Methods and systems for material modification

Abstract

Systems and methods for improving biocompatibility and mechanical properties of cardiac repair and regeneration devices are described. Laser techniques may be applied to material modify various components of the cardiac repair and regeneration device, including patterning on the frame, leaflet, and / or skirt material. The material modification may aid in prosthetic valve healing, tissue acceptance, and / or anchoring.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Patent Application No. 63 / 373,515, filed on August 25, 2022, the entire disclosure of which is incorporated by reference for all purposes. Technical Field

[0003] The present disclosure relates to methods and systems for producing materials, biomaterials, components, devices, implants and systems for cardiac repair and regeneration devices. More specifically, systems and methods for modifying cardiac repair devices by laser technology to promote mechanical properties and / or biocompatibility (such as endothelialization into materials and devices) to allow tissue regeneration and incorporation of native tissue. Background Art

[0004] Many materials / components currently used in cardiovascular prosthetic devices may have biocompatibility issues. These materials can activate immune responses by forming an avascular fibrous capsule that can separate the implantable device from the bloodstream with a wall and may create issues with long-term implant function.

[0005] One way to prevent encapsulation or the accompanying immune response is to promote endothelial cell growth. Stimulating endothelialization on blood-contacting surfaces is considered a key step in establishing long-term biocompatibility of cardiovascular devices. Biological tissues currently used in medical devices, such as animal pericardium (e.g., bovine, porcine) and implantable bioprostheses, such as bioprosthetic heart valves and vascular grafts, are primarily composed of cross-linked collagen. One drawback of cross-linked biological tissues used in bioprostheses is that the cross-linking effect promotes calcification or tissue overgrowth and pannus formation. Therefore, there is a need for a new synthetic or natural material that can promote re-endothelialization. Summary of the invention

[0006] Methods and systems for improving the biocompatibility and / or mechanical properties of cardiac repair and regeneration devices are described.

[0007] In some embodiments, a method for improving the biocompatibility of a structure used in a prosthesis comprises applying a laser process to at least one surface of the structure to produce at least one pattern on the at least one surface; wherein the laser process comprises at least one laser source; the laser process is selected from the group consisting of: direct laser writing, interference lithography, and any combination thereof; and the structure is at least one component of a device selected from the group consisting of: a prosthetic heart valve, a stent, and a heart patch.

[0008] In some embodiments, the component is selected from the group consisting of: a frame, a stent, a skirt, an outer skirt, an inner skirt, a suture, a leaflet, and valve tissue.

[0009] In some embodiments, the surface comprises a material selected from the group consisting of: metals, metal alloys, stainless steel, nitinol, titanium, Co-Cr alloys, polymers, polymethyl methacrylate, polyetherketone, polyimide, polyamide, polyethylene, polytetrafluoroethylene, nylon, polydimethylsiloxane, silicone, polyethylene terephthalate, polybutylene terephthalate, polyesters, biopolymers, block copolymers of polycarbonate, poly(sulfone of bisphenol-A) (PSU)-PBT copolymers, collagen, acrylate collagen, chitosan, and pericardial tissue.

[0010] In some embodiments, the at least one laser source is an ultrashort pulse laser.

[0011] In some embodiments, the ultrashort pulse laser has a pulse width of 3 picoseconds to 50 femtoseconds.

[0012] In some embodiments, the emission wavelength of the at least one laser source is selected from the group consisting of infrared wavelengths of 700nm to 1mm, near infrared wavelengths of 800nm ​​to 2500nm, visible light wavelengths of 380nm to 750nm, and ultraviolet wavelengths of 100nm to 400nm.

[0013] In some embodiments, the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm, and 193 nm.

[0014] In some embodiments, the direct laser writing is performed using a direct laser writing system comprising at least one laser beam, at least one substrate, and at least one galvanometer.

[0015] In some embodiments, the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce the plurality of patterns; or the at least one laser beam is fixed and the at least one substrate moves to produce the plurality of patterns; or the at least one substrate and the at least one laser beam move simultaneously to produce the plurality of patterns.

[0016] In some embodiments, the direct laser writing system comprises focusing optics selected from the group consisting of a microscope objective and an f-theta lens.

[0017] In some embodiments, the at least one pattern improves re-endothelialization and tissue regeneration of the structure.

[0018] In some embodiments, the laser process changes at least one property of the structure selected from the group consisting of: surface topography, thickness, and size.

[0019] In some embodiments, the at least one surface is flat, curved, uniform, or non-uniform.

[0020] In some embodiments, the at least one pattern is periodic or non-periodic.

[0021] In some embodiments, at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

[0022] In some embodiments, the laser process is part of a subtractive process or an additive process.

[0023] In some embodiments, the laser process is a laser ablation process, wherein the at least one pattern changes the thickness of the at least one surface.

[0024] In some embodiments, the laser ablation process profiles the at least one surface and creates different thicknesses on the at least one surface.

[0025] In some embodiments, the at least one pattern comprises a hierarchical structure or is multi-dimensional.

[0026] In some implementations, the at least one pattern comprises a pattern selected from the group consisting of lines, straight lines, curves, grooves, pillars, holes, ridges, waves, depressions, squares, and any combination thereof.

[0027] In some embodiments, the at least one pattern has at least one shape selected from the group consisting of circle, oval, oblong, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon, and any combination thereof.

[0028] In some implementations, the at least one pattern comprises parallel rows.

[0029] In some embodiments, at least one chemical agent is applied to the at least one surface prior to applying the laser process, wherein the laser process produces a surface coating of the at least one surface.

[0030] In some embodiments, the surface coating alters the contact angle of the at least one surface.

[0031] In some embodiments, a method for modifying a biomaterial for use in a prosthesis comprises adding a photoactive agent to a protein material; and applying a laser process comprising at least one laser source to the protein material; wherein the at least one laser source locally cross-links the photoactive agent to the protein material and changes the chemical structure of the protein material; and the protein material is at least one component of a system or device selected from the group consisting of: a prosthetic heart valve, a stent, and a cardiac patch.

[0032] In some embodiments, the photoactive agent is selected from the group consisting of: aryl azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoic acid (e.g., 2559 photoinitiator, CibaGeigy), methyl benzoylformate, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, 6-(4,4'-azidopentanamido)hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SDA, sulfo-NHS-LC-bisaziridine), triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipid, porphyrin and dihydrochlorin.

[0033] In some embodiments, the photoactive agent is added to the protein material by soaking the protein material in a solution comprising the photoactive agent or by surface coating the protein material with a solution comprising the photoactive agent.

[0034] In some embodiments, the photoactive agent is riboflavin and the protein material comprises collagen.

[0035] In some embodiments, the at least one laser source is an ultrashort pulse laser.

[0036] In some embodiments, the at least one laser source has an emission wavelength of 100 nm to 400 nm.

[0037] In some embodiments, the cross-linking alters at least one mechanical property of the biomaterial selected from the group consisting of ultimate tensile strength, fatigue strength, and Young's modulus.

[0038] In some embodiments, the laser process generates a gradient of cross-links in the protein material by controlling the at least one laser source.

[0039] In some embodiments, a prosthetic heart valve comprises an annular frame that is radially collapsible to a collapsed configuration and radially expandable to an expanded configuration. The frame has an inflow end and an outflow end, and defines a lumen along a longitudinal axis of the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration. The prosthetic heart valve comprises a leaflet structure that is positioned within the frame and fixed to the frame. The prosthetic heart valve comprises a skirt that comprises an inner skirt and an outer skirt, the inner skirt being positioned on the inner side of the frame and the outer skirt being positioned on the outer side of the frame. The inner skirt and the outer skirt are attached to at least a portion of the frame by a plurality of sutures. On the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back toward the outflow end of the frame at a fold line to form a cuff, and an edge portion of the outer skirt is fixed to the outer skirt downstream of the fold line so that the cuff forms an inflow end of a laminated sealing member. At least one surface of: the frame, the leaflets, the skirt, and the sutures is modified by a laser process comprising at least one laser source; and the laser process improves re-endothelialization and tissue regeneration of the prosthetic heart valve.

[0040] In some embodiments, the laser process is selected from the group consisting of direct laser writing, interference lithography, and any combination thereof.

[0041] In some embodiments, the at least one laser source is an ultrashort pulse laser.

[0042] In some embodiments, the ultrashort pulse laser has a pulse width of 1 millisecond to 1 femtosecond.

[0043] In some embodiments, the emission wavelength of the at least one laser source is selected from the group consisting of infrared wavelengths of 700nm to 1mm, near infrared wavelengths of 800nm ​​to 2500nm, visible light wavelengths of 380nm to 750nm, and ultraviolet wavelengths of 100nm to 400nm.

[0044] In some embodiments, the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm, and 193 nm.

[0045] In some embodiments, the direct laser writing is performed using a direct laser writing system comprising at least one laser beam, at least one substrate, and at least one galvanometer.

[0046] In some embodiments, the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce the plurality of patterns; or the at least one laser beam is fixed and the at least one substrate moves to produce the plurality of patterns; or the at least one substrate and the at least one laser beam move simultaneously to produce the plurality of patterns.

[0047] In some embodiments, the direct laser writing system comprises focusing optics selected from the group consisting of a microscope objective and an f-theta lens.

[0048] In some embodiments, the at least one surface is flat, curved, uniform, or non-uniform.

[0049] In some embodiments, the at least one surface comprises at least one pattern, the at least one pattern being produced by the laser process.

[0050] In some embodiments, the at least one pattern is periodic or non-periodic.

[0051] In some embodiments, at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

[0052] In some embodiments, the at least one pattern comprises a hierarchical structure or is multi-dimensional.

[0053] In some embodiments, the at least one pattern is selected from the group consisting of lines, straight lines, curves, grooves, pillars, holes, ridges, waves, depressions, squares, and any combination thereof.

[0054] In some embodiments, at least one pattern has at least one shape selected from the group consisting of circle, oval, oblong, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon, and any combination thereof.

[0055] In some implementations, the at least one pattern comprises parallel rows.

[0056] In some embodiments, the laser process is part of a subtractive process or an additive process.

[0057] In some embodiments, the laser process is a laser ablation process, wherein the laser ablation process changes the thickness of the at least one surface.

[0058] In some embodiments, the laser ablation process profiles the at least one surface and creates different thicknesses on the at least one surface.

[0059] In some embodiments, the laser process produces a surface coating on the at least one surface via at least one chemical agent applied to the at least one surface.

[0060] In some embodiments, the surface coating alters the contact angle of the at least one surface.

[0061] In some embodiments, the leaflet comprises pericardial tissue, and the laser process produces a consistent thickness throughout the leaflet.

[0062] In some embodiments, the laser process creates a pattern on the at least one surface of the frame, and the pattern allows for easy tissue ingrowth and prevents paravalvular leakage.

[0063] In some embodiments, the laser process modifies the surface energy and changes the contact angle of the at least one surface of the skirt or the seam.

[0064] In some embodiments, a prosthetic heart valve comprises an annular frame that is radially collapsible to a collapsed configuration and radially expandable to an expanded configuration, the frame having an inflow end and an outflow end, and defining a lumen along a longitudinal axis of the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration. The prosthetic heart valve comprises a leaflet structure that is positioned within the frame and fixed to the frame. The prosthetic heart valve comprises a skirt that comprises an inner skirt and an outer skirt, the inner skirt being positioned on the inner side of the frame and the outer skirt being positioned on the outer side of the frame. The inner skirt and the outer skirt are attached to at least a portion of the frame by a plurality of sutures. On the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back toward the outflow end of the frame at a fold line to form a cuff, and an edge portion of the outer skirt is fixed to the outer skirt downstream of the fold line so that the cuff forms an inflow end of a laminated sealing member. A laser process comprising at least one laser source locally cross-links the leaflet with a photoactive agent. The leaflet comprises a protein material, and the laser process alters the chemical structure of the protein material.

[0065] In some embodiments, the photoactive agent is selected from the group consisting of: aryl azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoic acid (e.g., 2559 photoinitiator, Ciba-Geigy), methyl benzoylformate, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, sulfosuccinimidyl 6-(4,4'-azidopentanamido)hexanoate (sulfo-LC-SDA, sulfo-NHS-LC-bis(aziridine)) and triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipids, porphyrin and chlorine.

[0066] In some embodiments, the photoactive agent is added to the protein material by soaking the protein material in a solution comprising the photoactive agent or by surface coating the protein material with a solution comprising the photoactive agent.

[0067] In some embodiments, the photoactive agent is riboflavin and the protein material comprises collagen.

[0068] In some embodiments, the at least one laser source is an ultrashort pulse laser.

[0069] In some embodiments, the at least one laser source has an emission wavelength of 100 nm to 400 nm.

[0070] In some embodiments, the cross-linking alters at least one mechanical property of the material selected from the group consisting of ultimate tensile strength, fatigue strength, and Young's modulus.

[0071] In some embodiments, the laser process generates a gradient of cross-links in the protein material by controlling the at least one laser source.

[0072] Additional embodiments and features are set forth in part in the following description, and in part will become apparent to those skilled in the art upon examination of the specification, or may be learned by practicing the disclosed subject matter. A further understanding of the nature and advantages of the present disclosure may be achieved by reference to the remainder of the specification and drawings which form a part of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The description will be more fully understood with reference to the following drawings, which present exemplary embodiments of the invention and should not be construed as a complete description of the scope of the invention, wherein

[0074] Figure 1A-1B An exemplary modification process using laser technology is shown.

[0075] Figures 2A-2C A schematic diagram of a laser interferometer lithography system is shown.

[0076] Figure 3 A block diagram of direct laser writing is shown.

[0077] Figures 4A-4B Examples of various patterns produced by laser technology are shown.

[0078] Figure 5A-5B Examples of various patterns produced on soft materials by laser technology are shown.

[0079] Figure 6A-6B An example of a layered pattern produced using a combination of interference lithography and direct laser writing processes is shown.

[0080] Figures 7A-7C Examples of various patterns produced on hard materials by laser technology are shown.

[0081] Figures 8A-8B Examples of laser ablation modifications performed on biological materials are shown.

[0082] Fig. 9 An example of laser-assisted local cross-linking of collagen with riboflavin is shown.

[0083] Fig.10 An example of laser modification performed on a bioprosthetic heart valve is shown. DETAILED DESCRIPTION

[0084] Turning now to the accompanying drawings, methods and systems for improving the biocompatibility and / or mechanical properties of cardiac repair and regeneration devices are described. Many aspects provide modifications, including (but not limited to) the morphology, surface patterning, mechanical properties, chemistry and surface chemistry of materials, including (but not limited to) soft materials, hard materials, biomaterials and synthetic materials. Examples of materials include (but not limited to) stainless steel, metals, metal alloys, ceramics, polymers, textiles, biomaterials, biopolymers, pericardial tissue and collagen. As can be easily understood, any of the various materials can be appropriately modified according to the requirements of the specific application according to the various examples of the present invention. In several examples, the material is a component of the following cardiac repair and regeneration device including (but not limited to): a heart valve, a prosthetic heart valve, a transcatheter heart valve, a mitral heart valve, an aortic valve, a prosthetic valve, a stent, a vascular stent, a patch, a vascular patch and a heart patch. As can be easily understood, any of the various biomedical devices can be appropriately modified according to the requirements of the specific application according to the various examples of the present invention. In some instances, the material can be used to manufacture components of cardiac repair and regeneration devices including, but not limited to, sutures, leaflets, prosthetic tissues, skirts, outer skirts, textile skirts, stents, and frames. In some instances, various micropatterns and / or nanopatterns can be produced on the surface of the material. The surface pattern can be produced by laser technology. The surface patterning shown in many instances can improve the biocompatibility of the material, including, but not limited to, accelerating endothelialization, improving cell adhesion, and regulating cell function. In many instances, laser modification can produce anti-thrombotic surface morphology. The laser-modified surface can resist thrombosis. In several instances, laser modification can provide more consistent thermal and / or mechanical properties throughout the material. Examples of mechanical properties include, but are not limited to, fatigue resistance, tear propagation rate, ultimate tensile strength in uniaxial mode and multiaxial mode, and Young's modulus in dynamic mode and static mode. In some instances, laser modification can provide controlled and consistent thickness throughout the material.

[0085] Many examples show that at least one surface of a material of a cardiac repair and regeneration device can be modified to have improved biocompatibility, including (but not limited to) endothelialization and tissue regeneration. In several examples, the modification method can be applied to materials suitable for constructing devices and / or equipment that can be used for cardiac and / or vascular repair. Examples of such devices include (but are not limited to) prosthetic heart valves, stents, and cardiac patches. Many examples show that the modification method can be applied to materials of systems that can be used to deliver repair devices, including (but not limited to) delivery devices and catheters.

[0086] Various methods are related to improving the biocompatibility of materials and the possibility of endothelialization by using laser technology. In some instances, laser can pattern the surface of the material and / or modify the surface to simulate the chemistry and / or structure and morphology of the naturally occurring extracellular matrix (ECM). The main components of the ECM network can include collagen, proteoglycans and fibronectin, and the collagen, the proteoglycans and the fibronectin can form a part of a three-dimensional structure with a circular cavity, and the circular cavity has different diameters, and the diameter is in the range between about 10 microns and about 100 microns. According to several examples, laser technology can produce a morphology similar to the morphology of ECM in various materials to allow cells to easily proliferate. In some instances, laser technology can achieve local crosslinking and / or gradient crosslinking with collagen matrix to change the mechanical properties of the support. In some instances, laser technology can improve surface chemistry and biocompatibility.

[0087] In several examples, laser technology can modify the mechanical properties of various materials. Mechanical properties, including but not limited to tensile strength and fatigue resistance, can be modified by adding chemical agents, including but not limited to photoactive crosslinkers or photoagent crosslinkers, to various materials. UV light lasers can be used to generate reactive species and form new chemical bonds in materials. Examples of materials include but are not limited to soft materials, polymers, biomaterials, proteins, polysaccharides, collagen, chitosan, materials from biological sources, and pericardial tissue.

[0088] In some instances, laser technology can change the thickness and / or structure of various materials. The thickness of the material can be changed by laser ablation, which can use a pulsed laser to remove the material from the substrate to produce microstructures and / or nanostructures. Many materials used in medical devices can be subjected to laser ablation. Laser ablation can produce contour processing on various materials, including (but not limited to) medical grade polymers, medical grade metals and metal alloys, and materials from biological sources. Examples of medical grade polymers include (but are not limited to) polymethyl methacrylate, polyetherketone, polyimide, polyamide, polyethylene, polytetrafluoroethylene, nylon, polydimethylsiloxane, silicone, polyethylene terephthalate, polyester (PET), polybutylene terephthalate (PBT), polyurethane, block copolymers of polycarbonate, poly (sulfone of bisphenol-A) (PSU)-PBT copolymer. Examples of medical grade metals include (but are not limited to) nitinol and titanium. Examples of materials from biological sources include, but are not limited to, collagen, acrylate collagen composites, chitosan, and pericardial tissue. As can be readily appreciated, any of the various materials can be appropriately modified according to the various examples of the present invention as required by a particular application. In many instances, pulsed lasers can provide high efficiency in material removal. The pulse width of pulsed lasers, including, but not limited to, ultrashort pulse (USP) lasers, can be in the range of a few milliseconds to a few sub-picoseconds. Various light sources can be used to ablate in medical devices. Examples of light sources include, but are not limited to, neodymium-doped yttrium aluminum garnet (Nd:YAG), excimers, carbon dioxide (CO2), and optical fibers. As can be readily appreciated, any of the various laser sources can be appropriately used according to the various examples of the present invention as required by a particular application. The emission wavelength can be concentrated in various ranges of the spectrum. In some instances, the emission can be in the infrared (IR) wavelength of about 700nm to about 1mm. In a non-limiting example, the emission can be concentrated in the IR at a wavelength of about 10.6μm. In several examples, the emission can be in the near infrared (NIR) wavelength of about 800nm ​​to about 2500nm. In one example, the emission can be concentrated in the NIR with a wavelength of about 1060nm and about 1030nm. In multiple examples, the emission can be concentrated in the visible wavelength of about 380nm to about 750nm. In a non-limiting example, the emission can be concentrated in the visible wavelength of about 530nm and about 515nm. In many examples, the emission can be concentrated in the ultraviolet (UV) wavelength of about 100nm to about 400nm. In a non-limiting example, the emission can be concentrated in the UV with a wavelength of about 355nm, about 343nm, about 248nm and about 193nm.

[0089] Laser technology can produce various surface topologies of materials. Various laser technologies can produce patterning on various surfaces, including (but not limited to) micropatterns and / or nanopatterns, including (but not limited to) uniform (regular or flat) surfaces and uneven (or irregular) surfaces. As can be easily understood, any surface in the various surfaces can be appropriately modified according to the requirements of the specific application according to the various examples of the present invention. The structure and / or pattern produced by laser technology according to several examples can be periodic and / or non-periodic. In some examples, subtractive laser technology can be applied, including (but not limited to) ablation. In multiple examples, additive laser technology can be used, including (but not limited to) polymerization. Examples of laser technology include (but not limited to) direct laser writing (DLW) and interference lithography. Both DLW and interference lithography can be used for subtractive and / or additive processes. As can be easily understood, any laser technology in the various laser technologies can be appropriately used according to the requirements of the specific application according to the various examples of the present invention.

[0090] Direct laser writing (DLW) can produce patterns with feature sizes ranging from about 1 micron to about 50 microns. The writing resolution of micropatterning by DLW can be about 1 μm. The DLW process can be used for surface areas of at least 1 mm 2 According to some examples, DLW can also produce periodic patterns and / or non-periodic patterns. In several examples, DLW can produce patterns on both uniform and non-uniform surfaces. DLW can also be referred to as maskless lithography.

[0091] Interference lithography can produce patterns with sizes ranging from a few nanometers to a few micrometers. The writing resolution of nanopatterning and / or micropatterning by interference lithography can be less than about 1 μm. The interference lithography process can be used for surface areas of at least 5 mm 2 According to some examples, interference lithography can also generate periodic patterns. Interference lithography can be applied on flat surfaces.

[0092] In many examples, the DLW process and the interference lithography process can be combined to produce a surface with a layered pattern. Many examples show that the layered pattern can be multi-dimensional. The feature size of the layered pattern can be about tens of nanometers to about hundreds of microns.

[0093] Various systems, devices, methods and apparatuses that can promote endothelialization, regeneration and / or healing. Certain examples use one or more laser pulses to produce surface topography of materials used to construct prosthetic valves, vascular stents and / or any other prosthetic devices. Some examples use pulsed lasers to modify components and / or materials used to construct prosthetic valves or stents, and the pulsed lasers include (but are not limited to) ultrashort pulse (USP) lasers. Material modification using USP lasers can be a single-step and non-contact method for surface micropatterning. USP lasers can be used for "cold ablation" and micromachining, in which melting and thermal effects may be harmful to the material, or post-processing may need to be avoided. Some examples use USP laser ablation to produce microgrooves with different geometries and patterns.

[0094] Various laser techniques can be used to modify soft materials, including but not limited to skirts, textile skirts, and leaflets. Laser techniques for soft materials can include but are not limited to UV lasers according to some examples. The UV laser can be a single wavelength, or can be a narrow band with a wavelength in the range of about 100 nm to about 400 nm. Some examples use a UV laser with a wavelength of about 360 nm.

[0095] Laser technology can be used to modify hard materials and / or metallic materials used in various devices, including but not limited to stents and frames. Examples of metallic materials for stents and frames include but are not limited to Nitinol, Co-Cr alloys, and stainless steel. According to some examples, laser technology for hard materials can include but is not limited to infrared (IR) lasers and near infrared (NIR) lasers. NIR lasers can be a single wavelength, or can be a narrow band with a wavelength ranging from about 780 nm to about 1060 nm. IR lasers are single wavelengths centered at about 10 μm.

[0096] Various laser techniques can change the surface morphology of a material. Some examples include that the surface texture may include one or more holes having a size and shape that encourages endothelial cells to implant (or colonize), grow and / or propagate. Other examples change the surface chemistry to encourage endothelial cells to implant (or colonize), grow and / or propagate. One or more laser pulses can change (e.g., add, remove, change, etc.) any other chemical changes in the surface of the ionization state, charge, functional group, antigen and / or material. In some examples, patterning can provide a lubricated surface to allow a device (e.g., a repair device and / or a delivery device) to be more easily manipulated, moved and / or navigated to its proper position (e.g., a valve position, a position in a blood vessel, etc.). Certain examples provide patterning that can reduce fibrotic responses, while other examples of patterning can increase fibrotic responses. Several examples provide devices combined with patterning, in which different properties may be desired at various locations of components of the device, as will be further described herein.

[0097] Further discussed below are systems and methods for modifying material properties and structures using laser technology, which may be used in biomedical devices, according to various examples of the present invention.

[0098] Material modification

[0099] Systems and methods for laser-assisted processes for modifying prosthetic devices and / or cardiac repair devices to modify mechanical properties and / or biocompatibility are described. Many examples show that laser technology can modify the physical and / or chemical properties of various materials that make up biomedical devices. Several examples show that laser-assisted processes can modify properties of materials including, but not limited to, morphology, surface patterning, mechanical properties, chemistry, and surface chemistry, including, but not limited to, soft materials, hard materials, biomaterials, and synthetic materials. The laser-assisted modifications shown in many examples can improve the biocompatibility of materials, including, but not limited to, accelerating endothelialization, improving cell adhesion, and modulating cell function.

[0100] Go to Figure 1A, showing a process of physical modification using laser technology according to an example of the present invention. Various laser technologies can be used to perform physical modification 101. Examples of laser technology include (but are not limited to) direct laser writing (DLW) and interference lithography. Both DLW and interference lithography can be used for subtractive and / or additive processes. In some examples, subtractive laser technology can be applied, and the subtractive laser technology includes (but is not limited to) ablation. In certain examples, additive laser technology can be used, and the additive laser technology includes (but is not limited to) polymerization. Various laser technologies can change the surface topology, and micro-patterns and / or nano-patterns can be produced on various surfaces. The surface can be a uniform (regular or flat) surface and / or an uneven (or irregular) surface. The structure and / or pattern produced by laser technology according to several examples can be periodic and / or non-periodic.

[0101] In several examples, laser technology can change the thickness and / or structure of various materials. The thickness of the material can be changed using laser ablation 102. Laser ablation according to some examples can be applied to different locations of the material to produce different thicknesses as needed. Contouring using laser ablation according to many examples can provide local changes and / or gradient changes in the thickness of the material. In some examples, laser ablation can use a pulsed laser to remove material from a substrate to produce microstructures and / or nanostructures. The pulse width of the pulsed laser can range from a few milliseconds to a few sub-picoseconds. Various light sources can be used to ablate in medical devices. Examples of light sources include (but are not limited to) Nd:YAG, excimer, CO2, and optical fiber. The emission wavelengths can be concentrated in various ranges of the spectrum, including (but not limited to) infrared (IR) wavelengths, near infrared (NIR) wavelengths, visible wavelengths, and ultraviolet (UV) wavelengths.

[0102] Many materials used in medical devices can be subjected to laser ablation. Laser ablation can produce contour processing on soft material 103 and / or hard material 104. Examples of soft and hard materials include, but are not limited to, medical grade polymers, medical grade metals and metal alloys, and materials from biological sources. Medical grade polymers may include, but are not limited to, polymethyl methacrylate, polyetherketone, polyimide, polyamide, polyethylene, polytetrafluoroethylene, nylon, polydimethylsiloxane, silicone, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyester, polyurethane, block copolymers of polycarbonate, poly(sulfone of bisphenol-A) (PSU)-PBT copolymers. Medical grade metals may include, but are not limited to, nitinol. Materials from biological sources may include, but are not limited to, collagen, acrylate collagen composites, chitosan, and pericardial tissue. In several examples, the material is a component of a cardiac repair and regeneration device including, but not limited to, a heart valve, a prosthetic heart valve, a transcatheter heart valve, a mitral heart valve, an aortic valve, a prosthetic valve, a stent, a vascular stent, a patch, a vascular patch, and a cardiac patch. In certain examples, the material can be used to manufacture components of a cardiac repair and regeneration device including, but not limited to, sutures, leaflets, prosthetic tissue, skirts, outer skirts, textile skirts, stents, and frames.

[0103] Go to Figure 1B , showing a process of chemical modification using laser technology according to an example of the present invention. Various laser technologies can be used to perform chemical modification 105. In several examples, laser modification can provide controlled thermal and / or mechanical properties throughout the material 106. Examples of mechanical properties include (but are not limited to) fatigue resistance, tear propagation rate, ultimate tensile strength, and Young's modulus. Mechanical properties can be changed by adding non-toxic chemical agents including (but not limited to) photoactive crosslinkers or photoagent crosslinkers to various materials. UV light lasers can be used to generate reactive species and form new chemical bonds in the material. Examples of materials include (but are not limited to) soft materials, polymers, biomaterials, proteins, polypeptides, polysaccharides, collagen, chitosan, silk, wool, cellulose, starch, pectin, gelatin, alginate, materials from biological sources, and pericardial tissue. The modification of mechanical properties can be achieved by laser-assisted coating techniques, including (but not limited to) laser alloying. In laser alloying, two materials can be attached or blended together by using a laser. Laser-assisted cross-linking can achieve precise cross-linking of materials at desired locations. In some examples, laser technology can achieve localized cross-linking and / or gradient cross-linking of collagen matrices to modify mechanical properties.

[0104] In some instances, laser processing can be used to change the surface chemistry 107. Surface chemical properties that can be altered using laser technology include (but are not limited to) functional groups, ionization, moieties, and / or other chemical compositions. Laser technology can be used to apply a coating to at least one component of a cardiac repair device. Surface coatings can change the hydrophilicity and / or hydrophobicity of a substrate. In some instances, laser-assisted coating of hydrophilic polymers can be used to modify biopolymers and / or biomaterials.

[0105] Although the above reference Figure 1A and 1B Various processes for modifying materials using laser technology are described, but any of a variety of processes for modifying properties using laser technology may be utilized in a biomedical device as appropriate according to the requirements of a particular application in accordance with various embodiments of the present invention. Processes for patterning using laser technology in accordance with various embodiments of the present invention are further discussed below.

[0106] Patterning

[0107] Various methods can modify prosthetic devices and / or cardiac repair devices to promote endothelialization. Several examples show patterning using laser direct writing and / or interference lithography. Many examples use lasers including (but not limited to) ultrashort pulse lasers to produce patterning on such devices. Laser patterning can be applied to soft materials and / or hard materials. Patterning using lasers according to many examples can be performed on uniform, non-uniform, flat and / or curved surfaces.

[0108] Cells can be highly influenced by surface topography, including influencing their cell size, shape, adhesion, migration, and / or proliferation. In addition to modulating cell-cell interactions, surface topography with submicron dimensions can also affect cell adhesion and cell function. In addition, specific surface textures and patterns can encourage endothelialization and / or promote anticoagulation.(See, e.g., Liliensiek SJ et al. "Modulation of human vascular endothelial cell behaviors by nanotopographic cues." Biomaterials 2010;31(20):5418–5426; Zheng N et al. "Preparation of micro-patterned surfaces of Si-NO films and their influence on adhesion behavior of endothelial cells." Sci China Tech Sci 2010;53(1):257–263; Franco D et al. "Control of initial endothelial spreading by topographic activation of focal adhesion kinase." Soft Matter 2011;7:7313–7324; Dickinson et al. "Preparation of micro-patterned surfaces of Si-NO films and their influence on adhesion behavior of endothelial cells." Sci China Tech Sci 2010;53(1):257–263; Franco D et al. "Control of initial endothelial spreading by topographic activation of focal adhesion kinase." Soft Matter 2011;7:7313–7324; LE et al., “Endothelial cell responses to micropillar substrates if varying dimensions and stiffness”. J Biomed Mater Res 2012;100A(6):1457–1466; and Aktas C et al., “Micro- and nanostructured Al2O3 surfaces for controlled vascular endothelial and smooth muscle cell adhesion and proliferation”. Mater Sci Eng C 2012;32:1017–1024; the entire disclosures of these references are incorporated by reference for all purposes.).

[0109] Many examples provide processes and methods for producing patterns that can improve, accelerate and / or encourage healthy re-endothelialization. In various examples, microscale patterns with different sizes and / or geometries can be produced on materials including (but not limited to) metals, metal alloys, ceramics, plastics and / or thin films by changing one or more laser parameters. Laser parameters, including (but not limited to) excitation wavelength, repetition rate, energy per pulse, and overlap distance between pulses, can be changed according to several examples to optimize groove quality and precision. Depending on the specific material being patterned, laser parameters such as energy per laser pulse can be changed to adapt to the process. In DLW, ablated grooves can be formed in a polymer substrate while increasing the depth distribution by increasing the laser power, while other parameters can be kept constant. In one non-limiting example, laser ablation can be performed with PMMA using a USP laser. The laser parameters used in the ablation of PMMA can include a wavelength of about 1030nm; a pulse duration of about 240fs; a frequency of about 610kHz; an energy of about 1μJ / pulse; and a scan rate of about 2mm / sec.

[0110] Various examples utilize one or more of interference lithography and direct laser writing to create patterns on surfaces. Figure 2A , an exemplary laser system for interference lithography is shown. Interference lithography is typically used to produce regular or periodic patterns on flat surfaces and can generally be used in a variety of size ranges from about 100 nm and larger. According to various examples, a laser system for interference lithography includes a laser source that produces a beam of light having a wavelength suitable for deposition or ablation, depending on the material and the desired patterning. In some examples, the beam passes through a beam splitter to route two beams that intersect at a certain angle to produce an interference pattern. In some aspects, one beam is routed a certain distance so that one beam is offset by a distance of 1 / 2 of the wavelength of the beam.

[0111] Go to Figure 2B , the intersecting light beams produce an interference pattern on the material to be patterned. Specifically, the two light beams intersect at an angle β to produce interference of the laser beams. In some instances, positive interference of the light beams increases the power at a specific location to allow ablation of the material. In other instances, negative interference of the light beams reduces the power of the light beams to prevent ablation of the material to be patterned. The specific distance between the interferences produces a spatial period (or periodicity) in the material. This periodicity is a function of the angle β and the wavelength of the laser. It should be noted that although the above examples describe subtractive methods, similar applications can be used for additive methods, such that positive interference allows material deposition or negative interference prevents material deposition.

[0112] Figure 2CAn exemplary patterning produced by an interference lithography system is shown, in which the interference pattern produced by intersecting light beams produces valleys in the material to be patterned with a specific periodicity.

[0113] Back to Figure 2A , additional features of the laser system include additional beam splitters for routing the beam to a power meter to monitor the laser intensity. Certain examples further include a power regulator that varies the laser intensity manually and / or by readings given by automatic feedback from a power meter. Some examples include a shutter and / or aperture that is used to affect the beam width or ability to transmit through the system. Additional examples include one or more lenses that are used to help focus and / or route the beam. Such lenses can be located at any position to provide proper routing or focusing of the beam. In addition, polarizers and retarders are used to ensure proper light polarization of the two beams at the interference position.

[0114] Go to Figure 3 , an exemplary system for direct laser writing is shown. Such a system includes a laser and an optical device for directing a laser beam to a stage. In many instances, the stage is at a location where the material to be patterned is located. In various instances, the stage can move in one or more directions (e.g., X-axis, Y-axis, Z-axis, rotation around one or more axes, etc.). In some instances, the laser beam can move to the pattern material located on the stage. A pattern can be produced on a substrate by using a galvanometer to move the laser beam on a fixed substrate and / or using a stage to move the substrate around a fixed laser beam. The laser beam and the substrate can move simultaneously. The optical device used in direct laser writing can be a focusing optical device, including (but not limited to) a microscope objective or an f-θ lens. Direct laser writing is known to produce patterns with feature sizes ranging from about 1 μm to about 50 μm. Direct laser writing also allows for customized patterns, including periodic and / or non-periodic patterning on materials. Additionally, patterning produced by direct laser writing can include subtractive (eg, laser ablation) or additive (eg, laser sintering) methods for the material to be patterned.

[0115] Linear patterning may affect the regeneration of healthy endothelial cell monolayers of human vascular venous endothelial cells and human cardiac microvascular endothelial cells. (See, e.g., Ding Y et al. “Directing vascular cell selectivity and hemocompatibility on patterned platforms featuring variable topographic geometry and size,” ACS Appl Mater Interfaces 2014;6:12062–12070; and Pacharra S et al. “Surface patterning of a novel PEG-functionalized poly-l-lactide polymer to improve its biocompatibility: Applications to bioresorbable vascular stents,” J Biomed Mater Res B Appl Biomater.)》2019;107(3):624–634;The entire disclosure of the document is incorporated by reference for all purposes. ) Many examples modify various surfaces by linear patterning to improve biocompatibility. Some examples use patterns of holes to promote anticoagulation. In various examples, the holes can have various shapes, including (but not limited to) circular, rectangular, square, hexagonal, octagonal and / or any other polygonal shape. As can be easily understood, any of the various shapes can be appropriately used according to the various examples of the present invention according to the requirements of a specific application. Several examples provide subtractive and / or ablation processes (removal of material) using laser technology to produce patterns. Many examples can produce patterning by material deposition (e.g., additive manufacturing methods). Patterns produced using additive laser processes include (but not limited to) elevated pillars, columns, and any elevated shapes.

[0116] Patterning can produce multi-dimensional structures and / or patterns, including (but not limited to) two-dimensional (2D), three-dimensional (3D), 2D and 3D, which can help re-endothelialization. Several examples provide that the structure and / or pattern can include various shapes, including (but not limited to) grooves, pillars, holes, ridges, waves and / or any other pattern shown to have a desired biological effect, including (but not limited to) endothelialization and healing. As can be easily understood, any of the various patterns can be used according to various examples of the present invention as appropriate according to the requirements of a specific application. Some examples provide that the surface can be patterned with periodic and / or random structures that can enhance cell adhesion, migration and proliferation, including (but not limited to) grooves, depressions and squares. Many examples provide that at least one dimension of the pattern and / or structure can be in the range of microscale (about 1 μm to about 999 μm) to nanoscale (about 10nm to about 999nm). Some examples provide that the pattern on the material can make the material anisotropic.

[0117] Micropatterns can be created on soft materials including, but not limited to, leaflets and skirts of cardiac prosthetic devices. Figure 4A , each example shows individual holes 402 in a series of rows 404 and columns 406, wherein the rows may be parallel to each other and each row, each column may be parallel to each column, and each row may be perpendicular to each column. Figure 4B As seen in FIG. 4 , some embodiments provide holes 402 in a series of parallel rows 404, wherein adjacent rows may be offset to form a honeycomb pattern. Figures 4A-4B Circular or round holes are shown, but such holes are merely representative of the general pattern. Thus, the holes in the various examples can be any geometric shape for promoting, encouraging and / or enhancing endothelialization, including but not limited to circular, oval, rectangular, triangular, quadrilateral (e.g., square, rectangular, diamond, trapezoidal), hexagonal, octagonal, any other regular or irregular shape or polygonal, and combinations thereof.

[0118] Other examples of patterning on soft materials can include parallel rows, such as Figure 5A-5B Such rows can be formed by material (e.g., valleys or grooves (e.g., Figure 5A )) ablation or removal or deposition or addition of material to produce ridges in the material (e.g., Figure 5B ) to produce. Such rows may have any suitable height (or depth), width, and spacing between them to encourage, enhance, and / or promote endothelialization. In the ablation example, Figure 5AThe valley 501 shown in FIG. 1 has a depth in the range of about 1 μm to about 10 μm, while the width of the valley 502 of about 5 μm to about 20 μm is suitable for cell implantation. The spacing between valleys 503 can be varied to allow cell growth and / or allow flexibility of the underlying material, and can be between about 5 μm and about 20 μm. In addition, in the deposition example, as Figure 5B The ridges 304 shown in FIG. 5 , the height of such ridges ranges from about 1 μm to about 10 μm, while the width of the ridges 505 of about 1 μm to about 5 μm is suitable for cell implantation. The spacing between ridges 506 can vary to allow cell growth and / or allow flexibility of the underlying material, and can be between about 5 μm and about 20 μm. Although Figure 5A-5B Linear rows are shown, but various examples provide zigzag, wavy, sinusoidal and / or another other patterned grooves and / or ridges on the material that promote, encourage or enhance endothelialization and / or provide desired properties (e.g., stiffness, flexibility, etc.) to the underlying material.

[0119] Other examples produce materials with multi-dimensional and / or multi-layer patterning. Some examples can produce smaller patterns (e.g., nanopatterns) within larger sized patterns (e.g., micropatterns). Examples of such patterning are shown in Figure 6A-6B middle. Fig. 6A A "checkerboard" pattern is shown, where a larger grid 601 is created on a smaller grid 602. The height of the larger grid 601 can be higher than the height of the smaller grid 602. The smaller grid 602 can be embedded in the larger grid 601. The grid lines of the larger grid can protrude from the surface. The larger grid and the smaller grid can be square or rectangular in shape. Figure 6B Shows an enlarged Fig. 6A A single smaller grid. Each square of the grid 603 produced by the grid lines of the smaller grid 602 can protrude from the surface. The size of the pattern can have any height (or depth), width, and spacing suitable for encouraging, enhancing, and / or promoting endothelialization. In the smaller grid 602, the depth of the protruding grid can be in the range of about 10nm to about 50μm; up to about 40μm; up to about 30μm; and up to about 20μm, while the width of the grid of about 10nm to about 50μm, up to about 40μm, up to about 30μm, and up to about 20μm is suitable for cell implantation. The spacing between the grids can be varied to allow cell growth and / or to allow flexibility of the underlying material. In various instances, the larger grid can be produced by direct laser writing or interference lithography, while the smaller pattern is produced by interference lithography. Direct laser writing can produce patterns on uniform and / or non-uniform surfaces. Interference lithography may be able to produce patterns on uniform surfaces. Although Figure 6A-6BA square shape is shown for the multi-dimensional structure, but such shapes are merely representative of the general pattern. Thus, the multi-dimensional structure in each example can be any geometric shape for promoting, encouraging and / or enhancing endothelialization, including but not limited to circular, oval, rectangular, triangular, quadrilateral (e.g., square, rectangular, diamond, trapezoid), hexagon, octagon, any other regular or irregular shape or polygon, and combinations thereof.

[0120] Examples of patterns on hard materials including, but not limited to, metals, metal alloys, Nitinol, Co-Cr alloys, and stainless steel may include, but not limited to, curves, straight lines, wrinkle lines, parallel rows, geometric shapes, squares, rectangles, and circles. Patterns on hard materials may be produced by material ablation or subtraction or material deposition or addition to produce ridges on the material. Interference lithography and / or direct laser writing processes may be used to produce various patterns on metal surfaces. Specific laser parameters may be tuned for metal surfaces. In some instances, infrared lasers may be used on metal surfaces. Interference lithography and / or direct laser writing processes may be applied to subtractive processes and / or laser ablation processes. In some instances, electroforming and / or laser sintering may be used to modify metal surfaces. Ti sapphire femtosecond lasers and / or Ti sapphire lasers may be used to modify the surfaces of metal materials such as Nitinol. In some examples, laser patterning and / or machining of a nitinol stent can create nano- and / or micro-grooves on the outer surface of the stent to allow for easier tissue ingrowth to prevent paravalvular (PVL) leakage. Figures 7A-7C An example of surface patterning on Nitinol using laser technology is shown in FIG. Fig. 7A A pattern of laser-generated microgrooves on a nitinol surface is shown. Microgrooves 701 may protrude from the surface and may be generated by an additive laser process. The microgrooves may additionally be generated by removing material from the nitinol surface using an ablative laser process. Alternatively, the microgrooves may be generated using an additive process in which functional materials including, but not limited to, materials having a pharmacological effect may be added to the surface. The microgrooves may be generated in the form of straight or curved continuous lines. The microgrooves may have a variety of shapes, including, but not limited to, circular. The depth of the microgrooves may vary from about 1 μm to about 100 microns. Figure 7B A pattern of micro grooves produced by a laser on a Nitinol surface is shown. The micro groove pattern 702 can be parallel straight lines. The width of the micro grooves can vary from about 10 nm to about 100 microns. The space between the micro grooves can vary from about 500 nm to about 100 microns. Figure 7CSurface patterns on a Nitinol surface after laser treatment are shown. The Nitinol surface 603 can be a flat surface or a curved surface (e.g., a rod). An irregular wrinkle pattern 604 can be produced on the Nitinol surface using laser treatment. The patterned lines may not be parallel and may not be straight. Although Figures 7A-7C Linear rows are shown, but various examples provide zigzag, wavy, sinusoidal, and / or another other patterned grooves and / or ridges. Thus, the pattern on the metal surface can be any geometry that promotes, encourages, and / or enhances endothelialization.

[0121] Although various processes for patterning materials using laser technology are described above with reference to FIGS. 4-7 , any of a variety of patterns that can be produced using laser technology to improve biocompatibility can be utilized in biomedical devices as appropriate according to the requirements of a particular application according to various examples of the present invention. Processes for surface modification using laser ablation according to various examples of the present invention are further discussed below.

[0122] Ablation

[0123] In some instances, laser-assisted processes can modify the thickness and / or structure of various materials. The thickness of a material can be modified by laser ablation, which can employ a pulsed laser to remove material from a substrate to produce microstructures and / or nanostructures. Many materials used in medical devices can be subjected to laser ablation. Laser ablation can produce contour treatments on various materials, including, but not limited to, medical grade polymers, medical grade metals, and metals from biological sources. Examples of medical grade biodegradable polymers include, but are not limited to, glycolide-based copolymers, lactide-based copolymers, poly(lactic-co-glycolic) acid, poly(α-hydroxy acid), caprolactone-based polymers, cross-linked polyester hydrogels, poly(orthoesters), poly(glycerol-co-sebacic acid) (PGS), polyaniline (PANI), polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT), polyanhydrides, polyethylene glycol, poly(vinyl alcohol) (PVA), albumin, melanin, dioxanone-based polymers. Examples of medical-grade biostable polymers include, but are not limited to, polyacrylates, polyethers, poly(styrene-b-isobutylene-b-styrene), polysulfones, polyethersulfones, polymethyl methacrylates, polyetherketones, poly(vinylidene fluoride) polyimides, polyamides, polyethylene, polytetrafluoroethylene, nylons, polydimethylsiloxanes, silicones, polyethylene terephthalate, polyesters, polyurethanes, polystyrenes, and polyvinyl chlorides. Examples of medical-grade metals include, but are not limited to, nitinol. Examples of materials from biological sources include, but are not limited to, collagen, chitosan, and pericardial tissue.

[0124] Many polymers used in medical devices can be subjected to laser ablation. In many instances, pulsed lasers can provide high efficiency in material removal. The pulse width of a pulsed laser can range from a few milliseconds to a few picoseconds to a few femtoseconds. Various laser sources including (but not limited to) neodymium-doped yttrium aluminum garnet (Nd:YAG), excimer, carbon dioxide (CO2), and optical fiber can be used for ablation in medical devices.

[0125] The emission wavelength can be concentrated in various ranges of the spectrum. In some instances, the emission can be in an infrared (IR) wavelength of about 700nm to about 1mm. In a non-limiting example, the emission can be concentrated in an IR with a wavelength of about 10.6μm. Examples of lasers that emit IR light can include carbon dioxide (CO2) lasers. The center wavelength of the CO2 laser is about 10.6μm, and it can be adjusted to produce microsecond long pulses with large laser average power. Due to its emission wavelength, IR lasers can be used for material ablation after a photothermal process. Infrared lasers can also be used for ablation and surface modification of materials. For example, infrared lasers can be used for surface texturing and ablation of PTFE and polyimide materials.

[0126] In several examples, the emission can be in the near infrared (NIR) wavelength of about 800nm ​​to about 2500nm. NIR lasers can produce sub-picosecond pulses at high filling rates (in the range of MHz), thereby providing efficient ablation with a large removal rate. The emission wavelength of the NIR laser can be about 800nm, about 1030nm and about 1050nm. Because pulsed NIR lasers can achieve high light intensity, substrate ablation with NIR lasers can occur through photophysical processes. In an example, the emission can be concentrated in the NIR at wavelengths of about 1060nm and about 1030nm.

[0127] In multiple examples, the emission can be concentrated in the visible wavelengths of about 380 nm to about 750 nm. In a non-limiting example, the emission can be concentrated in the visible wavelengths of about 530 nm and about 515 nm. The visible wavelength laser used in the material ablation can be a harmonic of the NIR laser. In some examples, a frequency-doubled Nd-YAG laser can produce nanosecond logarithmic pulses centered at about 532 nm, which are effective in the subtractive modification of different materials.

[0128] In many examples, the emission can be concentrated in ultraviolet (UV) wavelengths of about 100 nm to about 400 nm. Due to the emission wavelength and pulse energy, UV lasers such as excimer lasers can provide substrate ablation through photochemical processes. In a non-limiting example, the emission can be concentrated in UV wavelengths of about 355 nm, about 343 nm, about 248 nm, and about 193 nm. Examples of UV lasers include UV lasers based on the formation of excimer species in the gas phase. Examples of excimer lasers include ArF and KrF, whose emission wavelengths are concentrated at about 193 nm and about 248 nm, respectively.

[0129] NIR lasers with sub-picosecond pulses and their harmonics in the visible and UV regions of the spectrum are referred to as ultrashort pulse (USP) lasers. Ultrashort pulse (USP) lasers can be used for "cold ablation" and micromachining, in which melting and thermal effects may be harmful to the material, or post-processing may need to be eliminated. USP lasers can work on various types of materials and can be easily adapted and amplified for micropatterning of complex component shapes. In many instances, USP laser ablation can be used to produce microgrooves with different geometries and patterns. Such patterning according to several instances can allow tissue to grow inward, heal, regenerate, endothelialize and / or any other biological phenomenon that can increase the possibility of implant acceptance.

[0130] Various laser sources can be selected based on the material. In some instances, laser sources including (but not limited to) KrF, Nd:YdYAG, ArF, KrCl, XeCI and / or CO2 can be used for PMMA laser processing. In several instances, laser sources including (but not limited to) XeCI, KrF and / or Nd:YAG can be used for polyetherketone laser processing. In some instances, laser sources including (but not limited to) XeCI, KrF, ArF and / or XeF can be used for polyimide and / or polyamide laser processing. In multiple instances, laser sources including (but not limited to) iodine PALS can be used for polyethylene laser processing. In several instances, laser sources including (but not limited to) KrF can be used for PTFE laser processing. In some instances, laser sources including (but not limited to) XeCI can be used for nylon laser processing. In some instances, laser sources including, but not limited to, CO2 lasers, Ti sapphire lasers, ArF lasers, and / or erbium-doped fiber lasers can be used for PDMS and / or silicone laser treatment. In multiple instances, laser sources including, but not limited to, ArF, KrF, and / or XeCI can be used for PET and / or polyester laser treatment. In several instances, laser sources including, but not limited to, Ti sapphire femtosecond lasers can be used for nitinol laser treatment. In various instances, UV lasers (wavelengths of about 100 nm to about 400 nm) with laser sources including, but not limited to, Nd:YAG, fiber lasers, and / or excimer lasers can be used for laser treatment of biomaterials, biological tissues, collagen, chitosan, and / or pericardial tissue.

[0131] Laser ablation can be used to create various thicknesses throughout the material. In many instances, laser ablation can be used to contour the surface to achieve a desired thickness at specific areas. In certain instances, laser-assisted cross-linking can improve the mechanical properties of specific areas where the thickness has been reduced. In several instances, laser ablation can be used on pericardial tissue to alter the thickness by about 500 microns to about 150 microns. In certain instances, laser ablation can be used to create various patterns on the pericardial tissue to improve biocompatibility. Go to Figures 8A-8B , shows an example of laser ablation on pericardial tissue. Fig. 8A , laser ablation can be applied to modify the pericardial tissue before and / or after the tissue is cut into shape. The edges of the pericardial tissue 801 can be thicker. Laser ablation can be applied to selected areas 802 to even out the thickness of the entire pericardial tissue to achieve thickness consistency. The thickness of the pericardial tissue can be about 100 microns to about 500 microns. Laser ablation can be applied to selected areas 803 to create micro-patterns and / or nano-patterns on the pericardial tissue to modify the biocompatibility to promote, encourage and / or enhance endothelialization.

[0132] Laser techniques can be combined to produce the desired thickness and mechanical properties of the leaflet according to a number of examples. Laser ablation can efficiently remove material to modify thickness, while laser-assisted cross-linking can enhance the mechanical properties of the thinned material. Figure 8B A combination of laser ablation and laser assisted cross-linking on the leaflets of a heart valve is shown. Pericardial tissue can be connected to form the leaflets of a heart valve 810. Laser modification can be performed before and / or after the leaflets are made. The edges of the pericardial tissue 801 where the tissue is connected can be thicker. Laser ablation can be applied to reduce the thickness at various areas 802 and create a pattern at selected areas 803. Laser assisted cross-linking can be performed in or near area 804 to enhance the mechanical strength of the leaflet.

[0133] Although the above reference Fig. 8A -8B describes various processes for surface modification using laser ablation, but any of a variety of processes for modifying material properties using laser ablation may be utilized in biomedical devices as appropriate according to the requirements of a particular application in accordance with various embodiments of the present invention. Processes for laser-assisted cross-linking according to various embodiments of the present invention are further discussed below.

[0134] Cross-linking

[0135] A major challenge of implantable prostheses (e.g., prosthetic heart valves, vascular grafts) constructed with animal-derived pericardial tissue can be tissue durability in vivo. Tissue durability in vivo can be improved by changing tissue chemistry through cross-linking (e.g., glutaraldehyde (GA) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)). However, when chemical reagents are used as cross-linking agents, residues of unreacted chemicals and / or chemical byproducts are usually left behind. The residues may need to be washed off to minimize cytotoxicity. Many examples provide materials and systems that can form artificial cross-links in situ in tissues without the use of any toxic chemicals (e.g., GA). In addition, animal-derived tissues can have variable thickness and mechanical properties. Several examples show that laser processing, including (but not limited to) laser ablation and laser-assisted cross-linking, can change geometric dimensions and can improve the mechanical properties of various devices.

[0136] Laser-induced cross-linking of proteins including bovine serum albumin, hyaluronic acid, and collagen has been previously reported. (See, e.g., S. Shavkuta et al., Laser Physics Letter, 2018, Vol. 15, 015602.10; U.S. Patent Application Publication No. 2018 / 0193188A1 to S. Vukelic et al.; Sheldon J. J. et al., Optica 2016; 3(5): 469–472; the entire disclosure of the document is incorporated by reference for all purposes.) Many examples provide laser techniques for generating covalent bonds between intermolecular collagen structures, including, but not limited to, picosecond and / or femtosecond lasers in the wavelength range of the NIR from about 500 nm to about 700 nm. The effectiveness of laser treatment can depend on sample preparation, laser frequency, and laser power according to the example. At higher powers, femtosecond lasers are able to penetrate deeper into thicker collagen structures. Several examples provide that cytotoxic compounds may not be formed using laser cross-linking methods. In some examples, the laser cross-linking process is generally less aggressive in improving the mechanical properties of collagen than chemical methods.

[0137] For bioprosthetic valves using bovine or porcine pericardial tissue as leaflets, UV light at approximately 370 nm combined with riboflavin (vitamin B2) can improve the biomechanical strength of collagen fibers. During laser treatment of a material according to several examples, additional chemicals can be used to further improve the properties of the material. In some examples, a photoactive agent or a thermally active agent can be incorporated into the material by soaking the material in a solution of the agent. In certain examples, the photoactive agent or the thermally active agent can be applied to the surface of the material by a dipping or spray coating process prior to laser treatment. The use of lasers and photoactive agents including (but not limited to) riboflavin can eliminate the use of toxic agents including (but not limited to) glutaraldehyde during the cross-linking process. Examples of chemical agents that can be photo / UV or heat activated by lasers include, but are not limited to, aryl azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), deoxyribonucleic acid, bis-acylphosphine oxides, pyrolipids, porphyrins, chlorins; photopolymerization free radical photoinitiators such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (e.g., 2559 photoinitiator, Ciba-Geigy), methyl benzoylformate; phospholipid-based initiators such as phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide; 6-(4,4'-azidopentanamido)hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SDA, sulfo-NHS-LC-bisaziridine) and triethylamine. Examples of polymers that can be photo / UV or thermally activated by lasers include (but are not limited to) poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylvinyl (MEH-PPV), poly(3-butylthiophene-2,5-diyl), poly(9,9-dioctylfluorene-alt-bithiophene), poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PTO), poly[(9,9-bis(3'-(N,N-dimethylamino)propyl)-2,7 -fluorene)-alt-2,7-(9,9-dioctylfluorene)] (PFN-DOF), poly(2,5-bis(hexyloxy)cyano-p-terephthalylidene), poly(5-(2-ethylhexyloxy)-2-methoxy-cyano-p-terephthalylidene), poly(1,4-phenylene-1,2-ethanediyl) PPV copolymer, poly(9,9-bis-(2-ethylhexyl)-9H-fluorene-2,7-vinylene) and poly(2,5-dioctyl-1,4-phenylene). Thermal crosslinking agents that can be activated by laser include (but are not limited to) curcumin diferuloylmethane. As can be readily appreciated, any of a variety of chemical agents can be used according to various examples of the present invention as appropriate depending on the requirements of a particular application.

[0138] The concentration of the cross-linking reagent mixture according to several examples can vary between about 5 mM and about 25 mM, wherein the cross-linking reagent mixture is dissolved in a biocompatible solvent and / or solution, including but not limited to DMSO, PBS saline, and water. In some examples, the cross-linking agent can be a liquid or semi-solid at a temperature range of about 10° C. to about 50° C. The liquid cross-linking agent can form a melt, which means that it is liquid without the addition of other liquids.

[0139] Lasers can be used to activate crosslinking agents to achieve local crosslinking and / or gradient crosslinking. UV light lasers can be used to mechanically transform the surface of the material and change the chemical structure so that the material can acquire new biomechanical properties. Photoactivation of the agent can be achieved in a wavelength range of about 220 nm to about 400 nm. In many instances, the bioprosthetic valve can be immersed in a riboflavin solution to enable the pericardial tissue to absorb the riboflavin. In some instances, the absorption wavelength of riboflavin can be about 370 nm with a photoactivation time of less than about 1 hour.

[0140] In many instances, UV laser light at a wavelength including, but not limited to, about 370 nm may be used to focus directly on bioprosthetic valve tissue leaflets to activate the photoactive riboflavin molecules and allow the riboflavin to cross-link the collagen fibers of the leaflets. Fig. 9 Examples of local cross-linking and gradient collagen cross-linking using laser and riboflavin are shown. Bioprosthetic valve leaflets 901 can be made of pericardial tissue. Laser-assisted cross-linking can be applied to the leaflets before and / or after the valve is made. The pericardial tissue can include collagen fibers as one of the components. The collagen fibers can have a matrix-like structure 902. Riboflavin 904 can be added to the collagen network 902 before laser treatment. Riboflavin can be incorporated into collagen by soaking the pericardial tissue in a solution of riboflavin or applying riboflavin to the surface of the pericardial tissue. UV laser 903 can be used to activate the cross-linking process. The UV laser can be applied directly to the area of ​​the pericardial tissue where cross-linking is desired. Some examples use femtosecond laser pulses. The laser can activate riboflavin 904. The laser cross-linking mechanism includes the formation of interacting and cross-linking free oxygen radicals (not shown), which can stabilize the intramolecular and intermolecular collagen structure. Laser-assisted cross-linking achieves local cross-linking and gradient cross-linking of tissue 905. The laser enables precise cross-linking at the site where the laser is applied.

[0141] Many examples provide methods of cross-linking biomaterials to improve mechanical properties, including but not limited to collagen and elastin. The collagen material and / or the elastin material can be present in bovine pericardial tissue or porcine pericardial tissue. Cross-linking according to several examples can improve mechanical properties, including but not limited to fatigue strength of the pericardium or other tissue types. Modification of mechanical properties can be achieved by laser-assisted coating techniques, including but not limited to laser alloying. In laser alloying, two materials can be attached or blended together by using a laser.

[0142] In several instances, laser processing can achieve more consistent mechanical properties of biomaterials. Glutaraldehyde fixation can achieve high mechanical strength. The ultimate tensile strength (UTS) of bovine pericardial tissue after the glutaraldehyde fixation process is in any range between about 10MPa and about 35MPa. The disadvantages of glutaraldehyde fixation are its poor control and high variability from sample to sample. In many instances, laser-induced crosslinking can not only achieve collagen chemical crosslinking in the absence of glutaraldehyde, but also provide more consistent mechanical properties, thermal properties and thickness. Table 1 below lists the thickness and various mechanical properties of bovine pericardial tissue under different crosslinking treatments. Bovine pericardial (BP) tissue can be processed by glutaraldehyde fixation process or laser-assisted crosslinking. When compared to BP tissue under glutaraldehyde fixation process, laser treated BP tissue showed a more consistent thickness between about 200 microns and about 250 microns; a more consistent UTS between about 20 MPa and 25 MPa; a more consistent Young's modulus between about 35 MPa and about 40 MPa; and a more consistent shrinkage temperature between about 75°C and about 76°C. The durability (fatigue) of the laser treated tissue can be tested in an accelerated wear test (AWT) for heart valves. Leaflets with laser treated bovine pericardium passed the 300 million cycle requirement, thus, the laser process can maintain the same fatigue resistance of the tissue's collagen structure.

[0143] Table 1: Thickness and mechanical properties of bovine pericardial tissue.

[0144]

[0145]

[0146] Although the above reference Fig. 9 Various processes for cross-linking using lasers are described, but any of a variety of processes for cross-linking materials with chemical agents using laser technology can be utilized in biomedical devices as appropriate according to the requirements of a particular application in accordance with various embodiments of the present invention. Processes for surface coating using laser technology in accordance with various embodiments of the present invention are further discussed below.

[0147] Changing surface chemistry

[0148] Some examples use at least one laser process to change the surface chemistry. Surface chemical properties that can be modified using laser technology include (but are not limited to) functional groups, ionization, moieties and / or other chemical compositions. Laser technology can be used to apply a coating to at least one component of a cardiac repair device and / or grafted to at least one component. Laser-assisted grafting of chemical groups can change the hydrophilicity and / or hydrophobicity of the surface and / or the electrostatic (cationic or ionic) properties of the substrate. In some examples, bovine pericardial tissue can be modified using laser grafting of hydrophilic polymers, including (but not limited to) hyaluronic acid (HA), pure collagen, polysulfones, polyacrylate-based zwitterionic coating polypeptides, polysaccharides, collagen, chitosan, silk, wool, cellulose, starch, pectin, gelatin, alginate, polyvinyl alcohol, polyethylene glycol ethers, polyamides and urethane-based polymers.

[0149] In some examples, antimicrobial capability can be added by generating cationic groups on the surface of the substrate. Certain cationic chemical groups can bind and interact with negatively charged bacterial cell membranes, causing changes in the electrochemical potential on the bacterial cell membrane, inducing cell membrane damage and penetration of larger molecules such as proteins, disrupting cell morphology and membranes, and ultimately leading to cell death. Specific examples of polymer coatings that can be activated or modified with lasers include (but are not limited to) methacrylates, polyurethanes, polyimides with phosphorylcholine, cysteine, sulfobetaine, carboxybetaine functional groups. The laser process can form cross-linked polyzwitterionic acids.

[0150] Various laser sources can be used for the surface chemical modification process according to many examples. Laser sources with various emission wavelengths can be used for modification, including (but not limited to) ultraviolet (UV) lasers, visible (vis) lasers, near infrared (NIR) lasers, and infrared (IR) lasers. Examples of UV lasers include UV lasers based on the formation of excimer species in the gas phase. Examples of excimer lasers include ArF and KrF with emission wavelengths centered at about 193 nm and about 248 nm, respectively. Laser material modification techniques include (but not limited to) quenching, annealing, remelting, alloying, cladding, impact strengthening, glazing, texturing, and ablation.

[0151] Although various processes for laser-assisted surface coating are described above, any of a variety of processes for applying surface coatings using laser technology can be utilized in biomedical devices as appropriate according to the requirements of a particular application in accordance with various embodiments of the present invention. For purposes of illustration, a specific example of laser modification on a prosthetic heart valve according to various embodiments of the present invention is further discussed below.

[0152] Changing a prosthetic valve

[0153] Many examples provide laser modifications that can be applied to at least one surface of a cardiac repair and regeneration device, including (but not limited to) patterning of various patterns and / or shapes, laser ablation, laser-assisted crosslinking, and laser-assisted surface coating. Laser patterning modifications with micropatterns and nanopatterns according to some examples can increase the biocompatibility of various components of a prosthetic valve, including (but not limited to) leaflets, stents, and skirts. Laser ablation can produce patterns and / or various thicknesses (contour processing) across biopolymers and / or biomaterials used in prosthetic valves. Laser-assisted crosslinking and / or grafting can achieve local crosslinking and / or gradient crosslinking or specific chemistry of biomaterials used in prosthetic valves to enhance mechanical properties. The altered device and / or modified device surface can promote tissue ingrowth and endothelialization. Examples of devices include (but not limited to) prosthetic heart valves, prosthetic stents, heart patches, vascular patches, annuloplasty devices and / or rings, stents, and / or any other system whose textured surfaces can increase successful implantation, repair, and / or remodeling.

[0154] Prosthetic valves according to many examples can include many components constructed of various materials. For example, for the valve, the frame can be rigid (e.g., constructed of metal or metal alloy) to maintain its shape and form the body of the prosthetic heart valve. Additional features include internal materials that form functional aspects of the valve, such as leaflets. The leaflets can be made of biomaterials, including (but not limited to) bovine pericardial tissue. Additional examples include skirts that can extend on the inside or outside of the valve, which can provide a softer interface against natural tissue on the downstream edge of the prosthetic heart valve. The skirt can be made of synthetic materials, including (but not limited to) polymers and polyethylene terephthalate. Various materials (e.g., frames, internal materials, and skirts) are typically selected for the above selected properties, which makes it unlikely or impossible to use a single material in the construction of the prosthetic heart valve.

[0155] A significant obstacle in prosthetic valves and stents may be tissue rejection and / or damage caused by the implantation of the prosthesis. One method for improving acceptance is to promote tissue ingrowth into certain components of the prosthesis. In some instances, laser technology can be used to change certain components of the prosthetic valve, including (but not limited to) the skirt, to promote the formation of fibrotic tissue, which can help maintain the position of the prosthesis. Some examples show that laser technology can be used to change some components including (but not limited to) the inner skirt to promote endothelialization. Endothelialization can be beneficial to the anti-hemolytic, anti-thrombotic and anti-inflammatory activity of the prosthesis. Several examples provide that laser technology can be used to change components including (but not limited to) the frame to prevent or inhibit fibrosis and / or tissue overgrowth and / or provide lubrication properties to increase or improve manipulation, movement and / or navigation. In some instances, patterning (e.g., micropatterning and / or nanopatterning) can be the same or different on the inner skirt and the outer skirt.

[0156] Several examples have shown that components of bioprosthetic transcatheter valves can be altered using various laser techniques. Fig.10 Laser modification of a prosthetic transcatheter valve according to an example is shown. Prosthetic transcatheter valve 1000 may include leaflets 1001, expandable stents 1002, skirts 1003, and sutures 1004. Leaflets 1001 may be made of bovine pericardial tissue and / or porcine pericardial tissue. Laser ablation according to many examples may be applied to the leaflets to achieve a consistent thickness throughout the leaflets. Laser cross-linking with riboflavin according to several examples may be applied to the leaflets to improve mechanical properties. Expandable stent 1002 may be made of nitinol or titanium. Laser micromachining of nitinol stents according to some examples may produce nano-grooves and micro-grooves on the outer surface of the stent. Changes to the stent may allow tissue to grow more easily inward to prevent PVL leakage. Skirt 1003 may be made of polyester or polyethylene terephthalate (PET). Laser ablation according to certain examples may cause local melting on the surface of the skirt material. Melting can reduce the tendency of individual threads of polyester or PET fabric to become loose and protrude within the product. In addition, laser beam radiation can be applied to the skirt to change the surface energy by using a photoagent. The surface modification of the skirt can reduce the contact angle of the material, thereby improving hydrophilicity. Suture 1004 can be used to fix the skirt to the expandable support. The suture can be made of PTFE and PET. Laser beam radiation can be applied to the suture to change the surface energy by using a photoagent. The surface modification of the suture can reduce the contact angle of the material, thereby improving hydrophilicity.

[0157] Additional examples relate to cardiac repair devices and techniques, including but not limited to cardiac patches, vascular patches, annuloplasty devices and / or rings, stents, and / or any other system whose textured surface can increase successful implantation, repair, and / or remodeling.

[0158] Data and testing

[0159] The following sections provide specific examples of using different laser modification processes to alter various components of a bioprosthetic device. It should be understood that the specific examples are provided for illustrative purposes and do not limit the overall scope of the present disclosure, which must be considered in light of the entire specification, drawings, and claims.

[0160] Laser-assisted cross-linking with riboflavin

[0161] Bovine pericardial tissue can be cross-linked with riboflavin using laser. The laser cross-linking process can eliminate the use of toxic glutaraldehyde during the cross-linking process. The laser can achieve localized cross-linking sites.

[0162] Prior to laser treatment, the bovine pericardial tissue may be soaked in a solution comprising riboflavin and cyclodextrin, the solution being dissolved in saline or ethylenediaminetetraacetic acid (EDTA). The ratio of cyclodextrin to riboflavin may be about 25:1. The cyclodextrin may be in a range between about 2% and about 3% total weight; the EDTA may be about 0.05% total weight; and the salt may be about 0.25% total weight. The pH of the solution may be in a range between about 7 and about 7.5. The bovine pericardial tissue may be soaked in a riboflavin cyclodextrin solution at about 37°C for about 2 hours before laser cross-linking.

[0163] Surface modification

[0164] Laser beam radiation can be applied to the skirt and / or sutures of a bioprosthetic valve to change the surface chemistry and / or change the hydrophilicity. Surface energy modification can be performed with a Nd:YAG pulsed laser (wavelength = 266 nm, pulse width = 50-200 fs, e.g., 99 fs)) using a triethylamine photoreagent. An aqueous solution of triethylamine (TEA) (about 6.5-6.7 TEA wt % in H2O) can be applied to the polyester skirt of a surgical valve and / or PTFE suture. Laser beam radiation can then be applied to modify the surface energy of the material. The surface energy change can be confirmed by contact angle measurements. Both PTFE and PET showed a decrease in contact angle and a change in surface chemistry after radiation.

[0165] Principle of Equivalence

[0166] For the purpose of this description, certain aspects, advantages and novel features of examples of the present disclosure are described herein. The disclosed methods, devices and systems should not be construed as limiting in any way. On the contrary, the present disclosure relates to all novel and non-obvious features and aspects of the various disclosed examples (alone and in various combinations and sub-combinations with each other). The methods, devices and systems are not limited to any particular aspect or feature or combination thereof, nor do the disclosed examples require the presence of any one or more specific advantages or solutions to problems.

[0167] Although the operations of some of the disclosed examples are described in a particular sequential order for ease of presentation, it should be understood that this description encompasses rearrangement unless the specific language set forth below requires a specific order. For example, operations described in sequence may be rearranged or performed simultaneously in some cases. In addition, for simplicity, the accompanying drawings may not show the various ways in which the disclosed methods can be used in conjunction with other methods. In addition, this specification sometimes uses terms such as "providing" and "implementing" to describe the disclosed methods. These terms are high-level abstractions of the actual operations performed. The actual operations corresponding to these terms can vary according to the specific implementation and are easily discernible by those of ordinary skill in the art.

[0168] As used in this application and the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Additionally, the term "includes" means "comprises." Unless explicitly stated otherwise, reference to an object in the singular is not intended to mean "there is and only one," but rather "one or more." Furthermore, the terms "coupled" and "associated" generally mean electrically, electromagnetically, and / or physically (e.g., mechanically or chemically) coupled or connected, and do not exclude the presence of intervening elements between coupled or associated items in the absence of specific language to the contrary.

[0169] As used herein, the terms "substantially" and "approximately" are used to describe and explain small variations. When used in conjunction with an event or situation, the terms may refer to instances where the event or situation occurs precisely as well as instances where the event or situation occurs nearly. When used in conjunction with a numerical value, the terms may refer to a range of variation of less than or equal to ±10% of the numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%.

[0170] In addition, amounts, ratios and other numerical values ​​are sometimes presented in range format herein. It should be understood that such range formats are used for convenience and brevity, and should be flexibly understood to include numerical values ​​clearly specified as the limits of the range, and also include all individual numerical values ​​or sub-ranges covered within the range, as if each numerical value and sub-range is clearly specified. For example, a ratio within the range of about 1 to about 200 should be understood to include the clearly listed limits of about 1 and about 200, but also includes individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100.

[0171] In view of the many possible examples to which the principles of the disclosed technology can be applied, it should be recognized that the examples shown are only preferred examples and should not be taken as limiting the scope of the disclosure. On the contrary, the scope of the disclosure is at least as broad as the following claims.

[0172] Examples

[0173] Example 1: An example of a method for improving the biocompatibility of a structure used in a prosthesis, the method comprising:

[0174] applying a laser process to at least one surface of the structure to produce at least one pattern on the at least one surface;

[0175] wherein the laser process comprises at least one laser source;

[0176] wherein the laser process is selected from the group consisting of direct laser writing, interference lithography, and any combination thereof; and

[0177] Wherein the structure is at least one component of a device selected from the group consisting of: a prosthetic heart valve, a stent, and a cardiac patch.

[0178] Example 2: The example method according to Example 1, wherein the component is selected from the group consisting of: a frame, a stent, a skirt, an outer skirt, an inner skirt, a suture, a leaflet, and a valve tissue.

[0179] Example 3: An exemplary method according to Example 1 or 2, wherein the surface comprises a material selected from the group consisting of: metals, metal alloys, stainless steel, nitinol, titanium, Co-Cr alloys, polymers, polymethyl methacrylate, polyether ketone, polyimide, polyamide, polyethylene, polytetrafluoroethylene, nylon, polydimethylsiloxane, silicone, polyethylene terephthalate, polybutylene terephthalate, polyesters, biopolymers, block copolymers of polycarbonate, poly(sulfone of bisphenol-A) (PSU)-PBT copolymers, collagen, acrylate collagen, chitosan, and pericardial tissue.

[0180] Example 4: The example method of example 1, 2, or 3, wherein the at least one laser source is an ultrashort pulse laser.

[0181] Example 5: The exemplary method according to any one of Examples 1 to 4, wherein the pulse width of the ultrashort pulse laser is 3 picoseconds to 50 femtoseconds.

[0182] Example 6: An example method according to any one of Examples 1 to 5, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: infrared wavelengths of 700nm to 1mm, near-infrared wavelengths of 800nm ​​to 2500nm, visible light wavelengths of 380nm to 750nm, and ultraviolet wavelengths of 100nm to 400nm.

[0183] Example 7: The example method according to any one of Examples 1 to 6, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm and 193 nm.

[0184] Example 8: The example method according to any one of Examples 1 to 7, wherein the direct laser writing is performed using a direct laser writing system, the direct laser writing system comprising at least one laser beam, at least one substrate, and at least one galvanometer.

[0185] Example 9: The example method according to Example 8, wherein the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce a plurality of patterns; or the at least one laser beam is fixed and the at least one substrate moves to produce a plurality of patterns; or the at least one substrate and the at least one laser beam move simultaneously to produce the plurality of patterns.

[0186] Example 10: The example method of Example 8 or 9, wherein the direct laser writing system includes a focusing optic selected from the group consisting of a microscope objective and an f-theta lens.

[0187] Example 11: The exemplary method of any one of Examples 1 to 10, wherein the at least one pattern improves re-endothelialization and tissue regeneration of the structure.

[0188] Example 12: The example method of any of Examples 1 to 11, wherein the laser process changes at least one property of the structure selected from the group consisting of: surface topography, thickness, and size.

[0189] Example 13: The example method according to any one of Examples 1 to 12, wherein the at least one surface is flat, curved, uniform or non-uniform.

[0190] Example 14: The example method according to any one of Examples 1 to 13, wherein the at least one pattern is periodic or non-periodic.

[0191] Example 15: The exemplary method according to any one of Examples 1 to 14, wherein at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

[0192] Example 16: The example method of any one of Examples 1 to 15, wherein the laser process is part of a subtractive process or an additive process.

[0193] Example 17: The example method of any one of Examples 1 to 16, wherein the laser process is a laser ablation process, wherein the at least one pattern changes the thickness of the at least one surface.

[0194] Example 18: The example method of Example 17, wherein the laser ablation process profiles the at least one surface and produces different thicknesses on the at least one surface.

[0195] Example 19: The exemplary method of any one of Examples 1 to 18, wherein the at least one pattern comprises a layered structure or is multi-dimensional.

[0196] Example 20: The example method according to any one of Examples 1 to 19, wherein the at least one pattern comprises a pattern selected from the group consisting of: lines, straight lines, curves, grooves, pillars, holes, ridges, waves, depressions, squares, and any combination thereof.

[0197] Example 21: An exemplary method according to any one of Examples 1 to 20, wherein the at least one pattern has at least one shape selected from the group consisting of: circle, oval, rectangle, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon and any combination thereof.

[0198] Example 22: The example method of any one of Examples 1 to 21, wherein the at least one pattern comprises parallel rows.

[0199] Example 23: The exemplary method of any one of Examples 1 to 22, further comprising applying at least one chemical agent to the at least one surface prior to applying the laser process, wherein the laser process produces a surface coating of the at least one surface.

[0200] Example 24: The exemplary method of Example 23, wherein the surface coating changes the contact angle of the at least one surface.

[0201] Example 25: An example of a method for modifying a biomaterial for use in a prosthesis, the method comprising:

[0202] adding a photoactive agent to the protein material; and

[0203] applying a laser process comprising at least one laser source to the protein material;

[0204] wherein the at least one laser source locally cross-links the photoactive agent with the protein material and changes the chemical structure of the protein material; and

[0205] Wherein the proteinaceous material is at least one component of a system or device selected from the group consisting of: a prosthetic heart valve, a stent, and a cardiac patch.

[0206] Example 26: The exemplary method according to Example 25, wherein the photoactive agent is selected from the group consisting of: aryl azide, azido-methyl-coumarin, benzophenone, anthraquinone, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoic acid (e.g., 2559 photoinitiator, Ciba-Geigy), methyl benzoylformate, phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide, 6-(4,4'-azidopentanamido)hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SDA, sulfo-NHS-LC-bis(aziridine), triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipids, porphyrins and dihydrochlorins.

[0207] Example 27: According to the exemplary method described in Example 25 or 26, the photoactive agent is added to the protein material by soaking the protein material in a solution containing the photoactive agent or by coating the protein material with a solution containing the photoactive agent.

[0208] Example 28: The exemplary method of examples 25, 26, or 27, wherein the photoactive agent is riboflavin and the protein material comprises collagen.

[0209] Example 29: The example method according to any one of Examples 25 to 28, wherein the at least one laser source is an ultrashort pulse laser.

[0210] Example 30: The example method according to any one of Examples 25 to 29, wherein the emission wavelength of the at least one laser source is 100 nm to 400 nm.

[0211] Example 31: The exemplary method of any one of Examples 25 to 30, wherein the cross-linking alters at least one mechanical property of the biomaterial selected from the group consisting of ultimate tensile strength, fatigue strength, and Young's modulus.

[0212] Example 32: The exemplary method according to any one of Examples 25 to 31, wherein the laser process produces a gradient of cross-links in the protein material by controlling the at least one laser source.

[0213] Example 33: An example of a prosthetic heart valve, comprising:

[0214] an annular frame radially collapsible to a collapsed configuration and radially expandable to an expanded configuration, the frame having an inflow end and an outflow end and defining a lumen of the prosthetic heart valve having a longitudinal axis along the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration;

[0215] a leaflet structure positioned within and secured to the frame; and

[0216] a skirt portion, the skirt portion comprising an inner skirt portion and an outer skirt portion, the inner skirt portion being positioned on an inner side of the frame, the outer skirt portion being positioned on an outer side of the frame, the inner skirt portion and the outer skirt portion being attached to at least a portion of the frame by a plurality of sutures;

[0217] wherein on the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back at a fold line toward the outflow end of the frame to form a cuff, and an edge portion of the outer skirt is secured to the outer skirt downstream of the fold line so that the cuff forms an inflow end of a laminated sealing member;

[0218] wherein at least one surface of the frame, the leaflets, the skirt, and the sutures is modified by a laser process comprising at least one laser source; and

[0219] wherein the laser process improves re-endothelialization and tissue regeneration of the prosthetic heart valve.

[0220] Example 34: The example method of Example 33, wherein the laser process is selected from the group consisting of direct laser writing, interference lithography, and any combination thereof.

[0221] Example 35: The example method of Example 33 or 34, wherein the at least one laser source is an ultrashort pulse laser.

[0222] Example 36: The exemplary method according to Example 35, wherein the pulse width of the ultrashort pulse laser is 1 millisecond to 1 femtosecond.

[0223] Example 37: An example method according to any one of Examples 33 to 36, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: infrared wavelengths of 700nm to 1mm, near-infrared wavelengths of 800nm ​​to 2500nm, visible light wavelengths of 380nm to 750nm, and ultraviolet wavelengths of 100nm to 400nm.

[0224] Example 38: The example method according to any one of Examples 33 to 37, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm and 193 nm.

[0225] Example 39: The example method according to any one of Examples 33 to 38, wherein the direct laser writing is performed using a direct laser writing system, the direct laser writing system comprising at least one laser beam, at least one substrate, and at least one galvanometer.

[0226] Example 40: An example method according to any one of Examples 33 to 39, wherein the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce a plurality of patterns; or the at least one laser beam is fixed and the at least one substrate moves to produce the plurality of patterns; or the at least one substrate and the at least one laser beam move simultaneously to produce the plurality of patterns.

[0227] Example 41: The example method of any one of Examples 33 to 40, wherein the direct laser writing system comprises a focusing optical device selected from the group consisting of a microscope objective and an f-theta lens.

[0228] Example 42: An example method according to any one of Examples 33 to 41, wherein at least one of the surfaces is flat, curved, uniform or non-uniform.

[0229] Example 43: The example method according to any one of Examples 33 to 42, wherein the at least one surface comprises at least one pattern, and the at least one pattern is produced by the laser process.

[0230] Example 44: The example method of Example 43, wherein at least one of the patterns is periodic or non-periodic.

[0231] Example 45: The example method of Example 43 or 44, wherein at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

[0232] Example 46: The example method of Example 43, 44 or 45, wherein at least one of the patterns comprises a layered structure or is multi-dimensional.

[0233] Example 47: The example method according to any one of Examples 43 to 46, wherein the at least one pattern is selected from the group consisting of: lines, straight lines, curves, grooves, pillars, holes, ridges, waves, depressions, squares, and any combination thereof.

[0234] Example 48: An exemplary method according to any one of Examples 43 to 47, wherein the at least one pattern has at least one shape selected from the group consisting of: circle, oval, rectangle, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon and any combination thereof.

[0235] Example 49: The example method of any one of Examples 43 to 48, wherein the at least one pattern comprises parallel rows.

[0236] Example 50: The example method of any one of Examples 33 to 49, wherein the laser process is part of a subtractive process or an additive process.

[0237] Example 51: The example method according to any one of Examples 33 to 50, wherein the laser process is a laser ablation process, wherein the laser ablation process changes the thickness of the at least one surface.

[0238] Example 52: The example method of Example 51, wherein the laser ablation process profiles the at least one surface and produces different thicknesses on the at least one surface.

[0239] Example 53: The example method of any one of Examples 33 to 52, wherein the laser process produces a surface coating on the at least one surface via at least one chemical agent applied to the at least one surface.

[0240] Example 54: The exemplary method of Example 53, wherein the surface coating changes the contact angle of the at least one surface.

[0241] Example 55: The exemplary method of any of Examples 33 to 54, wherein the leaflet comprises pericardial tissue and the laser process produces a consistent thickness throughout the leaflet.

[0242] Example 56: The example method of any of Examples 33 to 55, wherein the laser process creates a pattern on the at least one surface of the frame, and the pattern allows for easy tissue ingrowth and prevents paravalvular leakage.

[0243] Example 57: The example method of any of Examples 33 to 56, wherein the laser process modifies the surface energy and changes the contact angle of the at least one surface of the skirt or the seam.

[0244] Example 58: An example of a prosthetic heart valve, comprising:

[0245] an annular frame radially collapsible to a collapsed configuration and radially expandable to an expanded configuration, the frame having an inflow end and an outflow end and defining a lumen of the prosthetic heart valve having a longitudinal axis along the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration;

[0246] a leaflet structure positioned within and secured to the frame; and

[0247] a skirt portion, the skirt portion comprising an inner skirt portion and an outer skirt portion, the inner skirt portion being positioned on an inner side of the frame, the outer skirt portion being positioned on an outer side of the frame, the inner skirt portion and the outer skirt portion being attached to at least a portion of the frame by a plurality of sutures;

[0248] wherein on the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back at a fold line toward the outflow end of the frame to form a cuff, and an edge portion of the outer skirt is secured to the outer skirt downstream of the fold line so that the cuff forms an inflow end of a laminated sealing member;

[0249] wherein a laser process comprising at least one laser source locally cross-links the leaflets with a photoactive agent; and

[0250] Wherein the leaflet comprises a protein material and the laser process alters the chemical structure of the protein material.

[0251] Example 59: According to the exemplary method described in Example 58, the photoactive agent is selected from the group consisting of: aromatic azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropenoic acid (e.g., 2559 photoinitiator, Ciba-Geigy), methyl benzoylformate, phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide, 6-(4,4'-azidopentanamido)hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SDA, sulfo-NHS-LC-bis(aziridine), triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipids, porphyrins and dihydrochlorins.

[0252] Example 60: According to the exemplary method described in Example 58 or 59, the photoactive agent is added to the protein material by soaking the protein material in a solution containing the photoactive agent or by coating the protein material with a solution containing the photoactive agent.

[0253] Example 61. The exemplary method of examples 58, 59, or 60, wherein the photoactive agent is riboflavin and the protein material comprises collagen.

[0254] Example 62: The example method of any one of Examples 58 to 61, wherein the at least one laser source is an ultrashort pulse laser.

[0255] Example 63: The example method according to any one of Examples 58 to 62, wherein the emission wavelength of the at least one laser source is 100 nm to 400 nm.

[0256] Example 64: The example method of any one of Examples 58 to 63, wherein the cross-linking changes at least one mechanical property of the material selected from the group consisting of: ultimate tensile strength, fatigue strength, and Young's modulus.

[0257] Example 65: The exemplary method according to any one of Examples 58 to 64, wherein the laser process produces a gradient of cross-links in the protein material by controlling the at least one laser source.

Claims

1. A method for improving the biocompatibility of a structure for use in a prosthesis, the method comprising: applying a laser process to at least one surface of the structure to produce at least one pattern on the at least one surface; wherein the laser process comprises at least one laser source; wherein the laser process is selected from the group consisting of: direct laser writing, interference lithography, and any combination thereof; and Wherein the structure is at least one component of a device selected from the group consisting of: a prosthetic heart valve, a stent, and a cardiac patch.

2. The method of claim 1, wherein the component is selected from the group consisting of: a frame, a stent, a skirt, an outer skirt, an inner skirt, sutures, leaflets, and valve tissue.

3. The method of claim 1 or 2, wherein the surface comprises a material selected from the group consisting of: metals, metal alloys, stainless steel, nitinol, titanium, Co-Cr alloys, polymers, polymethyl methacrylate, polyetherketone, polyimide, polyamide, polyethylene, polytetrafluoroethylene, nylon, polydimethylsiloxane, silicone, polyethylene terephthalate, polybutylene terephthalate, polyesters, biopolymers, block copolymers of polycarbonate, poly(sulfone of bisphenol-A) (PSU)-PBT copolymers, collagen, acrylate collagen, chitosan, and pericardial tissue.

4. The method of claim 1, 2 or 3, wherein the at least one laser source is an ultrashort pulse laser. 5 . The method according to claim 1 , wherein the ultrashort pulse laser has a pulse width of 3 picoseconds to 50 femtoseconds.

6. The method according to any one of claims 1 to 5, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: infrared wavelengths of 700 nm to 1 mm, near infrared wavelengths of 800 nm to 2500 nm, visible light wavelengths of 380 nm to 750 nm, and ultraviolet wavelengths of 100 nm to 400 nm.

7. The method according to any one of claims 1 to 6, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm and 193 nm.

8. The method according to any one of claims 1 to 7, wherein the direct laser writing is performed using a direct laser writing system comprising at least one laser beam, at least one substrate and at least one galvanometer.

9. The method of claim 8, wherein the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce a plurality of patterns; or the at least one laser beam is fixed and the at least one substrate is moved to produce a plurality of patterns; Alternatively, the at least one substrate and the at least one laser beam are moved simultaneously to generate the plurality of patterns.

10. The method of claim 8 or 9, wherein the direct laser writing system comprises focusing optics selected from the group consisting of a microscope objective and an f-theta lens.

11. The method of any one of claims 1 to 10, wherein the at least one pattern improves re-endothelialization and tissue regeneration of the structure.

12. The method of any one of claims 1 to 11, wherein the laser process changes at least one property of the structure selected from the group consisting of: surface topography, thickness, and size.

13. The method according to any one of claims 1 to 12, wherein the at least one surface is flat, curved, uniform or non-uniform.

14. The method according to any one of claims 1 to 13, wherein the at least one pattern is periodic or aperiodic.

15. The method according to any one of claims 1 to 14, wherein at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

16. The method according to any one of claims 1 to 15, wherein the laser process is part of a subtractive process or an additive process.

17. The method of any one of claims 1 to 16, wherein the laser process is a laser ablation process, wherein the at least one pattern changes the thickness of the at least one surface.

18. The method of claim 17, wherein the laser ablation process profiles the at least one surface and creates different thicknesses on the at least one surface.

19. The method of any one of claims 1 to 18, wherein the at least one pattern comprises a layered structure or is multi-dimensional.

20. The method of any one of claims 1 to 19, wherein the at least one pattern comprises a pattern selected from the group consisting of lines, straight lines, curves, grooves, pillars, holes, ridges, waves, depressions, squares, and any combination thereof.

21. The method of any one of claims 1 to 20, wherein the at least one pattern has at least one shape selected from the group consisting of circle, oval, oblong, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon, and any combination thereof.

22. The method of any one of claims 1 to 21, wherein the at least one pattern comprises parallel rows.

23. The method of any one of claims 1 to 22, further comprising applying at least one chemical agent to the at least one surface prior to applying the laser process, wherein the laser process produces a surface coating of the at least one surface.

24. The method of claim 23, wherein the surface coating changes the contact angle of the at least one surface.

25. A method for modifying a biomaterial for use in a prosthesis, the method comprising: adding a photoactive agent to the protein material; and applying a laser process comprising at least one laser source to the protein material; wherein the at least one laser source locally cross-links the photoactive agent with the protein material and changes the chemical structure of the protein material; and Wherein the proteinaceous material is at least one component of a system or device selected from the group consisting of: a prosthetic heart valve, a stent, and a cardiac patch.

26. The method of claim 25, wherein the photoactive agent is selected from the group consisting of aryl azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), folic acid, n-hydroxylated acrylate, succinimidyl ester (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, methyl benzoylformate, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, 6-(4,4'-azidopentanamido)hexanoic acid sulfosuccinimidyl ester (sulfo-LC-SDA, sulfo-NHS-LC-bisaziridine), triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipid, porphyrin and dihydrochlorin.

27. The method of claim 25 or 26, wherein the photoactive agent is added to the protein material by soaking the protein material in a solution comprising the photoactive agent or by surface coating the protein material with a solution comprising the photoactive agent.

28. The method of claim 25, 26 or 27, wherein the photoactive agent is riboflavin and the protein material comprises collagen.

29. The method of any one of claims 25 to 28, wherein the at least one laser source is an ultrashort pulse laser.

30. The method of any one of claims 25 to 29, wherein the at least one laser source has an emission wavelength of 100 nm to 400 nm.

31. The method of any one of claims 25 to 30, wherein the cross-linking alters at least one mechanical property of the biomaterial selected from the group consisting of ultimate tensile strength, fatigue strength, and Young's modulus.

32. The method of any one of claims 25 to 31, wherein the laser process produces a gradient of cross-links in the protein material by controlling the at least one laser source.

33. A prosthetic heart valve comprising: an annular frame radially collapsible to a collapsed configuration and radially expandable to an expanded configuration, the frame having an inflow end and an outflow end and defining a lumen of the prosthetic heart valve with a longitudinal axis along the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration; a leaflet structure positioned within and secured to the frame; as well as a skirt portion, the skirt portion comprising an inner skirt portion and an outer skirt portion, the inner skirt portion being positioned on an inner side of the frame, the outer skirt portion being positioned on an outer side of the frame, the inner skirt portion and the outer skirt portion being attached to at least a portion of the frame by a plurality of sutures; wherein on the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back at a fold line toward the outflow end of the frame to form a cuff, and an edge portion of the outer skirt is secured to the outer skirt downstream of the fold line; wherein at least one surface of the frame, the leaflets, the skirt, and the sutures is modified by a laser process comprising at least one laser source; and wherein the laser process improves re-endothelialization and tissue regeneration of the prosthetic heart valve.

34. The prosthetic heart valve of claim 33, wherein the laser process is selected from the group consisting of direct laser writing, interference lithography, and any combination thereof.

35. A prosthetic heart valve according to claim 33 or 34, wherein the at least one laser source is an ultrashort pulse laser.

36. The prosthetic heart valve of claim 35, wherein the ultrashort pulse laser has a pulse width of 1 millisecond to 1 femtosecond.

37. A prosthetic heart valve according to any one of claims 33 to 36, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: infrared wavelengths of 700nm to 1mm, near infrared wavelengths of 800nm ​​to 2500nm, visible light wavelengths of 380nm to 750nm, and ultraviolet wavelengths of 100nm to 400nm.

38. The prosthetic heart valve of any one of claims 33 to 37, wherein the emission wavelength of the at least one laser source is selected from the group consisting of: 10.6 μm, 1060 nm, 1030 nm, 530 nm, 515 nm, 370 nm, 355 nm, 343 nm, 248 nm and 193 nm.

39. A prosthetic heart valve according to any one of claims 33 to 38, wherein the direct laser writing is performed using a direct laser writing system comprising at least one laser beam, at least one substrate and at least one galvanometer.

40. The prosthetic heart valve of any one of claims 33 to 39, wherein the at least one substrate is fixed and the at least one galvanometer moves the at least one laser beam to produce a plurality of patterns; or the at least one laser beam is fixed and the at least one substrate is moved to produce the plurality of patterns; Alternatively, the at least one substrate and the at least one laser beam are moved simultaneously to generate the plurality of patterns.

41. The prosthetic heart valve of any one of claims 33 to 40, wherein the direct laser writing system comprises focusing optics selected from the group consisting of a microscope objective and an f-theta lens.

42. The prosthetic heart valve of any one of claims 33 to 41, wherein the at least one surface is flat, curved, uniform or non-uniform.

43. The prosthetic heart valve of any one of claims 33 to 42, wherein the at least one surface comprises at least one pattern, the at least one pattern being produced by the laser process.

44. The prosthetic heart valve of claim 43, wherein the at least one pattern is periodic or aperiodic.

45. The prosthetic heart valve of claim 43 or 44, wherein at least one dimension of the at least one pattern is in the range of 1 nm to 1 mm.

46. ​​The prosthetic heart valve of claim 43, 44 or 45, wherein the at least one pattern comprises a layered structure or is multi-dimensional.

47. The prosthetic heart valve of any one of claims 43 to 46, wherein the at least one pattern is selected from the group consisting of lines, straight lines, curves, grooves, struts, holes, ridges, waves, depressions, squares, and any combination thereof.

48. The prosthetic heart valve of any one of claims 43 to 47, wherein the at least one pattern has at least one shape selected from the group consisting of: circle, oval, oblong, triangle, quadrilateral, rectangle, square, diamond, trapezoid, hexagon, octagon, and any combination thereof.

49. The prosthetic heart valve of any one of claims 43 to 48, wherein the at least one pattern comprises parallel rows.

50. A prosthetic heart valve according to any one of claims 33 to 49, wherein the laser process is part of a subtractive process or an additive process.

51. A prosthetic heart valve according to any one of claims 33 to 50, wherein the laser process is a laser ablation process, wherein the laser ablation process changes the thickness of the at least one surface.

52. The prosthetic heart valve of claim 51 , wherein the laser ablation process contours the at least one surface and creates varying thicknesses on the at least one surface.

53. A prosthetic heart valve according to any one of claims 33 to 52, wherein the laser process produces a surface coating on the at least one surface via at least one chemical agent applied to the at least one surface.

54. The prosthetic heart valve of claim 53, wherein the surface coating alters the contact angle of the at least one surface.

55. The prosthetic heart valve of any one of claims 33 to 54, wherein the leaflets comprise pericardial tissue and the laser process produces a consistent thickness throughout the leaflets.

56. The prosthetic heart valve of any one of claims 33 to 55, wherein the laser process creates a pattern on the at least one surface of the frame, and the pattern allows for easy tissue ingrowth and prevents paravalvular leakage.

57. The prosthetic valve of any one of claims 33 to 56, wherein the laser process modifies surface energy and changes the contact angle of the at least one surface of the skirt or the suture.

58. A prosthetic heart valve comprising: an annular frame radially collapsible to a collapsed configuration and radially expandable to an expanded configuration, the frame having an inflow end and an outflow end and defining a lumen of the prosthetic heart valve with a longitudinal axis along the prosthetic heart valve when the prosthetic heart valve is in the expanded configuration; a leaflet structure positioned within and secured to the frame; as well as a skirt portion, the skirt portion comprising an inner skirt portion and an outer skirt portion, the inner skirt portion being positioned on an inner side of the frame, the outer skirt portion being positioned on an outer side of the frame, the inner skirt portion and the outer skirt portion being attached to at least a portion of the frame by a plurality of sutures; wherein on the outer side of the frame, the outer skirt extends in an upstream direction along the longitudinal axis and is folded back at a fold line toward the outflow end of the frame to form a cuff, and an edge portion of the outer skirt is secured to the outer skirt downstream of the fold line; wherein a laser process comprising at least one laser source locally cross-links the leaflets with a photoactive agent; and Wherein the leaflet comprises a protein material and the laser process alters the chemical structure of the protein material.

59. The prosthetic heart valve of claim 58, wherein the photoactive agent is selected from the group consisting of aryl azides, azido-methyl-coumarins, benzophenones, anthraquinones, diazo compounds, diaziridine psoralen derivatives, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B12 (cobalamin), phyllo Acid, n-hydroxysuccinimide ester of acrylic acid (ANHS), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, methyl benzoylformate, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, sulfosuccinimide 6-(4,4'-azidopentanamido)hexanoate (sulfo-LC-SDA, sulfo-NHS-LC-bis(aziridine), triethylamine, deoxyribonucleic acid, bis-acylphosphine oxide, pyrolipids, porphyrins and chlorins.

60. The prosthetic heart valve of claim 58 or 59, wherein the photoactive agent is added to the protein material by soaking the protein material in a solution comprising the photoactive agent or by surface coating the protein material with a solution comprising the photoactive agent.

61. The prosthetic heart valve of claim 58, 59 or 60, wherein the photoactive agent is riboflavin and the protein material comprises collagen.

62. The prosthetic heart valve of any one of claims 58 to 61, wherein the at least one laser source is an ultrashort pulse laser.

63. The prosthetic heart valve of any one of claims 58 to 62, wherein the at least one laser source has an emission wavelength of 100 nm to 400 nm.

64. The prosthetic heart valve of any one of claims 58 to 63, wherein the cross-linking alters at least one mechanical property of the material selected from the group consisting of: ultimate tensile strength, fatigue strength, and Young's modulus.

65. The prosthetic heart valve of any one of claims 58 to 64, wherein the laser process produces a gradient of cross-links in the protein material by controlling the at least one laser source.

Images