, where the one or more anticoagulant agents are selected from, without limitation, heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0181] In some instances, the polymeric leaflets can include one or more inhibitor agents coated thereon, where the one or more inhibitor agents are selected from, without limitation, CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0182] In some instances, the inclusion of agents, such as those named above, can reduce surface free energy to increase wetness, as well as reduce contact angle and adhesion and deposition of thrombotic proteins on the polymeric leaflets.

[0183] III. Methods of Making Polymeric Venous Valve Systems

[0184] Methods of making polymeric venous valve systems described above are detailed below.

[0185] In one non-limiting instance, a method of making can include the steps of:

[0186] (i) placing a supportive frame inside a cavity of a mold in a position suitable to facilitate flow of a polymer around the supportive frame, wherein the mold comprises a top core, a bottom core, and one or more encasement components which encase the top and bottom cores, wherein the top core and bottom core define a shape to form polymeric leaflets in a suitable orientation wherein the polymeric leaflets are formed optionally in a semi-open position having a zero residual stress conformation, wherein the polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; and

[0187] (ii) introducing at least one polymer into the mold;

[0188] (iii) molding or casting the polymeric leaflets and a polymeric sleeve around the supportive frame to form a polymeric venous valve system, wherein the polymeric leaflets and the polymeric sleeve are a continuum and each of the polymeric leaflets are connected to the polymeric sleeve at an attachment end; and

[0189] (iv) removing the polymeric venous valve system formed from the mold.

[0190] Typically, the polymeric venous valve system formed by the above method includes at least one of the following features:

[0191] (a’) the at least one polymer comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;

[0192] (b’ ) the at least one polymer is mixed or blended with one or more hydrophilic polymers which reduces protein deposition on the polymeric venous valve system in the venous environment during or prior to step (ii);

[0193] (c’) the at least one polymer is mixed or blended with one or more surfactant safe lipids during or prior to step (ii);

[0194] (d’) the at least one polymer comprises one or more pharmaceutically acceptable surfactants during step (ii);

[0195] (e’) the at least one polymer is mixed or blended with one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) during or prior to step (ii);

[0196] (f ’) the at least one polymer is mixed or blended with one or more carbon-based structures during or prior to step (ii); (g’) the at least one polymer is mixed or blended with one or more buffering agents during or prior to step (ii);

[0197] (h’) the at least one polymer is mixed or blended with one or more anticoagulant agents during or prior to step (ii);

[0198] (i’ ) the at least one polymer has a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons; j’) the at least one polymer is uncrosslinked polymer(s) or the at least one polymer is crosslinked during step (iii) to have a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;

[0199] (k’) the plurality of polymeric leaflets formed in step (iii) each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar;

[0200] (1’) the surfaces of the polymeric leaflets and optionally the polymeric sleeve formed in step (iii) are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and optionally the polymeric sleeve contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size.

[0201] In some instances of the method above, the method may include, prior to step (i), imaging (such as using MRI, CT, or other known imaging techniques suitable for visualizing venous structures) a venous valve structure in a subject, for example the vein or defective tricuspid valve, with imaging attention given to the proximal as well as distal region of the venous valve structure, as well as the valve itself. In performing imaging, dynamic images are obtained defining the range of any deformation of the venous valve throughout its functional cycle. This can then be compared to a range of normal function(s) without deformation and a suitable polymeric venous valve system can be designed / structured for formation by way of the method steps above to be precision formed and fit to correct the defect in a customized fashion. Such “precision fitting” can be used to design the supportive frame and / or mold used to form the polymeric leaflets and sleeve in the methods described.

[0202] As previously noted, the polymeric leaflets and the polymeric sleeve form a continuum (i.e., a single continuous piece). This differs from currently known valve systems that must suture natural valve components (bovine / porcine / ovine) to the valve. The instant method allows for formation of polymeric venous valves where the polymeric leaflets formed avoid punctures because no suturing is needed because the polymeric leaflets and the polymeric sleeve are fully attached to each other.

[0203] Although the method preferably produces polymeric leaflets in a semi-open position (which can reduce stresses, such as flexural stresses), the methods may also be used to produce polymeric leaflets in open or closed positions or any intermediate position. For example, Figure 5E shows how a mold can be used to form polymeric leaflets in the closed position while Figure 5F shows how a mold can be used to form polymeric leaflets in the semi-open position. The design of the top and bottom cores can be selected to produce polymeric leaflets of any desired position when these components are created / fabricated.

[0204] The mold used in the methods is a modular mold, where the interior of the mold and the sections that are used to form the polymeric venous valve are modular (e.g. symmetrically split to three parts in a circumferential axis) to facilitate easy extraction of the fabricated polymeric venous valve from the molding cavity. In some instances, the mold may include one or more vent holes which allow suction of air out of the mold cavity and / or the removal of excess polymer which may be introduced in step (ii). As shown in Figure 5A, a non-limiting mold (300) having a base core (310), encasement components (320), a top core (330), optionally having multiple axial leaflet lock registrations (340) can be placed around a supportive frame (110). The axial leaflet lock registrations (340) can be used to hold the supportive frame such as at the axial leaflet locking struts (150), shown in Figure 1 A. During step (ii) a polymer is introduced into the mold and the polymeric leaflets and the polymeric sleeve can be simultaneously molded or cast onto the supportive frame. As shown in Figure 5B, once the polymeric venous valve system (100) is formed it can be removed during step (iv) from the mold by disassembling the mold parts. As further shown in Figure 5B, certain parts of the supportive frame are not covered by the polymeric sleeve including the crown supporting struts and axial leaflet locking struts, as well as any anchors which may be present. Preferably, the mold is designed to not embed the crown supporting struts, axial leaflet locking struts, and any anchors present in the polymeric sleeve. In some instances, if the crown supporting struts, axial leaflet locking struts, and any anchors are covered by polymeric sleeve or any excess polymer, this may be removed thereafter.

[0205] In some instances, the mold and components thereof are formed of stainless steel, tool steel, aluminum, or any other suitable metal. The mold and components thereof may be fabricated using art known techniques, such as precision machining / CNC or 3-D metal printing techniques. The design of the mold cavities needed to produce the leaflets and polymeric sleeve on the supportive frame, having any requisite complexity of design, can be achieved in the mold parts using such precision machining / CNC or 3-D metal printing techniques or other precision machining or fabricating means including additive manufacturing. Further, the mold may include sealing elements, such as o-rings, or custom-shape and made sealing elements. For instance, if it is necessary to prevent the polymer from coating a part of the supportive frame, a sealing element with a custom shape can be made for that part of the supportive frame (e.g. from silicone or other suitable materials).

[0206] In some instances of the methods, positioning of the supportive frame into the mold cavity (in step (1)) involves the presence of an annular gap distance from the supportive frame the outer polymeric sleeve, to be formed thereon, in a size ranging from about 10 to 20 pm. To promote accurate placing of the supportive frame within the desired tolerance, arched segments (e.g. 0. 1-1.0 mm thick) may be placed or present in parts of the mold components, such as the encasement components, that protrude from the outer wall of the mold and hold the supportive frame in the desired radial position. In some instances, this allows for full alignment with the polymeric venous valve centerline. Such arched segments can be spaced, for example, every 3 to 10mm (in the long axis). In order to avoid any potential impairment of polymer flow inside the mold, slits can be cut out of the arched segments to for flow of the polymer in between the segments. In some instances, such arched segments may be retractable such that they can retracted from the mold body once the polymer has been cured sufficiently. In still other instances, instead of use of arched segments, these could be replaced with multiple pins that are spaced apart in the circumferential and longitudinal-axial directions of components of the mold. The arched segments should preferably be made of the same material as the mold so that heating and thermal expansion of the mold remains uniform throughout. Nevertheless, use of combinations of various metals or polymers can be used to form the arched segments or mold components that do not experience mechanical loading. As an example, a plunger to apply force / pressure to the polymer can be made of one type of steel (i.e., tool steel) while components with surfaces that are in contact with the valve / stent being molded / cast can be made of a different kind of steel (i.e., stainless steel). Moving parts, such as a plunger, may benefit from being made of harder steel to minimize potential wear and particle leaching.

[0207] In some instances of the methods, the mold, prior to step (i) or (ii) may be cleaned and prepared (chemically and / or mechanically). In some instances, the mold is heated during steps (ii) or (iii) to a suitable temperature, such as to ensure ease of flow of the polymer through the mold. Such heating temperatures can range from about 100 °C to 350 °C, and subranges within. The molding or casting of step (iv) can involve curing the polymer, where after curing is complete (a function of temperature and time) the mold is allowed to cool down, then the mold is opened and the cured polymeric venous valve removed. In some instances of the methods, a vacuum can be applied into the mold to remove air bubbles from the polymer introduced into the mold cavity which cured to produce the molded or cast polymer. The ability to produce a vacuum may be integrated into the mold itself. In some instances, when polymer curing is completed, the vacuum (if applied) is released, and the mold is partially opened up while still heated / hot and the internal mold parts that “wrap” the cured polymeric venous valve are then allowed to cool down, either slowly to room temperature, or quickly by immersion into water.

[0208] In some instances, as the polymer formed by, for example, compression / transfer / inj ection molding is cured under heat and pressure, the resulting polymer becomes denser and less porous. Manipulation of the outer surface roughness can assist in adhesion to the native tissue. Another potential advantage of such rough surface can be lower friction during crimping / collapsing / compacting of the valve system for deployment into a subject.

[0209] In some instances, the formed polymeric valve system can be carefully extracted from the mold in step (iv): by separation from the mold using, for example, a spatula, air pressure, liquid pressure (e.g. isopropyl alcohol), immersion in a solvent (e.g. alcohols, such as ethanol or isopropyl alcohol) optionally with sonication. Following step (iv), the methods described may also involve a further step of removing of any excess polymer from the valve which is not desired, such as by cutting, laser cutting, ultrasonic cutting, thermal cutting, or other cutting means. The methods may additionally involve a further step of cleaning the formed polymeric valve after removal from the mold in suitable solvent(s) optionally with ultrasonication and then drying the polymeric valve thereafter. Following step (iv), the method may further include a step of conformally coating at least part or all of the outer surfaces of the polymeric sleeve with a gel paving material, such as made from a hydrogel. In some instances, the gel paving material may be applied via forming gels as films and wrapping the external surface of the polymeric sleeve and / or polymeric leaflets with the gel paving material, allowing it to dry, thereby constriction boding to the surface. In some other instances, the external surface of the polymeric leaflets and / or polymeric sleeve may be doped with a layer of suitable adhesive to which the gel paving material - either wet or in desiccated form is applied. In still other cases, the external surface of the polymeric leaflets and / or polymeric sleeve may be coated with a photoreactive catalyst -e.g. eosin or riboflavin, and the gel formed as a layer via photocatalysis as described by Slepian in U.S. Patent 6,290,729. The thickness of the gel paving material, in desiccated form, may range from between about 0.5 to 5 mm.

[0210] In some instances of the methods, a plunger or other means of applying pressure may be used when the polymer is introduced in step (ii). The polymer may be introduced through, for example, an opening in the top core of the mold and a plunger may be used to apply pressure to the polymer to ensure it spreads throughout the cavities of the mold. Suitable pressures which can be used to flow the polymer during steps (ii) and (iii) can range from between about 1 to 10 tons, and sub-ranges or individual values contained within. For example, Figure 5C shows a cross-sectional representation of a mold where a polymer is applied under pressure by way of a plunger (350). As shown in Figure 5D the polymer flows between cavities in the encasement components and core components in order to embed the supportive frame (110) in the polymeric matrix.

[0211] In some instances, the polymeric sleeve formed further includes one or more anti -leak flaps which are formed by using a mold that defines the anti-leak flaps and forms the anti-leak flaps, when the polymer is molded / cast in step (iii).

[0212] In some cases, one or more releasing agents may be applied to the mold surfaces prior to step (ii) in order to facilitate removal of the polymeric venous valve system in step (iv). Suitable mold releasing agents include solvent-based, water-based agents, silicone agents, or resin-based agents, which may be sacrificial or semi-permanent. These agents can be sprayed onto the surfaces at room temperature or with heating (of about 50 to 200°C or about 100 to 150 °C) in a single or multiple layers. Various types of mold release agents are commercially available and known to those skilled in the art.

[0213] In some instances, the molding or casting of the at least one polymer in step (iii) is performed by a compression molding process, an injection molding process, a dip coating process, or a transfer molding process. Compression molding, for example, relies on part of the shape setting mold to move and compress the polymer, cause pressure and flow into the other mold cavities. Injection molding, for example, relies on an extruder system to heat and pressurize the polymer, causing it to flow into the mold cavities. Transfer molding, for example, is similar to injection molding but instead of an extruder generating the pressure, a plunger system is pressurized (compressed) into a cavity of heated polymer and injected into the cavities of the mold. Such processes and conditions for such processes are known to those of ordinary skill in the art. In one non-limiting example of the method, during step (ii) a polymer (e.g. pellets or powder form) is placed into the mold, if compression molding, or into a container adjacent to the mold, if transfer or injection molding is employed, and the mold is heated to a temperature that would make the raw polymer pliable in a fluid gel-like form.

[0214] Exemplary polymers, or blends thereof, which can be used to form the polymeric leaflets and polymeric sleeve in the methods described include, but are not limited to, thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), polyurethanes, silicones, PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), and poly(styrene-isobutylene-styrene) (SIBS). Thermoplastic elastomers (TPEs) can be formed of or contain polymyrcene, polymenthide, and poly(e-decalactone). Elastomeric biomaterials can include, for example, silicones, thermoplastic elastomers, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes. The polymers named herein can have any suitable weight average molecular weight that allows for a low level of stiffness for use in a low pressure and low shear venous environment. In some instances, the weight average molecular weight is in a range of between about 10,000 to about 50,000 Daltons, as well as sub-ranges or individual values contained within the aforementioned range. As appropriate, the skilled person would be able to select conditions (i.e., temperatures, solvent(s), etc.) needed to form polymer melts or form polymer solutions of the aforementioned for use in step (ii) and during molding / casting step (iii). In some instances, thermoplastic polymers can be chosen when instances of dip coating are used to form the systems described and thermoset polymers can be chosen when instances of compression, transfer, or injection molding are used to form the systems described. In still other instances, a combination of both dip coating of the polymeric sleeve and to attach them to previously molded polymeric leaflets can be used.

[0215] In some instances of the methods, the at least one polymer is chosen to be free of any crystallinity (i.e., crystalline phases or regions within) or substantially free of crystallinity, where “substantially free of crystallinity” refers to there being less than 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% crystalline phases or regions within the polymer when cast to form the polymeric leaflets and sleeve. The person of ordinary skill in the art is familiar with techniques for quantifying crystallinity in polymers. In some instances of the methods, the at least one polymer is an uncrosslinked polymer, such as those named herein. In some other instances, the at least one polymer is a crosslinkable or crosslinked polymer and the polymer when cast has a final degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%. The person of ordinary skill in the art is familiar with techniques for crosslinking polymer(s) and controlling the extent of crosslinking.

[0216] In some instances of the methods, the at least one polymer includes one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment. The one or more hydrophilic groups are typically functionalized on the at least one polymer. In some instances, the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates ( RSO3), carboxylates (RCOO ), phosphates (RPO4), and combinations thereof. In some instances, the polymeric matrix is formed of at least one polymer which was modified to include such hydrophilic groups. Methods of modifying polymers to add hydrophilic functional groups are known in the art. These can exclude, without limitation, exposure to a plasma with one or more gases selected, for example, from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof. The person of ordinary skill is familiar with other conditions and gases which can be used to functionalize polymers with hydrophilic functional groups.

[0217] In still other instances, the at least one polymer is mixed, admixed, or blended with one or more suitable hydrophilic polymers known to the person of ordinary skill in the art which are suitable for pharmaceutical use in the body and where the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment. In some instances, the one or more hydrophilic polymers include hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. In some instances, the one or more hydrophilic polymers are bloomed on the one or more surfaces of the at least one polymer following molding / casting. “Blooming” or “bloomed,” as used herein, refers to the effect of creating mixtures / admixtures with hydrophilic polymer(s) that when blended (for example via solvent mixing, physical blending, slurry dispersion, or other means) the hydrophilic polymers contained within the mixture become at least partially exposed on the surface(s) when the mixture is cast. The hydrophilic polymers migrate to create a hydrophilic surface, typically with hydrophobic layer underneath. For example, bulk SIBS can be blended with PEO, PVA, or PVP and then blend, either from a solvent or from bulk, can be cast and the hydrophilic polymer(s) will bloom to the surface.

[0218] In some instances, the inclusion of hydrophilic groups and / or hydrophilic polymers in the at least one polymer can alter surface charge of the polymeric leaflets to render them neutral or electrically repulsive to one or more thrombotic proteins present in a venous environment. Such thrombotic proteins can include, without limitation, fibrinogen, phosphorylcholine, and combination thereof. The person of ordinary skill is familiar with the surface charges of known thrombotic proteins and can select suitable hydrophilic groups and / or hydrophilic polymers to render the polymeric matrix electrically repulsive to the one or more thrombotic proteins present in a venous environment. In some instances, thrombotic proteins may have negative or positive charges, or be zwitterionic.

[0219] In some instances of the methods, the at least one polymer can include one or more surfactant safe lipids therein, where the surfactant safe lipids can be selected, without limitation, from glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0220] In some instances of the methods, the at least one polymer can include one or more pharmaceutically acceptable surfactants therein, where the one or more pharmaceutically acceptable surfactants are selected from, without limitation, polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof. Other pharmaceutical surfactants, including nonionic, anionic, cationic, and amphoteric are known in the art and may be suitable.

[0221] In some instances of the methods, the at least one polymer can include one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) therein, where the one or more fluorocarbon polymers are selected from, without limitation, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), pluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and the one or more perfluoroalkyl substances (PFAS) are selected from, without limitation, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof. In some instances, the one or more fluorocarbon polymers and the one or more perfluoroalkyl substances are present at concentrations of less than about 100 micromolar (pM) or less than about 10 wt.% in the polymeric matrix.

[0222] In some instances of the methods, the at least one polymer can include one or more carbon-based structures therein, where the one or more carbon-based structures are selected from, without limitation, carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0223] In some instances of the methods, the at least one polymer can include one or more buffering agents therein, where the one or more buffering agents are selected from, without limitation, acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

[0224] In some instances of the methods, the at least one polymer can include one or more anticoagulant agents therein, where the one or more anticoagulant agents are selected from, without limitation, heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0225] In some instances of the methods, the at least one polymer can include one or more inhibitor agents therein, where the one or more inhibitor agents are selected from, without limitation, CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof. In some instances, the methods described further include a step of coating the polymeric leaflets, and optionally the polymeric sleeve, following step (iii) or (iv), with at least one of the following: one or more hydrophilic polymers; one or more surfactant safe lipids; one or more pharmaceutically acceptable surfactants; one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS); one or more carbon-based structures; one or more buffering agents; one or more anticoagulant agents; one or more inhibitor agents;

[0226] The selection of the above can be made from the examples of such hydrophilic polymers, surfactant safe lipids, pharmaceutically acceptable surfactants, fluorocarbon polymers, PFASes, carbon-based structures, buffering agents, anticoagulant agents, and inhibitor agents named immediately above.

[0227] It is understood that when the at least one polymer is said to be mixed, blended, or admixed with other polymer(s) or agent(s), such as those named above, that a mixture is introduced into the mold during step (ii).

[0228] In some instances of the above methods, the surfaces of the plurality of polymeric leaflets and / or the polymeric sleeve are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and / or the polymeric sleeve contain asperities which are (on average) no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size. “Substantially free of surface asperities,” refers to surfaces that are at least 95%, 96%, 97%, 98%, 99%, or greater free of any asperities greater than about 1, 2, 3, 4, or 5 nm in size. In a low shear venous environment with greater pooling and time for deposition, low surface roughness (high smoothness) is desirable. The person of ordinary skill in the art is familiar with methods for measuring surface smoothness and the average size of asperities contained on a given total surface area, or portion thereof. Such methods can include (optical) profilometry and electron microscopy methods (AFM, SEM).

[0229] Details of the supportive frame, polymeric sleeve, polymeric leaflets, and anti-leak flap which are formed according to the methods described to provide polymeric venous valve systems are given below. 1. Supportive Frame

[0230] In some instances, the supportive frame used in the methods is formed of an armature or scaffold-like construct formed from a plurality of connected struts, wherein each strut is connected to one or more other struts via a joint. In some other instances, the armature or scaffold-like construct may be in the form of a cage having tubular or wire-like elements configured in a stent-like configuration. The armature or scaffold-like construct is expandable from its crimped, compacted, or collapsed back up to its size, as formed, or any desired size in between. Preferably, the armature or scaffold-like construct is an expandable stent which is selfexpandable or otherwise requires active expansion by balloon expansion or heat expansion. Expandable stents are plastically deformed with mechanical energy, such as by balloon expansion, into an “opened” or deployed shape. Self-expandable stents can be thermally fixed or shape set after expansion. Such expandable stents and materials for making such stents are known in the art. Suitable materials, dimensions, characteristics, and methods of manufacturing the supportive frame are described above. Further, as previously noted, the supportive frame may include optional components including one or more anchors and / or one or more indentations which are preferably not covered / coated by any polymer or polymeric matrix during or following steps (ii), (iii), and (iv), or where any polymer thereon can be removed after these steps are performed.

[0231] 2. Polymeric Sleeve

[0232] In some instances, the thickness of the embedding polymeric matrix forming the polymeric sleeve can have any suitable thickness thereon. The thickness of the extraluminal polymeric matrix material covering the supportive frame can, for example, when formed by compression molding or other molding techniques have a thickness in a range from about 0 to 500 microns in the circumferential direction and / or a thickness ranging from about 0 to 400 microns in the radial direction of the struts or wire-like elements of the supportive frame. In some instances, an average thickness of about 400 microns in the circumferential direction (i.e., about 200 microns are on each side of the strut) is present. Suitable materials, dimensions, and characteristics of the polymeric sleeve which can be formed according to the methods herein are described above. As previously noted, in some instances, the outer surface may be coated with a gel paving material subsequent to formation of the polymeric sleeve and removal from the mold. 3. Polymeric Leaflets

[0233] As noted above, the polymeric leaflets of the system can be achieved, for example, by forming the polymeric leaflets and polymeric sleeve (onto the supportive frame) at the same time during the molding process (i.e., single manufacturing step) whereby they form a single polymeric component containing both the polymeric leaflets and polymeric sleeve. The polymeric leaflets can be formed of polymers as previously specified, and are typically made of the same polymer as the polymeric sleeve.

[0234] However, in less preferred instances of the methods, polymeric leaflets may be formed / molded as a first component and then the leaflets and a supportive frame can be dip coated into a suitable polymer melt or solution to form the polymeric sleeve. During such instances, the polymer melt or solution forms the polymeric sleeve over the supportive frame and simultaneously attaches to the polymeric leaflets in the mold. Thus, the leaflets become an inseparable part of the formed polymeric sleeve.

[0235] The polymeric leaflets forming the valve can have any suitable dimension, shape, or size needed. In most instances, the valve system includes three polymeric leaflets which each have a curvilinear or wavy profile in a circumferential axis and are preferably formed / molded in a semi-open conformation. The design of the top and bottom cores can be selected to produce polymeric leaflets of any desired position when these mold components are created / fabricated; see Figure 5E and 5F.

[0236] The polymeric leaflets can each independently have uniform or non-uniform thicknesses. However, in some preferred instances, the polymeric leaflets each independently have a non- uniform (i.e., variable) thickness across any cross-sectional direction of the leaflet. Such variable thickness can be imparted by the selection of the design of the top and bottom cores of the mold in order to produce polymeric leaflets of any desired thickness and having any desired variability in thickness therein, when these mold components are created / fabricated.

[0237] 4. Anti-Leak Flap

[0238] The polymeric venous valve systems formed according to the methods above can include one or more anti-leak flaps that encircle the calcific leaflet level of the system. The anti-leak flaps are defined by the mold, which can be designed to produce such flaps on the polymeric sleeve. The anti-leak flaps can be formed of polymers as previously specified, and are typically made of the same polymer as the polymeric sleeve and / or polymeric leaflets. In some instances, the one or more anti-leak flaps include a plurality of optional slits which can improve flexibility and the ability of the anti-leak flap to cover or abut against the native calcific or defective leaflets of the venous valve.

[0239] 5. Polymeric Leaflet Planarity

[0240] The polymeric leaflets formed according to the methods above demonstrate planarity and reduced concavity to prevent or limit the possibility of stagnation, separation, puddling, and / or pooling of fluids, such as blood, thereon.

[0241] Controlling planarity and imparting reduced concavity to the polymeric leaflets can be achieved by designing the mold used to form / cast / shape the polymeric leaflets. For instance, each polymeric leaflet independently is cast to have a surface, which may be defined by three curves: a free-edge curve, a belly curve, and an attachment curve, as shown in Figure 6A. The free-edge curve defines the top or downstream edge of the polymeric leaflet. The belly curve defines the sweep of the polymeric leaflet. The attachment curve defines the surface curvature at or near the edge of the polymeric leaflet, which forms part of the operative end of the valve and where the polymeric leaflets in a valve system are able to open and close and abut each other, and can influence the closure stresses or buckling / folding during opening / closing of the polymeric leaflets.

[0242] In some instances, planarity of the surface can be controlled by varying the curvature of the above three defining curves. Planarity of the surface can be influenced by larger radii or linear lines. Spline curves can be measured for curvature Fpree Edge based on the inverse of the local radii, where the surface curvature can be measured as a mean curvature, defined as average r in two principal directions, as shown in the top of Figure 6B. As further shown in the sectional views at the bottom of Figure 6B, the mean curvature can be selected to produce either curved polymeric leaflet valves and planar polymeric leaflet valves. These parameters can be used to create an appropriate mold to form and shape the polymeric leaflets to have any desired degree of surface planarity. It is possible to modify the overall curvature of the leaflets. In some instances, the curvature of the of a portion of the leaflet, which extends from the central region to the leaflet edges / tips is modified to be more planar (i.e. reduced concavity). Typically, the curvature of the leaflet in the region around the outer annulus is not modified. As explained above, planarity and reduced concavity of the surface of the leaflet can provide benefits for the polymeric venous valve systems described herein when used in low pressure and low shear venous environments. In most instances, at least a portion of the aforementioned surface of each polymeric leaflet is planar. In some instances, the surface is at least about 1 -99% planar based on the total surface area of the surface. In some instances, the surface is at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface. “Total surface area of the surface,” refers to entire planar area of a polymeric leaflet regardless of any curvature which may be present thereon.

[0243] IV. Uses of Polymeric Venous Valve Systems

[0244] The polymeric venous valve systems described above can be used to replace venous valves in a subject, such as human. In some instances, the polymeric venous valve systems can replace defective venous valves. In still other instances, the polymeric venous valve system is not limited to use only in the veins, where it can be used in other luminal structures organs, or organ components of the body of a subject.

[0245] In some instances, the polymeric venous valve systems can be implanted in a subject in need thereof to replace a defective venous valve, such as a venous valve having calcific leaflets. A non-limiting exemplary method can include the steps of:

[0246] (1) inserting a polymeric venous valve system in a crimped, collapsed, or compacted state into the subject in need thereof;

[0247] (2) delivering the polymeric venous valve system to a defective valve in the subject in need thereof;

[0248] (3) implanting the polymeric venous valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state which localizes or fixes the polymeric venous valve system at the defective venous valve and replaces the function of the defective venous valve.

[0249] In some instances of the above method, the subject is a human and the defective venous valve is selected from venules, veins, vena cava, pulmonary vein, coronary sinus, or tricuspid valve. In some instances, the insertion in step (1) involves the use of a delivery catheter or similar extendable member or delivery system. In some instances, delivery is by a minimally invasive technique, such as a percutaneous approach, or delivery may occur by surgical means. In some instances, delivery is done through a transcatheter having a size up to one inch in diameter. In still other instances, the transcatheter size can range from 25 French up to 45 French. In some cases, the polymeric venous valve system is crimped, collapsed, or compacted immediately prior to use and then inserted into a delivery catheter. In some instances, the system may be used in a method of treating a subject in need thereof, the method including the steps of:

[0250] (1’) inserting a polymeric venous valve system, as described herein, in a crimped, collapsed, or compacted state into the subject in need thereof;

[0251] (2’) delivering the polymeric valve system to a vein in the subject in need thereof;

[0252] (3’) implanting the polymeric venous valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state, which localizes or fixes the polymeric venous valve system at the vein.

[0253] In some instances, replacing a defective tricuspid valve with a polymeric venous valve system in a subject can treat or ameliorate tricuspid regurgitation. Tricuspid regurgitation is a condition that is increasingly being recognized with attempts at therapy being mounted as it causes significant morbidity and mortality. In some instances, replacing a defective tricuspid valve with a polymeric venous valve system in a subject can improve tricuspid hemodynamics, as compared to the hemodynamics of the defective valve. In some instances, a method of replacing a tricuspid valve in a subject in need thereof, includes the steps of:

[0254] (1”) deploying a transcatheter tricuspid valve replacement device as described herein, wherein the supportive frame has a suitable shape and dimensions to fit within the tricuspid valve annulus of the subject in need thereof; and

[0255] (2”) allowing the polymeric leaflets to function as primary valve leaflets for controlling blood flow through the tricuspid valve of the subject in need thereof.

[0256] In some instances of the above method, the step of deploying of the transcatheter tricuspid valve replacement device is performed via a minimally invasive technique, such as via a percutaneous approach.

[0257] In some instances, replacing a defective venous valve with a polymeric venous valve system in a subject can treat or ameliorate one or more symptoms of a (chronic) venous disease. For example, chronic venous insufficiency is a prevalent disease process. Chronic venous insufficiency pathophysiology is typically manifested as either reflux (backward flow) or obstruction of venous blood flow. Chronic venous insufficiency can develop from the protracted valvular incompetence of superficial veins, deep veins, or perforating veins that connect them. In all cases, the result is venous hypertension of the lower extremities. In some instances, replacement of a defective venous valve with a polymeric venous valve system can be used to treat or ameliorate deep vein dysfunction, which is usually related to deep venous thrombosis (DVT) and results in inflammation, valve scarring and adhesion, and luminal narrowing.

[0258] In some instances, replacing a defective venous valve with a polymeric venous valve system in a subject can serve to improve or restore the Coanda flow effect, when comparing the effect in the defective venous valve with the effect following replacement with the polymeric venous valve system. Restoring the Coanda flow effect can help prevent the polymeric valve leaflets from prolapsing into the atrium.

[0259] The disclosed polymeric venous valve systems, and methods of making and using thereof, can be further understood through the following enumerated paragraphs.

[0260] 1 . A polymeric venous valve system comprising: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame comprises a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve; wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

[0261] 2. The polymeric venous valve system of paragraph 1, wherein the polymeric venous valve system comprises at least one of the following features:

[0262] (a) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;

[0263] (b) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic polymers therein and / or coated thereon, wherein the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment;

[0264] (c) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more surfactant safe lipids therein and / or coated thereon;

[0265] (d) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more pharmaceutically acceptable surfactants therein and / or coated thereon;

[0266] (e) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) therein and / or coated thereon;

[0267] (f) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more carbon-based structures therein and / or coated thereon;

[0268] (g) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more buffering agents therein and / or coated thereon;

[0269] (h) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more anticoagulant agents therein and / or coated thereon;

[0270] (i) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more inhibitor agents coated thereon; j) the plurality of polymeric leaflets, and optionally the polymeric matrix, have an elastic modulus in a range of between about 1-20 MPa;

[0271] (k) the plurality of polymeric leaflets, and optionally the polymeric matrix, have a Young’s modulus in a range of between about 1-20 MPa;

[0272] (l) the plurality of polymeric leaflets, and optionally the polymeric matrix, are free of crystallinity or are substantially free of crystallinity;

[0273] (m) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of polymer(s) having a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons;

[0274] (n) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of uncrosslinked polymer(s) or the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of crosslinked polymer(s) having a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;

[0275] (o) the plurality of polymeric leaflets each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar; and

[0276] (p) the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size.

[0277] 3. The polymeric venous valve system of paragraph 2, wherein the one or more hydrophilic groups are functionalized on the one or more surfaces of the plurality of polymeric leaflets and / or the polymeric matrix and at least partially exposed on the one or more surfaces.

[0278] 4. The polymeric venous valve system of paragraph 3, wherein the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

[0279] 5. The polymeric venous valve system of any one of paragraphs 2-4, wherein the plurality of polymeric leaflets and / or the polymeric matrix are each independently formed of at least one polymer which was modified to include the one or more hydrophilic groups optionally by exposure to a plasma with one or more gases selected from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof.

[0280] 6. The polymeric venous valve system of any one of paragraphs 2-5, wherein the one or more hydrophilic polymers comprise hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof. 7. The polymeric venous valve system of any one of paragraphs 2-6, wherein the one or more hydrophilic polymers are mixed, admixed, or blended within the plurality of polymeric leaflets and / or the polymeric matrix.

[0281] 8. The polymeric venous valve system of paragraph 7, wherein the one or more hydrophilic polymers are bloomed on the one or more surfaces of the plurality of polymeric leaflets and optionally the polymeric matrix.

[0282] 9. The polymeric venous valve system of any one of paragraphs 2-8, wherein the one or more hydrophilic groups, and optionally the one or more hydrophilic polymers, as may be present, alter surface charge of the plurality of polymeric leaflets, and optionally the polymeric matrix, to render them neutral or electrically repulsive to one or more thrombotic proteins present in the venous environment.

[0283] 10. The polymeric venous valve system of paragraph 9, wherein the thrombotic proteins are selected from the group consisting of fibrinogen, phosphorylcholine, and combination thereof.

[0284] 11. The polymeric venous valve system of any one of paragraphs 2-10, wherein the one or more surfactant safe lipids are selected from the group consisting of glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0285] 12. The polymeric venous valve system of any one of paragraphs 2-11, wherein the one or more pharmaceutically acceptable surfactants are selected from the group consisting of polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof. 13. The polymeric venous valve system of any one of paragraphs 2-12, wherein the one or more fluorocarbon polymers are selected from the group consisting of polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), pluorinated ethylene propylene (FEP), poly vinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof.

[0286] 14. The polymeric venous valve system of any one of paragraphs 2-13, wherein the one or more perfluoroalkyl substances are selected from the group consisting of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

[0287] 15. The polymeric venous valve system of any one of paragraphs 13 or 14, wherein the one or more fluorocarbon polymers and the one or more perfluoroalkyl substances are present at concentrations of less than about 100 micromolar (pM) or less than about 10 wt.%, on the plurality of polymeric leaflets and optionally on the polymeric matrix.

[0288] 16. The polymeric venous valve system of any one of paragraphs 2-15, wherein the one or more carbon-based structures are selected from the group consisting of carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0289] 17. The polymeric venous valve system of any one of paragraphs 2-16, wherein the one or more buffering agents are selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer MOPPS buffer, Goodes buffer, and combinations thereof.

[0290] 18. The polymeric venous valve system of any one of paragraphs 2-17, wherein the one or more anticoagulant agents are selected from the group consisting of heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0291] 19. The polymeric venous valve system of any one of paragraphs 2-18, wherein the one or more inhibitor agents are selected from the group consisting of CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0292] 20. The polymeric venous valve system of any one of paragraphs 2-19, wherein the surface is at least about 1-99% planar based on the total surface area of the surface.

[0293] 21. The polymeric venous valve system of any one of paragraphs 2-19, wherein the surface is at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface.

[0294] 22. The polymeric venous valve system of any one of paragraphs 1-21, wherein the supportive frame is formed from a plurality of connected struts each connected to one or more other struts via a joint.

[0295] 23. The polymeric venous valve system of paragraph 22, wherein the plurality of connected struts each comprise anchors and / or wherein the plurality of connected struts and / or the one or more joints each comprise indentations and / or openings.

[0296] 24. The polymeric venous valve system of paragraph 22, wherein the plurality of connected struts each comprise one or more surfaces having surface features ranging from smooth and featureless to others having micro and / or macro asperities and the one or more surfaces are not exposed in order to prevent risk of thrombus formation.

[0297] 25. The polymeric venous valve system of any one of paragraphs 1-24, wherein the supportive frame further comprises a crown region in which the polymeric matrix is not located, optionally wherein the crown region comprises one or more anchors.

[0298] 26. The polymeric venous valve system of any one of paragraphs 1-25, wherein the supportive frame is in the form of an armature or scaffold-like construct which is expandable.

[0299] 27. The polymeric venous valve system of any one of paragraphs 1-26, wherein the supportive frame is made of a metal or metal alloy selected from the group consisting of spring steel, stainless steel, platinum, tantalum alloys, cobalt chromium, NiTi, NiTiCo, NiTiCr, NiTiCu, and NiTiNb.

[0300] 28. The polymeric venous valve system of any one of paragraphs 1-27, wherein the polymeric sleeve and / or the polymeric leaflets are made of a biocompatible, hemocompatible, and mechanically stable polymer.

[0301] 29. The polymeric venous valve system of any one of paragraphs 1-28, wherein the polymeric sleeve is formed of or comprise one or more polymers selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene-styrene) (SIBS), polymyrcene, polymenthide, and poly(s-decalactone), silicones, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes.

[0302] 30. The polymeric venous valve system of any one of paragraphs 1-29, wherein the polymeric sleeve further comprises one or more anti-leak flaps thereon.

[0303] 31. The polymeric venous valve system of any one of paragraphs 1-30, wherein the polymeric sleeve further comprises a gel paving material on one or more outer surfaces of the polymeric sleeve.

[0304] 32. The polymeric venous valve system of any one of paragraphs 1-31, wherein the polymeric sleeve has a thickness of about 0 to 500 pm. 33. The polymeric venous valve system of any one of paragraphs 1-32, wherein the polymeric leaflets are formed of or comprise one or more polymers selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene-styrene) (SIBS), polymyrcene, polymenthide, and poly(e-decalactone), silicones, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes.

[0305] 34. The polymeric venous valve system of any one of paragraphs 1-33, wherein each of the leaflets in the plurality of leaflets comprises variable thickness having a center line of symmetry, where in a given cross-section each of the leaflets has at least two or more thicknesses.

[0306] 35. The polymeric venous valve system of paragraph 34, wherein each of the leaflets has a minimum thickness in a range from about 50 to 200 pm.

[0307] 36. The polymeric venous valve system of paragraph 34, wherein each of the leaflets has a maximum thickness in a range from about 200 to 600 pm.

[0308] 37. The polymeric venous valve system of any one of paragraphs 1-36, wherein the polymeric sleeve is formed from the same polymeric material as the polymeric leaflets, or from a different polymeric material than the polymeric leaflets.

[0309] 38. The polymeric venous valve system of any one of paragraphs 1-37, wherein the supportive frame and / or supportive sleeve comprise radiopaque materials.

[0310] 39. A method of making a polymeric venous valve system, the method comprising the steps of:

[0311] (i) placing a supportive frame inside a cavity of a mold in a position suitable to facilitate flow of a polymer around the supportive frame, wherein the mold comprises a top core, a bottom core, and one or more encasement components which encase the top and bottom cores, wherein the top core and bottom core define a shape to form polymeric leaflets in a suitable orientation wherein the polymeric leaflets are formed optionally in a semi-open position having a zero residual stress conformation, wherein the polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; and

[0312] (ii) introducing at least one polymer into the mold;

[0313] (iii) molding or casting the polymeric leaflets and a polymeric sleeve around the supportive frame to form a polymeric venous valve system, wherein the polymeric leaflets and the polymeric sleeve are a continuum and each of the polymeric leaflets are connected to the polymeric sleeve at an attachment end; and

[0314] (iv) removing the polymeric venous valve system formed from the mold.

[0315] 40. The method of paragraph 39, wherein the polymeric venous valve system comprises at least one of the following features:

[0316] (a’) the at least one polymer comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;

[0317] (b’) the at least one polymer is mixed, admixed, or blended with one or more hydrophilic polymers which reduces protein deposition on the polymeric venous valve system in the venous environment during or prior to step (ii);

[0318] (c’) the at least one polymer is mixed or blended with one or more surfactant safe lipids during or prior to step (ii);

[0319] (d’) the at least one polymer comprises one or more pharmaceutically acceptable surfactants during step (ii);

[0320] (e’) the at least one polymer is mixed or blended with one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) during or prior to step (ii);

[0321] (f’) the at least one polymer is mixed or blended with one or more carbon-based structures during or prior to step (ii); (g’) the at least one polymer is mixed or blended with one or more buffering agents during or prior to step (ii);

[0322] (h’) the at least one polymer is mixed or blended with one or more anticoagulant agents during or prior to step (ii);

[0323] (i’ ) the at least one polymer has a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons; j’) the at least one polymer is uncrosslinked polymer(s) or the at least one polymer is crosslinked during step (iii) to have a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;

[0324] (k’) the plurality of polymeric leaflets formed in step (iii) each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar;

[0325] (1’) the surfaces of the polymeric leaflets and optionally the polymeric sleeve formed in step (iii) are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and optionally the polymeric sleeve contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size.

[0326] 41. The method of any one of paragraphs 39-40, wherein the method further comprises a step of coating the polymeric leaflets, and optionally the polymeric sleeve, following step (iii) or (iv), with at least one of the following: one or more hydrophilic polymers; one or more surfactant safe lipids; one or more pharmaceutically acceptable surfactants; one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS); one or more carbon-based structures; one or more buffering agents; one or more anticoagulant agents; or one or more inhibitor agents. 42. The method of any one of paragraphs 40-41 , wherein the one or more hydrophilic groups are functionalized on the one or more surfaces of the polymeric leaflets and / or the polymeric sleeve and at least partially exposed on the one or more surfaces following step (iii).

[0327] 43. The method of any one of paragraphs 40-42, wherein the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

[0328] 44. The method of any one of paragraphs 39-43, wherein prior to step (ii) the at least one polymer was modified to include the one or more hydrophilic groups optionally by exposure to a plasma with one or more gases selected from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof.

[0329] 45. The method of any one of paragraphs 40-44, wherein the one or more hydrophilic polymers comprise hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

[0330] 46. The method of any one of paragraphs 40-45, wherein the one or more hydrophilic polymers are mixed, admixed, or blended within the at least one polymer during step (ii).

[0331] 47. The method of paragraph 46, wherein the one or more hydrophilic polymers bloom on the one or more surfaces of the polymeric leaflets and / or the polymeric sleeve during or following step (iii).

[0332] 48. The method of any one of paragraphs 40-47, wherein the one or more hydrophilic groups and / or the one or more hydrophilic polymers, as may be present, alter surface charge of the polymeric leaflets and / or the polymeric sleeve formed to render them neutral or electrically repulsive to one or more thrombotic proteins present in the venous environment. 49. The method of any one of paragraphs 40-48, wherein the one or more surfactant safe lipids are selected from the group consisting of glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

[0333] 50. The method of any one of paragraphs 40-48, wherein the one or more pharmaceutically acceptable surfactants are selected from the group consisting of polysorbates ((Tween series): Examples include polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof.

[0334] 51. The method of any one of paragraphs 40-50, wherein the one or more fluorocarbon polymers are selected from the group consisting of polytetrafluoroethylene (PTFE), perfluoroalkoxy (PF A), pluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof.

[0335] 52. The method of any one of paragraphs 40-51 , wherein the one or more perfluoroalkyl substances are selected from the group consisting of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

[0336] 53. The method of any one of paragraphs 51 or 52, wherein the one or more fluorocarbon polymers and the one or more perfluoroalkyl substances are present at concentrations of less than about of less than about 100 micromolar (pM) or less than about 10 wt.%, on the polymeric leaflets and / or the polymeric sleeve.

[0337] 54. The method of any one of paragraphs 40-53, wherein the one or more carbon-based structures are selected from the group consisting of carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

[0338] 55. The method of any one of paragraphs 40-54, wherein the one or more buffering agents are selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

[0339] 56. The method of any one of paragraphs 40-55, wherein the one or more anticoagulant agents are selected from the group consisting of heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

[0340] 57. The method of any one of paragraphs 40-56, wherein the one or more inhibitor agents are selected from the group consisting of CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

[0341] 58. The method of any one of paragraphs 40-57, wherein the surface is at least about 1-99% planar based on the total surface area of the surface.

[0342] 59. The method of any one of paragraphs 40-57, wherein the surface is at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface.

[0343] 60. The method of any one of paragraphs 39-59, wherein the one or more encasement components further comprise one or more arched segments or pins and / or one or more sealing elements; wherein the one or more arched segments or pins hold the supportive frame. 61 . The method of any one of paragraphs 39-60, wherein the method includes a mold cleaning step prior to step (i).

[0344] 62. The method of any one of paragraphs 39-61 , wherein the mold is heated during steps (ii) and / or (iii) to a temperature ranging from about 100 °C to 350 C.

[0345] 63. The method of any one of paragraphs 39-62, wherein step (ii) comprises applying pressure in a range from about 1 to 10 tons by way of a plunger to spread the at least one polymer through the mold.

[0346] 64. The method of any one of paragraphs 39-63, wherein step (iii) is performed by a compression molding process, transfer molding process, or injection molding process.

[0347] 65. The method of any one of paragraphs 39-63, wherein step (iii) is performed by dip coating process.

[0348] 66. The method of any one of paragraphs 39-65, further comprising, prior to step (i), applying one or more release agents to the surfaces of the mold to facilitate removal of the polymeric venous valve system after formation.

[0349] 67. The method of any one of paragraphs 39-66, wherein the supportive frame is formed from a plurality of connected struts each connected to one or more other struts via a joint.

[0350] 68. The method of any one of paragraphs 39-67, wherein the supportive frame is in the form of an armature or scaffold-like construct which is expandable.

[0351] 69. The method of any one of paragraphs 39-68, wherein the supportive frame is made of a metal or metal alloy selected from the group consisting of spring steel, stainless steel, platinum, tantalum alloys, cobalt chromium, NiTi, NiTiCo, NiTiCr, NiTiCu, and NiTiNb.

[0352] 70. The method of any one of paragraphs 39-69, wherein the at least one polymer is selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene- styrene) (SIBS), polymyrcene, polymenthide, and poly(8-decalactone), silicones, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane -urea elastomers, polyurethanes, and combinations thereof.

[0353] 71. The method of any one of paragraphs 39-70, wherein the polymeric sleeve further comprises one or more anti-leak flaps thereon.

[0354] 72. The method of any one of paragraphs 39-71 , wherein the method further comprises a step of coating the polymeric sleeve, after step (iv), with a gel paving material onto one or more outer surfaces of the polymeric sleeve.

[0355] 73. The method of any one of paragraphs 39-72, wherein each of the polymeric leaflets comprises variable thickness across cross-sections of each of the polymeric leaflets running from an attachment end to an operative end thereof.

[0356] 74. The method paragraph 73, wherein each of the polymeric leaflets has a minimum thickness in a range from about 50 to 200 pm.

[0357] 75. The method of paragraph 73, wherein each of the polymeric leaflets has a maximum thickness in a range from about 200 to 600 pm.

[0358] 76. The method of any one of paragraphs 39-75, wherein step (i) comprises placing the supportive frame inside the cavity of the mold while inducing the supportive frame to comprise a degree of oversizing during molding or casting step (iii).

[0359] 77. A polymeric venous valve system formed according to the method of any one of paragraphs 39-76. 78. A method of replacing a defective venous valve in a subject in need thereof, the method comprising the steps of:

[0360] (1) inserting a polymeric venous valve system of any one of paragraphs 1-38 in a crimped, collapsed, or compacted state into the subject in need thereof;

[0361] (2) delivering the polymeric venous valve system to the defective venous valve in the subject in need thereof; and

[0362] (3) implanting the polymeric venous valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state, which localizes or fixes the polymeric venous valve system at the defective venous valve and replaces the function of the defective venous valve.

[0363] 79. The method of paragraph 78, wherein the defective venous valve is selected from venules, veins, vena cava, pulmonary vein, coronary sinus, and tricuspid valve.

[0364] 80. The method of any one of paragraphs 78-79, wherein the polymeric venous valve system in the crimped, collapsed, or compacted state is inserted during step (i) via a delivery catheter.

[0365] 81. The method of any one of paragraphs 78-80, wherein the polymeric venous valve system is crimped, collapsed, or compacted state prior to step (i).

[0366] 82. The method of any one of paragraphs 78-81, wherein expanding of the crimped, collapsed, or compacted polymeric venous valve system in step (3) is performed by balloon expansion or heat expansion.

[0367] 83. A method of treating a subject in need thereof, the method comprising the steps of:

[0368] (1 ’) inserting a polymeric valve system of any one of paragraphs 1-38 in a crimped, collapsed, or compacted state into the subject in need thereof;

[0369] (2’) delivering the polymeric valve system to a vein in the subject in need thereof; and

[0370] (3’) implanting the polymeric valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state, which localizes or fixes the polymeric venous valve system at the vein. 84. A transcatheter tricuspid valve replacement device comprising: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame comprises a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve; wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

[0371] 85. The transcatheter tricuspid valve replacement device of paragraph 84, wherein the supportive frame is a nitinol stent comprising a distal end and a proximal end adapted for deployment within a tricuspid valve annulus.

[0372] 86. The transcatheter tricuspid valve replacement device of any one of paragraphs 84-85, wherein the plurality of polymeric leaflets each have a variable thickness.

[0373] 87. The transcatheter tricuspid valve replacement device of paragraph 86, wherein the variable thickness of the polymeric leaflets minimizes flexural stresses of the polymeric leaflets during their opening and closing providing enhanced durability.

[0374] 88. The transcatheter tricuspid valve replacement device of any one of paragraphs 86-87, wherein the variable thickness of the polymeric leaflets provides improved hemodynamic performance resulting in increased blood flow and reduced regurgitation, as compared to hemodynamic performance of a native tricuspid valve which is replaced with the transcatheter tricuspid valve replacement device.

[0375] 89. The transcatheter tricuspid valve replacement device of any one of paragraphs 84-88, where the transcatheter tricuspid valve replacement device restores Coanda flow effect which helps to prevent the polymeric leaflets from prolapsing into an atrium.

[0376] 90. A method of replacing a tricuspid valve in a subject in need thereof, comprising: (1”) deploying a transcatheter tricuspid valve replacement device of any one of paragraphs 84-89, wherein the supportive frame has a suitable shape and dimensions to fit within the tricuspid valve annulus of the subject in need thereof; and

[0377] (2”) allowing the polymeric leaflets to function as primary valve leaflets for controlling blood flow through the tricuspid valve of the subject in need thereof.

[0378] 91. The method of paragraph 90, wherein the step of deploying of the transcatheter tricuspid valve replacement device is performed via a minimally invasive technique, such as via a percutaneous approach.

Claims

We claim:

1. A polymeric venous valve system comprising: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame comprises a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve; wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

2. The polymeric venous valve system of claim 1, wherein the polymeric venous valve system comprises at least one of the following features:(a) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;(b) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprises one or more hydrophilic polymers therein and / or coated thereon, wherein the one or more hydrophilic polymers reduce protein deposition on the polymeric venous valve system in the venous environment;(c) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more surfactant safe lipids therein and / or coated thereon;(d) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more pharmaceutically acceptable surfactants therein and / or coated thereon;(e) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) therein and / or coated thereon;(f) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more carbon-based structures therein and / or coated thereon;(g) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more buffering agents therein and / or coated thereon;(h) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more anticoagulant agents therein and / or coated thereon;(i) the plurality of polymeric leaflets, and optionally the polymeric matrix, each independently comprise one or more inhibitor agents coated thereon;(j) the plurality of polymeric leaflets, and optionally the polymeric matrix, have an elastic modulus in a range of between about 1 -20 MPa;(k) the plurality of polymeric leaflets, and optionally the polymeric matrix, have a Young’s modulus in a range of between about 1-20 MPa;(l) the plurality of polymeric leaflets, and optionally the polymeric matrix, are free of crystallinity or are substantially free of crystallinity;(m) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of polymer(s) having a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons;(n) the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of uncrosslinked polymer(s) or the plurality of polymeric leaflets, and optionally the polymeric matrix, are formed of crosslinked polymer(s) having a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;(o) the plurality of polymeric leaflets each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar; and(p) the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and / or the polymeric matrix contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size.

3. The polymeric venous valve system of claim 2, wherein the one or more hydrophilic groups are functionalized on the one or more surfaces of the plurality of polymeric leaflets and / or the polymeric matrix and at least partially exposed on the one or more surfaces.

4. The polymeric venous valve system of claim 3, wherein the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

5. The polymeric venous valve system of any one of claim 2, wherein the plurality of polymeric leaflets and / or the polymeric matrix are each independently formed of at least one polymer which was modified to include the one or more hydrophilic groups optionally by exposure to a plasma with one or more gases selected from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof.

6. The polymeric venous valve system of any one of claim 2, wherein the one or more hydrophilic polymers comprise hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

7. The polymeric venous valve system of claim 2, wherein the one or more hydrophilic polymers are mixed, admixed, or blended within the plurality of polymeric leaflets and / or the polymeric matrix.

8. The polymeric venous valve system of claim 7, wherein the one or more hydrophilic polymers are bloomed on the one or more surfaces of the plurality of polymeric leaflets and optionally the polymeric matrix.

9. The polymeric venous valve system of claim 2, wherein the one or more hydrophilic groups, and optionally the one or more hydrophilic polymers, as may be present, alter surface charge of the plurality of polymeric leaflets, and optionally the polymeric matrix, to render themneutral or electrically repulsive to one or more thrombotic proteins present in the venous environment.

10. The polymeric venous valve system of claim 9, wherein the thrombotic proteins are selected from the group consisting of fibrinogen, phosphorylcholine, and combination thereof.

11. The polymeric venous valve system of claim 2, wherein the one or more surfactant safe lipids are selected from the group consisting of glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

12. The polymeric venous valve system of claim 2, wherein the one or more pharmaceutically acceptable surfactants are selected from the group consisting of polysorbates ((Tween series, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 8, and Brij 98), Triton X surfactants (such as Triton X- 100 and Triton X-l 14), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60)), labrasol, Myrj surfactants (such as Myrj 52 and Myrj 59), and combinations thereof.

13. The polymeric venous valve system of claim 2, wherein the one or more fluorocarbon polymers are selected from the group consisting of polytetrafluoroethylene (PTFE), perfluoroalkoxy (PF A), pluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and optionally wherein the one or more fluorocarbon polymers are present at concentrations of less than about 100 micromolar (pM) or less than about 10 wt.%, on the plurality of polymeric leaflets and optionally on the polymeric matrix.

14. The polymeric venous valve system of claim 2, wherein the one or more perfluoroalkyl substances are selected from the group consisting of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

15. The polymeric venous valve system of claim 14, wherein the one or more perfluoroalkyl substances are present at concentrations of less than about 100 micromolar ( M) or less than about 10 wt.%, on the plurality of polymeric leaflets and optionally on the polymeric matrix.

16. The polymeric venous valve system of claim 2, wherein the one or more carbon-based structures are selected from the group consisting of carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

17. The polymeric venous valve system of claim 2, wherein the one or more buffering agents are selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer MOPPS buffer, Goodes buffer, and combinations thereof.

18. The polymeric venous valve system of claim 2, wherein the one or more anticoagulant agents are selected from the group consisting of heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

19. The polymeric venous valve system of claim 2, wherein the one or more inhibitor agents are selected from the group consisting of CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

20. The polymeric venous valve system of claim 2, wherein the surface is at least about 1- 99% planar based on the total surface area of the surface.

21. The polymeric venous valve system of claim 2-, wherein the surface is at least about 1 %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface.

22. The polymeric venous valve system of claim 1, wherein the supportive frame is formed from a plurality of connected struts each connected to one or more other struts via a joint.

23. The polymeric venous valve system of claim 22, wherein the plurality of connected struts each comprise anchors and / or wherein the plurality of connected struts and / or the one or more joints each comprise indentations and / or openings.

24. The polymeric venous valve system of claim 22, wherein the plurality of connected struts each comprise one or more surfaces having surface features ranging from smooth and featureless to others having micro and / or macro asperities and the one or more surfaces are not exposed in order to prevent risk of thrombus formation.

25. The polymeric venous valve system of claim 1, wherein the supportive frame further comprises a crown region in which the polymeric matrix is not located, optionally wherein the crown region comprises one or more anchors.

26. The polymeric venous valve system of claim 1, wherein the supportive frame is in the form of an armature or scaffold-like construct which is expandable.

27. The polymeric venous valve system of claim 1, wherein the supportive frame is made of a metal or metal alloy selected from the group consisting of spring steel, stainless steel, platinum, tantalum alloys, cobalt chromium, NiTi, NiTiCo, NiTiCr, NiTiCu, and NiTiNb.

28. The polymeric venous valve system of claim 1, wherein the polymeric sleeve and / or the polymeric leaflets are made of a biocompatible, hemocompatible, and mechanically stable polymer.

29. The polymeric venous valve system of claim 1, wherein the polymeric sleeve is formed of or comprise one or more polymers selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene- isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene-styrene) (SIBS), polymyrcene,polymenthide, and poly(e-decalactone), silicones, polyolefins, polydiene elastomers, poly( vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes.

30. The polymeric venous valve system of claim 1, wherein the polymeric sleeve further comprises one or more anti-leak flaps thereon.

31. The polymeric venous valve system of claim 1 , wherein the polymeric sleeve further comprises a gel paving material on one or more outer surfaces of the polymeric sleeve.

32. The polymeric venous valve system of claim 1, wherein the polymeric sleeve has a thickness of about 0 to 500 pm.

33. The polymeric venous valve system of claim 1, wherein the polymeric leaflets are formed of or comprise one or more polymers selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene-styrene) (SIBS), polymyrcene, polymenthide, and poly(s-decalactone), silicones, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, and polyurethanes.

34. The polymeric venous valve system of claim 1, wherein each of the leaflets in the plurality of leaflets comprises variable thickness having a center line of symmetry, where in a given cross-section each of the leaflets has at least two or more thicknesses.

35. The polymeric venous valve system of claim 34, wherein each of the leaflets has a minimum thickness in a range from about 50 to 200 pm.

36. The polymeric venous valve system of claim 34, wherein each of the leaflets has a maximum thickness in a range from about 200 to 600 pm.

37. The polymeric venous valve system of claim 1, wherein the polymeric sleeve is formed from the same polymeric material as the polymeric leaflets, or from a different polymeric material than the polymeric leaflets.

38. The polymeric venous valve system of claim 1, wherein the supportive frame and / or supportive sleeve comprise radiopaque materials.

39. A method of making a polymeric venous valve system, the method comprising the steps of:(i) placing a supportive frame inside a cavity of a mold in a position suitable to facilitate flow of a polymer around the supportive frame, wherein the mold comprises a top core, a bottom core, and one or more encasement components which encase the top and bottom cores, wherein the top core and bottom core define a shape to form polymeric leaflets in a suitable orientation wherein the polymeric leaflets are formed optionally in a semi-open position having a zero residual stress conformation, wherein the polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; and(ii) introducing at least one polymer into the mold;(iii) molding or casting the polymeric leaflets and a polymeric sleeve around the supportive frame to form a polymeric venous valve system, wherein the polymeric leaflets and the polymeric sleeve are a continuum and each of the polymeric leaflets are connected to the polymeric sleeve at an attachment end; and(iv) removing the polymeric venous valve system formed from the mold.

40. The method of claim 39, wherein the polymeric venous valve system comprises at least one of the following features:(a’) the at least one polymer comprises one or more hydrophilic groups, wherein the one or more hydrophilic groups reduce protein deposition on the polymeric venous valve system in a venous environment;(b’) the at least one polymer is mixed, admixed, or blended with one or more hydrophilic polymers which reduces protein deposition on the polymeric venous valve system in the venous environment during or prior to step (ii);(c’) the at least one polymer is mixed or blended with one or more surfactant safe lipids during or prior to step (ii);(d’) the at least one polymer comprises one or more pharmaceutically acceptable surfactants during step (ii);(e’) the at least one polymer is mixed or blended with one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS) during or prior to step (ii);(f ) the at least one polymer is mixed or blended with one or more carbon-based structures during or prior to step (ii);(g’) the at least one polymer is mixed or blended with one or more buffering agents during or prior to step (ii);(h’) the at least one polymer is mixed or blended with one or more anticoagulant agents during or prior to step (ii);(i’) the at least one polymer has a weight average molecular weight in a range of between about 10,000 to about 50,000 Daltons;(j’) the at least one polymer is uncrosslinked polymer(s) or the at least one polymer is crosslinked during step (iii) to have a degree of crosslinking of less than about 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%;(k’) the plurality of polymeric leaflets formed in step (iii) each comprise a surface defined by three curves: a free-edge curve, a belly curve, and an attachment curve; and at least a portion of the surface is planar;(1’) the surfaces of the polymeric leaflets and optionally the polymeric sleeve formed in step (iii) are free or substantially free of surface asperities (i.e., smooth) or the surfaces of the plurality of polymeric leaflets and optionally the polymeric sleeve contain asperities which are no greater than about 200, 175, 150, 125, 100, 75, 50, or 25 nm in size.

41. The method of claim 39, wherein the method further comprises a step of coating the polymeric leaflets, and optionally the polymeric sleeve, following step (iii) or (iv), with at least one of the following: one or more hydrophilic polymers;one or more surfactant safe lipids; one or more pharmaceutically acceptable surfactants; one or more fluorocarbon polymers and / or perfluoroalkyl substances (PFAS); one or more carbon-based structures; one or more buffering agents; one or more anticoagulant agents; or one or more inhibitor agents.

42. The method of claims 40, wherein the one or more hydrophilic groups are functionalized on the one or more surfaces of the polymeric leaflets and / or the polymeric sleeve and at least partially exposed on the one or more surfaces following step (iii).

43. The method of claim 40, wherein the one or more hydrophilic groups are selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

44. The method of claim 39, wherein prior to step (ii) the at least one polymer was modified to include the one or more hydrophilic groups optionally by exposure to a plasma with one or more gases selected from the group consisting of ammonium, oxygen, peroxide, a nitrogen / oxygen mixture, and combinations thereof.

45. The method of claim 40, wherein the one or more hydrophilic polymers comprise hydrophilic moieties selected from the group consisting of hydroxyl groups, carbonyl groups, carboxyl groups, amino groups, sulfhydryl groups, sulfates (ROSO3-), sulfonates (RSO3-), carboxylates (RCOO-), phosphates (RPO4-), and combinations thereof.

46. The method of claim 40, wherein the one or more hydrophilic polymers are mixed, admixed, or blended within the at least one polymer during step (ii).

47. The method of claim 46, wherein the one or more hydrophilic polymers bloom on the one or more surfaces of the polymeric leaflets and / or the polymeric sleeve during or following step (iii).

48. The method of claim 40, wherein the one or more hydrophilic groups and / or the one or more hydrophilic polymers, as may be present, alter surface charge of the polymeric leaflets and / or the polymeric sleeve formed to render them neutral or electrically repulsive to one or more thrombotic proteins present in the venous environment.

49. The method of claim 40, wherein the one or more surfactant safe lipids are selected from the group consisting of glycerides, phospholipids, squalane, squalene, ceramides, fatty alcohols, pegylated lipids, and combinations thereof.

50. The method of claim 40, wherein the one or more pharmaceutically acceptable surfactants are selected from the group consisting of polysorbates ((Tween series): Examples include polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB), sodium deoxycholate, Brij surfactants (such as Brij 35, Brij 58, and Brij 98), Triton X surfactants (such as Triton X-100 and Triton X-114), Pluronic (Poloxamer) block copolymers with hydrophilic and hydrophobic segments, glyceryl monostearate, sorbitan esters (such as sorbitan monostearate (Span 60), labrasol, Myrj surfactants (such as Myrj 52 and Myij 59), and combinations thereof.

51. The method of claim 40, wherein the one or more fluorocarbon polymers are selected from the group consisting of polytetrafluoroethylene (PTFE), perfluoroalkoxy (PF A), pluorinated ethylene propylene (FEP), poly vinylidene fluoride (PVDF), ethylene tetrafluoroethylene (ETFE), and combinations thereof; and optionally wherein the one or more fluorocarbon polymers are present at concentrations of less than about 100 micromolar (pM) or less than about 10 wt.%, on the plurality of polymeric leaflets and optionally on the polymeric matrix.

52. The method of claims 40, wherein the one or more perfluoroalkyl substances are selected from the group consisting of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluoropentanoic acid (PFPeA), perfluoroundecanoic acid (PFUnA), perfluoromethylcyclohexane sulfonate (F-53B), and combinations thereof.

53. The method of claim 52, wherein the one or more perfluoroalkyl substances are present at concentrations of less than about of less than about 100 micromolar (pM) or less than about 10 wt.%, on the polymeric leaflets and / or the polymeric sleeve.

54. The method of claim 40, wherein the one or more carbon-based structures are selected from the group consisting of carbon nanotubes (CNTs), graphene, fullerenes, carbon quantum dots (CQDs), carbon nanodots, graphene oxide (GO), carbon black nanoparticles, activated carbon nanoparticles, and combinations thereof.

55. The method of claim 40, wherein the one or more buffering agents are selected from the group consisting of acetate buffer, phosphate buffer, citrate buffer, Tris buffer, histidine buffer, glycine buffer, borate buffer, citrated phosphate buffer, ammonium acetate buffer, carbonate buffer, HEPES buffer, MES buffer, TES buffer, BIS buffer, MOPPS buffer, Goodes buffer, and combinations thereof.

56. The method of claim 40, wherein the one or more anticoagulant agents are selected from the group consisting of heparin (such as low molecular weight heparin, heparin pentasaccharide), coumadin, dicumarol, Factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, dabigatran, etc.), direct thrombin inhibitors (such as argatroban, hirudin hirulog, lepruidin, bivalrudin, etc.), Factor-XII inhibitors, and combinations thereof.

57. The method of claim 40, wherein the one or more inhibitor agents are selected from the group consisting of CARMEDA, PEG (such as low molecular weight PEG), lubricious coatings (e.g., polyvinylpyrrolidone (PVP), polytetrafluoroethylene (PTFE), silicone), and combinations thereof.

58. The method of claim 40, wherein the surface is at least about 1-99% planar based on the total surface area of the surface.

59. The method of claim 40, wherein the surface is at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% planar based on the total surface area of the surface.

60. The method of claim 39, wherein the one or more encasement components further comprise one or more arched segments or pins and / or one or more sealing elements; wherein the one or more arched segments or pins hold the supportive frame.

61. The method of claim 39, wherein the method includes a mold cleaning step prior to step (i).

62. The method of claim 39, wherein the mold is heated during steps (ii) and / or (iii) to a temperature ranging from about 100 °C to 350 C.

63. The method of claim 39, wherein step (ii) comprises applying pressure in a range from about 1 to 10 tons by way of a plunger to spread the at least one polymer through the mold.

64. The method of claim 39, wherein step (iii) is performed by a compression molding process, transfer molding process, or injection molding process.

65. The method of claim 39, wherein step (iii) is performed by dip coating process.

66. The method of claim 39, further comprising, prior to step (i), applying one or more release agents to the surfaces of the mold to facilitate removal of the polymeric venous valve system after formation.

67. The method of claim 39, wherein the supportive frame is formed from a plurality of connected struts each connected to one or more other struts via a joint.

68. The method of claim 39, wherein the supportive frame is in the form of an armature or scaffold-like construct which is expandable.

69. The method of claim 39, wherein the supportive frame is made of a metal or metal alloy selected from the group consisting of spring steel, stainless steel, platinum, tantalum alloys, cobalt chromium, NiTi, NiTiCo, NiTiCr, NiTiCu, and NiTiNb.

70. The method of claim 39, wherein the at least one polymer is selected from the group consisting of thermoplastic polymers / elastomers, thermoset polymers, thermally crosslinkable polymers, elastomeric polymer biomaterials, polymers containing polysulfone(s), PTFE, crosslinked poly(styrene-isobutylenese-styrene) (xSIBS), poly(styrene-isobutylene-styrene) (SIBS), polymyrcene, polymenthide, and poly(e-decalactone), silicones, polyolefins, polydiene elastomers, poly(vinyl chloride), natural rubbers, heparinized polymers, hydrogels, polypeptides elastomers, polysiloxane-urea elastomers, polyurethanes, and combinations thereof.

71. The method of claim 39, wherein the polymeric sleeve further comprises one or more anti-leak flaps thereon.

72. The method of claim 39, wherein the method further comprises a step of coating the polymeric sleeve, after step (iv), with a gel paving material onto one or more outer surfaces of the polymeric sleeve.

73. The method of claim 39, wherein each of the polymeric leaflets comprises variable thickness across cross-sections of each of the polymeric leaflets running from an attachment end to an operative end thereof.

74. The method claim 73, wherein each of the polymeric leaflets has a minimum thickness in a range from about 50 to 200 pm.

75. The method of claim 73, wherein each of the polymeric leaflets has a maximum thickness in a range from about 200 to 600 pm.

76. The method of claim 39, wherein step (i) comprises placing the supportive frame inside the cavity of the mold while inducing the supportive frame to comprise a degree of oversizing during molding or casting step (iii).

77. A polymeric venous valve system formed according to the method of claim 39.

78. A method of replacing a defective venous valve in a subject in need thereof, the method comprising the steps of:(1) inserting a polymeric venous valve system of claim lin a crimped, collapsed, or compacted state into the subject in need thereof;(2) delivering the polymeric venous valve system to the defective venous valve in the subject in need thereof; and(3) implanting the polymeric venous valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state, which localizes or fixes the polymeric venous valve system at the defective venous valve and replaces the function of the defective venous valve.

79. The method of claim 78, wherein the defective venous valve is selected from venules, veins, vena cava, pulmonary vein, coronary sinus, and tricuspid valve.

80. The method of claim 78, wherein the polymeric venous valve system in the crimped, collapsed, or compacted state is inserted during step (i) via a delivery catheter.

81. The method of claim 78, wherein the polymeric venous valve system is crimped, collapsed, or compacted state prior to step (i).

82. The method of claim 78, wherein expanding of the crimped, collapsed, or compacted polymeric venous valve system in step (3) is performed by balloon expansion or heat expansion.

83. A method of treating a subject in need thereof, the method comprising the steps of:(1 ’) inserting a polymeric valve system of claim lin a crimped, collapsed, or compacted state into the subject in need thereof;(2’) delivering the polymeric valve system to a vein in the subject in need thereof; and(3’) implanting the polymeric valve system by expanding the crimped, collapsed, or compacted polymeric venous valve system into an expanded state, which localizes or fixes the polymeric venous valve system at the vein.

84. A transcatheter tricuspid valve replacement device comprising: a supportive frame and a plurality of polymeric leaflets; wherein the supportive frame comprises a plurality of openings, and wherein the supportive frame is embedded in a polymeric matrix in the form of a polymeric sleeve;wherein each of the plurality of polymeric leaflets are a continuum of the polymeric sleeve without sutures, and each of the plurality of polymeric leaflets are connected to the polymeric sleeve at an attachment end; wherein the plurality of polymeric leaflets are able to open and close at an operative end when subjected to flow in a low pressure environment, having a pressure ranging from about 0 mmHg to 50 mmHg, and a low shear environment, having a shear stress ranging from about 0.1 to 0.5 Pa; wherein when the plurality of leaflets are in the closed position, the operative ends of the leaflets abut each other.

85. The transcatheter tricuspid valve replacement device of claim 84, wherein the supportive frame is a nitinol stent comprising a distal end and a proximal end adapted for deployment within a tricuspid valve annulus.

86. The transcatheter tricuspid valve replacement device of claim 84, wherein the plurality of polymeric leaflets each have a variable thickness.

87. The transcatheter tricuspid valve replacement device of claim 86, wherein the variable thickness of the polymeric leaflets minimizes flexural stresses of the polymeric leaflets during their opening and closing providing enhanced durability.

88. The transcatheter tricuspid valve replacement device of claim 86, wherein the variable thickness of the polymeric leaflets provides improved hemodynamic performance resulting in increased blood flow and reduced regurgitation, as compared to hemodynamic performance of a native tricuspid valve which is replaced with the transcatheter tricuspid valve replacement device.

89. The transcatheter tricuspid valve replacement device of claim 84, where the transcatheter tricuspid valve replacement device restores Coanda flow effect which helps to prevent the polymeric leaflets from prolapsing into an atrium.

90. A method of replacing a tricuspid valve in a subject in need thereof, comprising:(1”) deploying a transcatheter tricuspid valve replacement device of claim 84, whereinthe supportive frame has a suitable shape and dimensions to fit within the tricuspid valve annulus of the subject in need thereof; and(2”) allowing the polymeric leaflets to function as primary valve leaflets for controlling blood flow through the tricuspid valve of the subject in need thereof.

91. The method of claim 90, wherein the step of deploying of the transcatheter tricuspid valve replacement device is performed via a minimally invasive technique, such as via a percutaneous approach.

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