Bioprosthetic device and methods of manufacturing the same

Abstract

A bioprosthesis device includes a frame and a bioprosthesis tissue that contains collagen and includes a plurality of pores. The bioprosthesis tissue is attached to the frame. The bioprosthesis device includes a plurality of sutures that extend through the plurality of pores. In aspects, a perimeter of the plurality of pores has a greater collagen cross-linking density or elastic modulus than a bulk of the bioprosthesis tissue. The bioprosthesis device can be a prosthetic heart valve assembly. Alternatively, a collagen-containing scaffold can have a predetermined location that has a greater collagen cross-linking density or elastic modulus than a bulk of the collagen-containing scaffold. Methods include: applying a cross-linking agent to the predetermined location. Methods further include: cross-linking collagen at the predetermined location by irradiating the predetermined location with a light beam, but a majority of a surface area of the bioprosthesis tissue does not have collagen cross-linked by the irradiation.

Description

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 568043, filed March 21, 2024, pursuant to 35 USC § 119, the contents of which are based on and incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure generally relates to biological prosthetic devices and methods of manufacturing thereof, and more specifically, to a prosthetic heart valve device having a biological prosthetic tissue comprising collagen and a method of manufacturing thereof. Background Technology

[0003] A prosthetic heart valve assembly is known for implantation into a target site within a patient's vascular system. The heart valve prosthesis can be moved from a radially constricted position to a radially expanded position.

[0004] It is known to use sutures to attach bioprosthetic tissue to the framework of a prosthetic heart valve assembly. However, the prosthetic heart valve assembly can be damaged, for example, when the sutures are pulled out of the bioprosthetic tissue due to manipulation or even ordinary abrasion. Damage to the prosthetic heart valve assembly can lead to serious health consequences and require expensive medical procedures to replace the prosthetic heart valve assembly. Therefore, there is a need to improve the suture pull-out resistance of bioprosthetic tissue used in bioprosthetic devices, including prosthetic heart valve assemblies. Summary of the Invention

[0005] The following is a simplified overview of this disclosure to provide a basic understanding of some of the aspects described in the detailed description.

[0006] This article describes a bioprosthetic tissue (e.g., as part of a bioprosthetic device) having increased mechanical properties and / or crosslinking density of collagen at one or more predetermined locations, and a method for manufacturing the bioprosthetic tissue (e.g., selectively crosslinking collagen in the bioprosthetic tissue). These one or more predetermined locations may correspond to locations in the bioprosthetic tissue where pores exist, for example, where the bioprosthetic tissue is sutured to the remainder of the bioprosthetic device (e.g., a frame). Providing increased corresponding properties at and / or near the pores (e.g., corresponding to suture locations) at these one or more predetermined locations in the bioprosthetic tissue, relative to the crosslinking density, elastic modulus, shear modulus, and / or sound velocity of the bioprosthetic tissue itself, can improve the resistance of the bioprosthetic tissue and / or the corresponding bioprosthetic device to suture pull-out. In various respects, the regions at the one or more predetermined locations with enhanced properties can be surrounded by an intermediate region whose properties lie between those at the one or more predetermined locations and those of the bulk of the bioprosthetic tissue. This can further improve the resistance to suture pull-out, for example, by smoothing the transition between the properties at the one or more predetermined locations and those of the bulk of the bioprosthetic tissue. Providing enhanced mechanical properties allows the bioprosthetic tissue to closely mimic the properties of biological tissue in the bulk, while improving the resistance to suture pull-out at the one or more predetermined locations corresponding to the positions of multiple sutures. Moreover, the method of this disclosure selectively crosslinks collagen at one or more predetermined locations in the bioprosthetic tissue by applying a crosslinking agent and then activating the crosslinking agent by irradiating it with an optical wavelength to which it is sensitive.

[0007] In various aspects, a bioprosthetic device includes a frame and a bioprosthetic tissue comprising collagen, the bioprosthetic tissue including multiple pores. The bioprosthetic tissue can be attached to the frame. Multiple sutures can extend through the multiple pores. The periphery of the multiple pores can have a greater collagen cross-linking density compared to the body of the bioprosthetic tissue.

[0008] In various aspects, a bioprosthetic device includes a frame and a bioprosthetic tissue comprising collagen, the bioprosthetic tissue including multiple pores. The bioprosthetic tissue can be attached to the frame. Multiple sutures can extend through the multiple pores. The periphery of the multiple pores can have a greater elastic modulus compared to the body of the bioprosthetic tissue.

[0009] In various aspects, a method for selectively crosslinking bioprosthetic tissue includes applying a crosslinking agent to one or more predetermined sites of the bioprosthetic tissue containing collagen. The method further includes crosslinking the collagen at the one or more predetermined sites by irradiating them with a light beam. The light beam includes an optical wavelength to which the crosslinking agent is sensitive. A significant portion of the surface area of ​​the bioprosthetic tissue may not contain collagen crosslinked by the irradiation.

[0010] Additionally or alternatively, an increasing gradient (including smooth, continuous, and / or stepwise increases) of crosslink density and / or mechanical properties can be formed in the bioprosthetic tissue and / or collagen-containing scaffold. Providing an increasing gradient of crosslink density and / or mechanical properties can promote upward migration of cells along the increasing gradient of the collagen-containing scaffold and / or enhanced colonization of cells at or near the maximum value of the increasing gradient. Furthermore, enhanced migration of cells along the increasing gradient and / or enhanced colonization at (or near) the maximum value of the increasing gradient can provide further increases in the mechanical properties, biocompatibility, and / or lifespan of the resulting material (e.g., bioprosthetic tissue formed by colonization of a collagen-containing scaffold with an increasing gradient of crosslink density and / or mechanical properties, wherein this increased gradient will still remain in the resulting bioprosthetic tissue.

[0011] Additional features and advantages of the aspects disclosed herein will be set forth in the following detailed description, and will be apparent in part to those skilled in the art from that description, or will be recognized by practice of the aspects described herein, including the following detailed description, the claims, and the drawings. It should be understood that the foregoing general description and the following detailed description present aspects intended to provide an overview or framework for understanding the nature and characteristics of the aspects disclosed herein. The drawings are included to provide further understanding and are incorporated in and form a part of this specification. The drawings illustrate various aspects of this disclosure and, together with the specification, explain the principles and operation of this disclosure. Attached Figure Description

[0012] These and other features, aspects, and advantages will be better understood when the following detailed description is read with reference to the accompanying drawings: Figure 1 Examples of transcatheter heart valve prostheses according to various aspects of this disclosure are illustrated schematically. Figure 2 A top view of a transcatheter heart valve prosthesis is shown, illustrating various aspects of the present disclosure. Figure 3A side view of a delivery assembly for delivering a transcatheter heart valve prosthesis is shown, according to various aspects of this disclosure. Figure 4 A side view of a delivery assembly for delivering a transcatheter heart valve prosthesis is shown, according to various aspects of this disclosure. Figure 5 The guide sheath is shown in accordance with the various aspects of this disclosure; Figure 6 The guide sheath is shown in accordance with the various aspects of this disclosure; Figure 7 A side view of a bioprosthetic heart valve with sutures, as shown in various aspects of this disclosure, is presented. Figure 8 Showing Figure 7 Bottom view of a biological prosthetic heart valve; Figure 9 A side view of another bioprosthetic heart valve with sutures is shown, according to various aspects of this disclosure; Figure 10 The steps of dispensing a crosslinking agent into a collagen-containing bioprosthetic tissue are illustrated schematically according to various aspects of the method. Figure 11 Showed along Figure 10 A schematic diagram of collagen extracted by line 11-11; Figure 12 A schematic diagram of a collagen-containing and porous bioprosthetic tissue stretched according to various aspects of the method is shown. Figure 13 The method demonstrates how to irradiate one or more predetermined locations of a biological prosthetic tissue with a light beam to induce collagen cross-linking, according to various aspects of the method. Figure 14 The diagram schematically illustrates cross-linked collagen in a bioprosthetic tissue, which, for example, corresponds to the method described in this disclosure. Figure 11 The biological prosthetic tissue shown; Figure 15 The diagram schematically illustrates cross-linked collagen in a bioprosthetic tissue, wherein the cross-linking is confined to the peripore area, and this bioprosthetic tissue corresponds, for example, to the method described in this disclosure. Figure 12 The biological prosthetic tissue shown; and Figure 16 This schematically illustrates a collagen-containing scaffold and / or bioprosthetic tissue in which the cross-linking density increases toward a predetermined location. Detailed Implementation

[0013] The aspects will now be described more fully below with reference to the accompanying drawings, in which example aspects are shown. Wherever possible, the same reference numerals are used throughout the drawings to refer to the same or similar parts. However, this disclosure may be implemented in many different forms and should not be construed as limited to the aspects set forth herein.

[0014] As used herein, the term “about” means that quantities, dimensions, formulations, parameters and other quantities and characteristics are not and need not be precise, but can be approximated and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors and other factors known to those skilled in the art.

[0015] A range in this text can be expressed as from “about” one value and / or to “about” another value. When such a range is expressed, each aspect includes the transition from one value to another. Similarly, when a value is expressed as an approximation using the antecedent “about,” it will be understood that the value forms another aspect. It will be further understood that each endpoint of a range is significant both relative to and independent of the other endpoint.

[0016] The directional terms used in this article, such as up, down, right, left, front, back, top, bottom, upper, lower, etc., are for reference only with reference to the accompanying drawings and are not intended to imply absolute orientation.

[0017] Unless expressly stated otherwise, it is never intended to interpret any method set forth herein as requiring its steps to be performed in a particular order, nor should any device be required to have a particular orientation. Accordingly, where a method claim does not actually describe the order in which its steps are to be followed, or where any device claim does not actually describe the order or orientation of the components, or where the claims or description do not otherwise specifically state that the steps will be limited to a particular order, or where no particular order or orientation of the components of the device is described, it is never intended to infer any order or orientation. This applies to any possible non-express basis of interpretation, including logical questions relating to the arrangement of steps, the flow of operation, the order of components, or the orientation of components; the general meaning derived from grammatical organization or punctuation; and the number or type of aspects described in the description.

[0018] As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, unless the context clearly indicates otherwise, a reference to “a” component includes aspects having two or more such components.

[0019] The terms “exemplary,” “example,” or their various forms are used herein to mean something that serves as an example, instance, or illustration. Any aspect or design described herein as “exemplary” or “example” is not necessarily to be construed as preferred or advantageous over other aspects or designs. Furthermore, examples are provided solely for clarity and understanding and are not intended to limit or constrain the disclosed subject matter or relevant portions of this disclosure in any way. It is understood that numerous additional or alternative examples of varying scope may be presented, but these examples have been omitted for the sake of brevity.

[0020] As used herein, unless otherwise indicated, the terms “including,” “comprising,” and their variations shall be interpreted as synonymous and open-ended. A list of elements following the transitional phrase “including” or “comprising” is a non-exclusive list, allowing for the presence of elements other than those specifically described in the list.

[0021] As used herein, the terms “substantial,” “substantially,” and their variations are intended to mean that the described feature is equal to or approximately equal to a value or description. For example, a “substantially planar” surface is intended to mean a planar or approximately planar surface. Furthermore, “substantially” is intended to mean that two values ​​are equal or approximately equal. The term “substantially” can mean values ​​within approximately 10% of each other, for example, within approximately 5% of each other or within approximately 2% of each other.

[0022] Modifications to this disclosure may be made without departing from the scope or spirit of the claimed subject matter. Unless otherwise stated, terms such as "first," "second," etc., are not intended to imply temporal, spatial, or sequential aspects. Rather, such terms are used only as identifiers or names of features, elements, items, etc. For example, the first end and the second end typically correspond to end A and end B, or two distinct ends.

[0023] Unless otherwise indicated, the terms “distal” and “proximal” are used in the following description to refer to a position or orientation relative to the clinician performing the treatment. “Distal” and “towards distal” are positions away from the clinician or in a direction away from the clinician, and “proximal” and “towards proximal” are positions close to the clinician or in a direction toward the clinician. Additionally, the term “self-expanding” may be used in the following description of one or more valve or stent structures of the prosthesis described herein and is intended to convey that these structures are shaped or formed from materials capable of possessing mechanical memory, such that the structure returns from a compressed or contracted delivery configuration to an expanded unfolded configuration, and vice versa. Exemplary, non-exhaustive, self-expanding materials include stainless steel, pseudoelastic metals (such as nitinol or nickel-titanium alloys), various polymers, or so-called superalloys (which may have a base metal of nickel, cobalt, chromium, or other metals). Mechanical memory can be imparted to the wiring or stent structure by heat treatment, for example, to achieve spring tempering in stainless steel, or to set shape memory in a sensitive metal alloy (such as nickel-titanium). Various polymers that can be formulated to possess shape memory properties are also suitable for use in the various aspects described herein, including polymers such as polynorbornene, trans-polyisoprene, styrene-butadiene, and polyurethane. PolyLD lactic acid copolymers, oligomeric caprolactone copolymers, and polycyclooctylene can also be used alone or in combination with other shape memory polymers.

[0024] Diseases associated with heart valves (such as those caused by damage or defects) may include stenosis and valvular insufficiency or regurgitation. For example, valvular stenosis makes the valve narrow and stiff, which may prevent blood from flowing to the downstream chambers of the heart at the proper flow rate and may cause the heart to work harder to pump blood through the diseased valve. Valvular insufficiency or regurgitation occurs when the valve does not close completely, causing blood to flow back and thus reducing the heart's efficiency. Valve disease or damage, which may be congenital, age-related, drug-induced, or in some cases caused by infection, can cause the heart to enlarge and thicken, losing elasticity and efficiency. Some symptoms of heart valve disease may include weakness, shortness of breath, dizziness, syncope, palpitations, anemia, and edema, as well as blood clots that may increase the likelihood of stroke or pulmonary embolism. Symptoms can often be severe enough to debilitate and / or be life-threatening.

[0025] This disclosure generally relates to bioprosthetic devices comprising bioprosthetic tissue containing collagen. Example aspects of such bioprosthetic devices include stents and prosthetic heart valve assemblies, including surgical prosthetic heart valve assemblies and transcatheter heart valve assemblies. Prosthetic heart valve assemblies can be configured to replace the function of the mitral, tricuspid, pulmonary, or aortic valve. While transcatheter heart valve assemblies (e.g., for replacing the function of the aortic valve) are discussed below, it should be understood that this is exemplary, and locally increased collagen crosslink density, locally increased elastic modulus, locally increased sound velocity, etc., and their associated formation methods are applicable to bioprosthetic devices generally comprising all prosthetic heart valve assemblies. Furthermore, bioprosthetic tissue includes autologous tissue, xenograft material, or cultured tissue or other synthetic tissue, provided that the bioprosthetic tissue contains collagen (e.g., fibrils).

[0026] Heart valve prostheses have been developed for the repair and replacement of diseased and / or damaged heart valves. Such heart valve prostheses can be percutaneously delivered and deployed at the site of the diseased heart valve using a catheter-based delivery system. These heart valve prostheses typically comprise a frame or stent and a prosthetic valve housed within the frame. Such heart valve prostheses are delivered in a radially compressed or coiled configuration to allow the prosthesis to advance through the patient's vascular system. Once positioned at the treatment site, the heart valve prosthesis inflates to engage with tissue located in the region of the diseased heart valve, thereby, for example, securing the heart valve prosthesis in place.

[0027] Figures 1 to 2 An example transcatheter heart valve prosthesis 10 is shown. The delivery components described herein can be used with the transcatheter heart valve prosthesis 10 and / or other transcatheter heart valve prostheses. The transcatheter heart valve prosthesis 10 is shown to facilitate the description of this disclosure. The following description of the transcatheter heart valve prosthesis 10 is merely exemplary in nature and is not intended to limit the invention or its application and use.

[0028] Figures 1 to 2 The images show a side view and a top (outflow end) view of a transcatheter heart valve prosthesis 10. The transcatheter heart valve prosthesis 10 includes a radially expandable frame 15 and a prosthetic valve 20. The frame 15 of the transcatheter heart valve prosthesis 10 supports the prosthetic valve 20 within the frame 15. Figure 1 and Figure 2 In the example transcatheter heart valve prosthesis 10 shown, the frame 15 is self-expanding. However, this is not intended to be limiting, and in other respects, the frame 15 may be balloon-expandable or mechanically expandable.

[0029] The prosthetic valve 20 includes at least one leaflet 21 disposed within and fixed to the frame 15. Figure 1 and Figure 2 In the aspect shown, the prosthetic valve 20 includes exactly three leaflets 21, as... Figure 2 As shown. However, this is not intended to be limiting, as the prosthetic valve 20 may include more or fewer leaflets 21. The leaflets 21 open and close to regulate flow through the transcatheter heart valve prosthesis 10. See below for reference. Figures 7 to 8 As discussed, one or more leaflets 21 can be attached (e.g., fixed) to the frame 15 using multiple sutures 723 and 801.

[0030] like Figure 1 As shown, the transcatheter heart valve prosthesis 10 includes an inflow end 11 and an outflow end 12. A leaflet 21 is attached to a frame 15 at a slit 25 such that when the pressure at the inflow end 11 exceeds the pressure at the outflow end 12, the leaflet 21 opens to allow blood to flow from the inflow end 11 through the transcatheter heart valve prosthesis 10 to the outflow end 12. When the pressure at the outflow end 12 exceeds the pressure at the inflow end 11, the leaflet 21 closes to prevent blood from flowing from the outflow end 12 to the inflow end 11. Accordingly, the at least one leaflet (e.g., leaflet 21) can be attached to a plurality of struts 16, either directly at the slit 25 or indirectly, for example, by attachment to a skirt, a slit bracket, or other structure (e.g., a mechanical actuator) attached to the plurality of struts 16.

[0031] The frame 15 of the transcatheter heart valve prosthesis 10 further includes a plurality of struts 16 arranged to form a plurality of units, such as a first unit 18 and / or an inlet unit 14, which are arranged circumferentially and longitudinally around a longitudinal axis LA of the transcatheter heart valve prosthesis 10 to form a tubular structure defining a central lumen 13 of the transcatheter heart valve prosthesis 10. For example, the frame 15 may extend along the longitudinal axis LA between an inlet end 11 and an outlet end 12. The frame 15 is configured to secure the prosthetic valve 20 within the central lumen 13 of the frame 15 and to secure the transcatheter heart valve prosthesis 10 in the appropriate position within the patient's vascular system. The struts 16 are defined herein as elongated connecting segments of the frame 15. The struts 16 converge to form a coronal portion 17 or a node 19, as shown below. Figure 1 As can be seen, the frame 15 of the transcatheter heart valve prosthesis 10 includes multiple units (e.g., a first unit 18, an entry unit 14) defined as spaces between multiple coronals 17, multiple nodes 19, and multiple struts 16. The frame 15 and therefore the multiple struts 16 can be adjustable between a radially collapsed position and a radially expanded position.

[0032] exist Figure 1 In the illustrated example, the plurality of units may be rhomboid. In the illustrated example, the plurality of units includes a plurality of first units 18 and access units 14. Specifically, the access units are larger than the first units 18, and when the transcatheter heart valve prosthesis 10 is implanted in a patient, the access units provide access to one or more coronary arteries. In the illustrated example, there are exactly three access units 14. However, this is not intended to be limiting, as the frame 15 of the transcatheter heart valve prosthesis 10 may include more, fewer, or no access units 14. Each access unit 14 has an enlarged area relative to or compared to the first units 18, such as... Figure 1 As can be seen in the image. Furthermore, entry into unit 14 can be located in addition to... Figure 1 Other locations besides those shown. Although not shown, in some respects, the transcatheter heart valve prosthesis 10 may include an outer skirt (see [reference]). Figure 7 The outer skirt 721 and / or the inner skirt 711, and / or Figure 9 The skirt 931 shown in the overall diagram extends circumferentially around the outer periphery of the frame 15 at or near the inflow end 11 to prevent paravalvular leakage of blood around the outside of the transcatheter heart valve prosthesis once the transcatheter heart valve prosthesis 10 is implanted in the patient.

[0033] Figures 3 to 4 A side view of a delivery assembly 30 for delivering and deploying a transcatheter heart valve prosthesis (e.g., transcatheter heart valve prosthesis 10) according to aspects herein is schematically shown. Those skilled in the art will recognize that... Figures 3 to 4 An example of delivery component 30 is shown, and it can be removed. Figures 3 to 4 The components shown are shown in the diagram and / or additional components may be added. The delivery assembly 30 includes a proximal end 32, a distal end 31, and a handle 33. The handle 33 allows a physician to manipulate the distal portion of the delivery assembly 30 and includes an actuator for moving a portion of the delivery assembly 30 relative to the other portions. In the delivery assembly 30, an outer shaft 34 is coupled to an actuator 39 of the handle 33 for moving the outer shaft 34 relative to an inner shaft 36.

[0034] The distal portion of the outer shaft 34 (referred to as the sac 35) is configured to surround the transcatheter heart valve prosthesis (e.g., transcatheter heart valve prosthesis 10) during delivery to the treatment site (e.g., autologous heart valve) and retract from the transcatheter heart valve prosthesis to expose it, thereby allowing it to self-expand. The inner shaft 36 is coupled to the handle 33, and movement of the handle 33 translates into movement of the inner shaft 36 and a distal end 37 (e.g., a head cone) coupled to the distal end of the inner shaft 36. The inner shaft 36 and the distal end 37 (e.g., the head cone) can also be translated relative to the outer shaft 34 and the handle 33 via an end retraction device. In the illustrated aspect, the inner shaft 36 includes a retainer 38 (e.g., a main shaft) for receiving the flaps of the transcatheter heart valve prosthesis 10.

[0035] When actuator 39 is actuated, actuator 39 causes the outer shaft 34 and the bladder portion 35 to move relative to the inner shaft 36, such as Figure 4 As shown. As those skilled in the art know, when the delivery assembly 30 is in place such that the transcatheter heart valve prosthesis 10 is in the desired position at the treatment site in the patient's vascular system, the actuator 39 is actuated to move the balloon 35 relative to the inner shaft 36 and the transcatheter heart valve prosthesis 10 disposed between the inner shaft 36 and the balloon 35, thereby allowing the transcatheter heart valve prosthesis 10 to expand at the treatment site via self-expansion and be released from the retainer 38, as Figure 4 As shown (transcatheter heart valve prosthesis 10 is not shown).

[0036] Minimally invasive percutaneous interventional procedures (including endovascular procedures) require access to the venous or arterial system. Typically, the goal is to create the smallest possible incision point with the shortest possible tissue contact time upon entry into the body. Smaller incisions and shorter tissue contact times generally improve patient outcomes, reduce complications, and minimize trauma to the blood vessel or organ being accessed, as well as to the skin and tissue through which the entry point is created. Various medical procedures that percutaneously deliver or implant structural elements (such as heart valves, heart valve repair devices, occluders, grafts, electrical stimulators, leads, etc.) require access. Some procedures use relatively large devices that require relatively large sheaths to deliver the device to the intended site within the body. With such procedures, entry site trauma can occur, which typically leads to vascular injury, excessive bleeding, increased case management time, increased risk of infection, and longer hospital stays. To minimize entry trauma, physicians attempt to use the smallest possible device and place the smallest possible sheath. However, it can be problematic if a physician discovers during the procedure that a larger device is needed. This necessitates a larger sheath, which is a lengthy procedure and increases risks to the patient. The expandable sheath can expand inside the body and therefore does not need to be removed to increase its size.

[0037] The expandable sheath design can be regionally or locally expandable to selectively and temporarily expand as the device passes through the area of ​​the sheath and retract or return to its original position when the device has not passed through or has passed through the sheath. The aspects disclosed herein can be used in conjunction with an expandable guide sheath that can address these and other issues contributing to vascular trauma. The expandable guide sheath disclosed herein is described in relation to percutaneous access for transcatheter heart valve repair or replacement, and it should be understood that one or more features of the expandable guide sheath can be used alone or in combination for other medical procedures requiring percutaneous access, including but not limited to stent placement, angioplasty, clearance of arterial or venous calcifications, and pre- or post-dilation.

[0038] The aspects disclosed herein may include a guide sheath having a selectively inflatable diameter to allow relatively large devices to pass through, and further configured to return to the original diameter of the guide sheath after the device has passed through. These aspects can reduce damage to surrounding tissues by minimizing contact and by eliminating the need to change sheaths of different sizes. Therefore, compared to known sheaths, these aspects can shorten procedure time, reduce vascular trauma, reduce bleeding, and lower the risk of resulting infection and other complications. However, it should be understood that this disclosure is not limited to use with inflatable guide sheaths. Rather, one or more features of this disclosure may be used alone or in combination, without a guide sheath, with a non-inflatable guide sheath, or with an inflatable guide sheath. Similarly, if a guide sheath is used, it may be an integral guide sheath (e.g., a guide sheath integrated with a delivery component) or a non-integral guide sheath (e.g., a guide sheath separate from the delivery component but configured for use with the delivery component).

[0039] Figures 5 to 6 An exemplary aspect of a guide sheath 50 is depicted, which is positioned through an incision 60 in the patient's skin 65 and enters into the patient's blood vessel 40. The guide sheath 50 has a tubular shaft 55 and a proximal hub 56, which has a hemostatic seal and a Luer lock 57. Figure 5 The guide sheath 50, positioned within the blood vessel 40, is shown in its normal, uninflated state. Figure 6 A guide sheath 50 positioned within a blood vessel 40 is shown, wherein a delivery device 75 delivers another device 70, which is advanced through the guide sheath 50, causing a tubular shaft 55 to expand or deform at the location where the device 70 passes. As the device 70 passes, the tubular shaft 55 expands at an expansion region 58, and then retracts or returns to its original diameter after the device 70 moves past or is removed from the tubular shaft. Thus, the tubular shaft 55 is configured to be both expandable and retractable.

[0040] In all respects, the expandability of the tubular shaft 55 (and any shaft described according to any aspect set forth herein) is achieved by the elasticity of the tubular shaft 55, which allows the tubular shaft 55 to be self-expanding or self-expanding or mechanically expandable or mechanically expandable. For the purposes of this application, self-expanding means that the tubular shaft 55 is configured to automatically expand to a predetermined or nominal diameter (without any type of actuation, whether mechanical or otherwise). Further, for the purposes of this application, mechanically expandable means that the tubular shaft 55 is configured to expand when a positionable medical device is positioned to pass through the tubular shaft 55. That is, the device passing through the tubular shaft 55 itself causes the expansion of the tubular shaft 55, such as Figure 6 As described in [the text]. Alternatively, the expandable properties of a tubular shaft can be caused by factors other than elasticity.

[0041] The tubular shaft 55 is configured to be retractable, retractable, or return to its original unexpanded state after the device has passed through it, such as... Figure 5 As depicted in the description. In some aspects, retractability can be achieved by the elasticity of the tubular shaft 55, which can make the tubular shaft 55 self-retractable, self-recovering, self-contracting, or mechanically retractable, mechanically recoverable, or mechanically retractable. For the purposes of this application, self-retractability means that the tubular shaft 55 is configured to automatically retract to a predetermined or nominal diameter (without any type of actuation, whether mechanical or otherwise). Further, for the purposes of this application, mechanical retractability means that the tubular shaft 55 is configured to retract when a device or component is used to retract or recover the tubular shaft 55. Alternatively, the retractability characteristic of the tubular shaft 55 can be caused by factors other than elasticity.

[0042] For the purposes of this application, any device that can be positioned by a guide sheath according to any aspect disclosed or contemplated herein may be referred to as a positionable medical device or an insertable medical device. Such devices include guidewires, dilators, delivery devices (for delivery and / or placement of structural elements such as heart valves, heart valve repair devices, occluders, grafts, electrical stimulators, leads, etc.), guiding catheters, guide sheaths, diagnostic catheters, stent delivery systems, balloon catheters, and other known vascular devices. Other devices may include non-vascular devices such as endoscopes and other common surgical instruments. Further, the guide sheath is configured to receive tissue or organ. Thus, by way of non-limiting example, the guide sheath 50 is described as an inflatable guide sheath 50 for guiding a delivery assembly 30 including a transcatheter heart valve prosthesis 10. In another example, the guide sheath 50 is used to guide a guiding catheter that includes an inflation device for pre-dilation or post-dilation procedures.

[0043] Figures 7 to 8 The sutures 723 and 801 on the transcatheter heart valve prosthesis 10 and the skirt (e.g., inner skirt 711 and / or outer skirt 721) are clearly shown. For example, as discussed above and as... Figure 7 As shown, at least one leaflet 21 can be attached to the frame 15 at the suture 25 via a suture 723. The at least one leaflet 21 may include an attachment edge 701 at which the suture 723 attaches the frame 15 to the outer skirt 721 and / or the inner skirt 711, for example, thereby forming a continuous outer surface 725 or inner surface 803 of the prosthetic valve 20 containing bioprosthetic tissue. The leaflet 21, the outer skirt 721, and / or the inner skirt 711 may contain bioprosthetic tissue. Moreover, as... Figure 8 As shown in the bottom view, the inner surface 803 may include an inner skirt 711 attached to the frame 15 by a plurality of stitches 801, which can be connected to... Figure 7 The suture 723 shown is the same as or a supplement to it.

[0044] Figure 9 Another aspect of the bioprosthetic device 901 is shown, which may be the same as or different from the transcatheter heart valve prosthesis 10 discussed above. The bioprosthetic device 901 includes an outflow end 912 (and an inflow end opposite the outflow end). As shown, a plurality of sutures 921 can attach a skirt 931 (which may generally correspond to the outer skirt 721 and / or inner skirt 711 discussed above) to a frame 911. It should be understood that, without departing from the scope of this disclosure, in another aspect, the location and number of sutures in the plurality of sutures 921 may be different. For example, the plurality of sutures 921 between the skirt 931 and the frame 911 may be independent of the location of any leaflet, for example, substantially uniformly distributed on the skirt 931, concentrated at the ends of the skirt 931, or in combination thereof, or in a completely different arrangement.

[0045] Figure 15 The diagram schematically illustrates the portion of the bioprosthetic tissue 1501 corresponding to the location where the bioprosthetic tissue 1501 is sutured (directly or indirectly) to the frame. For example, see reference... Figure 2 and Figure 7 , Figure 15 The biological prosthetic tissue 1501 may correspond to the portion of one or more leaflets 21 attached to the suture 25 (e.g., via suture 723). Additionally or alternatively, as... Figures 8 to 9 As shown, Figure 15The bioprosthetic tissue 1501 can be attached to the frame 15 or 911 at a location corresponding to the skirt (e.g., inner skirt 711, outer skirt 721, skirt 931). Furthermore, as discussed above, the bioprosthetic tissue 1501 contains collagen (e.g., shown as triple helices of collagen fibers as fibrils 1241, 1243, 1231, and 1233). As schematically shown by asterisk 1535, fibrils 1231 and 1233 can be cross-linked together.

[0046] like Figure 15 As shown, opening 1211 is defined by the inner periphery 1213 of the bioprosthetic tissue 1501, which is a location through which sutures of the plurality of sutures can extend (not shown for clarity) to attach the bioprosthetic tissue 1501 to the frame of the bioprosthetic device (e.g., directly or indirectly). In various aspects, the collagen crosslinking density at and / or near the inner periphery 1213 may be greater than the bulk collagen crosslinking density of the bioprosthetic tissue 1501. In various aspects, the elastic modulus and / or shear modulus at and / or near the inner periphery 1213 may be greater than the corresponding elastic modulus and / or shear modulus of the bioprosthetic tissue 1501. In various aspects, the sound velocity of the bioprosthetic tissue 1501 at and / or near the inner periphery 1213 may be greater than the bulk sound velocity of the bioprosthetic tissue 1501. Providing one or more properties (e.g., increased crosslinking density, increased elastic modulus, increased shear modulus, increased sound velocity) at and / or near pores in the bioprosthetic tissue (e.g., corresponding to the location of the suture) can improve the resistance of the bioprosthetic tissue and / or the corresponding bioprosthetic device to suture pull-out.

[0047] like Figure 15As shown, region 1523 (shaded) can extend a distance 1529 from the inner periphery of region 1523 to the outer periphery 1521, and this region may have properties different from the bulk of the bioprosthetic tissue 1501. In various respects, distance 1529 may be 0.5 mm or greater, 1.0 mm or greater, 2 mm or greater, 3 mm or less, 5 mm or greater, 10 mm or less, 8 mm or less, 6 mm or less, 4 mm or less, or 2 mm or less. In various respects, distance 1529 may be in the range of 0.5 mm to 10 mm, 1.0 mm to 8 mm, 2 mm to 6 mm, 3 mm to 4 mm, or any range or subrange thereof. As discussed above with respect to the properties at and / or near the inner periphery 1213, region 1523 may have increased crosslinking density, increased elastic modulus, increased shear modulus, and / or increased sound velocity relative to the corresponding properties of the bulk of the bioprosthetic tissue 1501. Additionally, in another respect, as indicated by the dashed boundary, the crosslinking density, elastic modulus, shear modulus and / or sound velocity of the intermediate region 1551 between region 1523 and the remainder of the bioprosthetic tissue 1501 (e.g., the body) may be intermediate between the corresponding properties in region 1523 and the corresponding properties in the body (i.e., between them), although the intermediate region may not exist in other respects.

[0048] Alternatively or additionally, crosslinking density and / or mechanical properties can increase smoothly, continuously, and / or stepwise through multiple adjacent regions. Although Figure 15 Two regions are shown (i.e., the intermediate region 1551 extending to the outer periphery 1521 of region 1523, and region 1523), but it should be understood that this can be extended to multiple regions where the crosslinking density and / or mechanical properties increase sequentially and / or regions where the crosslinking density and / or mechanical properties increase gradient. Figure 16As shown, the bioprosthetic tissue 1601 and / or collagen backbone 1611 may have collagen fibrils 1603 with increasing crosslinking density (e.g., crosslinking 1625 and / or mechanical properties) in direction 1627. Depending on the method used to process the bioprosthetic tissue and / or collagen backbone, the corresponding increase may be smooth and / or continuous. For example, the crosslinking density and / or mechanical properties may increase monotonically toward a region of maximum (e.g., a predetermined location) (i.e., increasing alternately and remaining constant without decreasing). In another aspect, the crosslinking density and / or mechanical properties may increase continuously in direction 1627 toward a predetermined location 1605. Alternatively, as shown, the crosslinking density and / or mechanical properties may have a more stepwise increase in direction 1627 toward a predetermined location 1605, sequentially through different regions 1653, 1643, 1633, and 1623 (e.g., the crossing boundaries indicated by dashed lines 1641, 1631, and 1621). The rate of increase of these increased properties can be constant, linear, exponential, polynomial, or follow some other relationship. As used herein, a significant increase in crosslinking density and / or mechanical properties will be referred to as an “increase gradient,” regardless of the type or manner of the increase in crosslinking density and / or mechanical properties (e.g., continuous, stepwise). It should be understood that such an increase gradient can exist in any location or situation discussed herein (e.g., around the one or more predetermined locations 1105, opening 1211, etc.).

[0049] In all respects, the elastic modulus of the bioprosthetic tissue 1501 in region 1523 and / or in its inner periphery 1213 may be 5% or more, 10% or more, 20% or more, 50% or more, 80% or more, 100% or more, 120% or more, 150% or more, 10,000% or less, 1,000% or less, 200% or less, 150% or less, 120% or less, 100% or less, 80% or less, or 60% or less (in percentage of the bulk elastic modulus). In all respects, the elastic modulus of the bioprosthetic tissue 1501 in region 1523 and / or at its inner periphery 1213 may be 5% to 10,000%, 10% to 1,000%, 20% to 200%, 50% to 150%, 80% to 120%, 80% to 100%, or any range or subrange thereof (in percentage of the bulk elastic modulus) greater than the bulk elastic modulus. Alternatively or additionally, the shear modulus and / or velocity of sound in region 1523 and / or at its inner periphery 1213 may be greater than the corresponding properties in the bulk by one or more of the ranges discussed above in this paragraph (in percentage of the corresponding properties in the bulk). In all respects, the crosslinking density of the bioprosthetic tissue 1501 in region 1523 and / or in the inner periphery 1213 may be 20% or more, 50% or more, 80% or more, 100% or more, 150% or more, 200% or more, 500% or more, 20,000% or less, 10,000% or less, 5,000% or less, 1,000% or less, 800% or less, 600% or less, 400% or less, or 200% or less (in percentage of the bulk crosslinking density). In all respects, the crosslinking density of the bioprosthetic tissue 1501 in region 1523 and / or in its inner periphery 1213 may be 20% to 20,000%, 50% to 10,000%, 80% to 5,000%, 100% to 1,000%, 150% to 800%, 200% to 600%, 200% to 400%, or any range or subrange thereof (in percentage of the bulk crosslinking density) greater than the bulk crosslinking density.

[0050] In various aspects, the portion of the surface area of ​​the bioprosthetic tissue with increased crosslinking density, increased elastic modulus, increased shear modulus, and / or increased sound velocity can be less than 50%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. Therefore, the majority of the surface area of ​​the bioprosthetic tissue does not include the increased properties. In this way, the bioprosthetic tissue (e.g., in a bioprosthetic device) has the property of being selectively located in multiple predetermined locations (e.g., corresponding to multiple sutures) to provide increased suture retention force.

[0051] Throughout this disclosure, the measurement method for "suture retention strength" is as previously described (Gui et al., 2016, Biomaterials [Biomaterials] 102, 120-129), differing in that the suture retention strength is assessed as follows: a weight is added to a loop of 5-0 Dyneema suture (DSMBiomedical) passing through the bioprosthetic tissue at a location 2 mm from the end, where it is cross-linked according to this disclosure, and the force is applied axially to the bioprosthetic tissue. The weight is added in 10 g increments until failure. Four replicates are performed, and the reported value is the average of these replicates. As used herein, the load is reported based on the applied mass in grams; however, it should be understood that the actual force from the weight is in grams-forces (gf), where 101.97 gf = 1 Newton. In all respects, the bioprosthetic device and / or bioprosthetic tissue can exhibit suture retention strength of 200 g or higher, 220 g or higher, 240 g or higher, 260 g or higher, 280 g or higher, 300 g or higher, 400 g or lower, 350 g or lower, 300 g or lower, 280 g or lower, or 250 g or lower. In all respects, the bioprosthetic device and / or bioprosthetic tissue can exhibit suture retention strength of 200 g to 400 g, 220 g to 350 g, 240 g to 300 g, 260 g to 300 g, or 280 g to 300 g. In all respects, the suture retention strength measured at a location with increased collagen crosslinking density can be 20% or more, 50% or more, 100% or more, 200% or more, 1,000% or less, 500% or less, 250% or less, 150% or less, 100% or less, or 70% or less (e.g., 20% to 1,000%, 50% to 500%, 100% to 250%, 100% to 150%, or any range or subrange thereof) greater than the suture retention strength measured at another location (without increased collagen crosslinking density).

[0052] Now refer to Figures 10 to 15 Methods for forming bioprosthetic tissues and / or bioprosthetic devices by selectively cross-linking bioprosthetic tissues are discussed. For example... Figure 10As shown, the method may include applying a crosslinking agent 1003 to one or more predetermined locations 1015 of a collagen-containing bioprosthetic tissue 1011. In various aspects, as shown, applying the crosslinking agent 1003 may include dispensing the crosslinking agent 1003 (e.g., a solution containing the crosslinking agent) from a container 1001 (e.g., a micropipette, syringe). In another aspect, as shown, the crosslinking agent 1003 may be dispensed at the one or more predetermined locations 1015 onto the surface 1013 of the bioprosthetic tissue, although the crosslinking agent may be applied by inserting a container (e.g., a syringe) into the bioprosthetic tissue at the one or more predetermined locations. In various aspects, the crosslinking agent 1003 may be activated by irradiating it with an optical wavelength to which it is sensitive, which may induce crosslinking of collagen in the bioprosthetic tissue. Exemplary aspects of the crosslinking agent 1003 include riboflavin, rose Bengal, eosin Y, or combinations thereof.

[0053] Figure 11 Showed along Figure 10 A schematic diagram of collagen cut from line 11-11. As shown, the bioprosthetic tissue 1011 (e.g., surface 1013) comprises multiple collagen fibrils 1101 and 1103. At least some of the collagen fibrils (e.g., collagen fibrils 1101 and 1103) may remain uncrosslinked upon application of the crosslinking agent. Although some degree of crosslinking may exist between the collagen fibrils upon application of the crosslinking agent, this crosslinking density is lower than the crosslinking density produced at the predetermined locations(s) at the end of the method.

[0054] In all aspects, such as Figure 12 As shown, the method may include stretching the bioprosthetic tissue 1201 in one or more directions (as indicated by arrows 1203 and / or 1205). Stretching may expose previously obscured (e.g., hidden) locations where collagen can be cross-linked by the method. In another aspect, stretching may occur during the application of a cross-linking agent. In yet another aspect, stretching may be performed by irradiating the one or more predetermined locations 1015 with a light beam 1307 (as referenced below). Figure 13 The stretching occurs (e.g., independently of stretching during or after the application of the crosslinking agent). The beam can be configured to irradiate a region 1223 around an opening 1211 corresponding to one or more predetermined positions in a predetermined location (e.g., this region is defined by dashed lines 1221, and...). Figure 15 (Corresponding to region 1523 in the text).

[0055] like Figure 13As shown, the method includes: cross-linking collagen at a predetermined location 1015. As illustrated, the predetermined location 1015 is irradiated with a light beam 1307, which includes an optical wavelength to which the cross-linking agent 1003 is sensitive. Irradiation of the predetermined location 1015 with the light beam 1307 activates the cross-linking agent 1003 and causes collagen to cross-link at the predetermined location 1015 (e.g., see cross-linked fibrils 1231 and 1233 indicated by asterisk 1535 in region 1523 corresponding to the predetermined location in one or more of the predetermined locations). In various aspects, the light beam 1307 may be generated by a light-emitting diode (LED) or a laser (e.g., a laser diode) configured to emit a specific optical wavelength. In various aspects, the light beam 1307 may primarily include the wavelength that activates the cross-linking agent 1003 or consist only of said wavelength. For example, riboflavin can be activated by UV-A light and / or blue light (e.g., 360 nm to 450 nm), while Bengal rose and eosin Y can be activated by green light (e.g., 500 nm to 570 nm, 520 nm to 560 nm, 530 ± 5 nm, or 560 ± 5 nm). In another aspect, the light beam may primarily consist of light with optical wavelengths of 360 nm to 450 nm (e.g., 370 nm to 430 nm, 380 nm to 400 nm) or 500 nm to 560 nm (e.g., 520 nm to 540 nm, approximately 530 nm) and / or composed of such light.

[0056] In all aspects, such as Figure 13 As shown, a photomask 1305 can be positioned between a light source 1301 emitting a light beam 1307 and a bioprosthetic tissue 1011 having one or more predetermined locations. The photomask confines the irradiated (and thus crosslinked) area to the one or more predetermined locations by preventing an additional light beam 1303 from irradiating the surface 1013 of the bioprosthetic tissue 1011. In another aspect, the photomask 1305 can be a grayscale mask, which allows the light beam to have limited intensity around the periphery of the apertures in the photomask 1305, thereby creating an intermediate region (…). Figure 15The intermediate region 1551 has a certain degree of crosslinking induced by the light beam, but this degree of crosslinking is lower than that at the center closer to the predetermined location 1015 (see region 1523). Alternatively, multiple irradiation steps can occur, each using a different photomask to form region 1523 and intermediate region 1551. In other respects, there can be a relatively abrupt transition between the properties in region 1523 and the properties in the rest of the bioprosthetic tissue. As discussed above, the area corresponding to the one or more predetermined locations where crosslinking occurs during irradiation can be relatively limited (e.g., less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%). Therefore, the majority of the surface area of ​​the bioprosthetic tissue does not include the increased crosslinking density formed by irradiation. Alternatively, by controllably applying the crosslinking agent 1003 to a predetermined location 1015 (wherein the crosslinking agent diffuses minimally or not at other locations) (e.g., by precisely dispensing the crosslinking agent using a syringe or micropipette), the method can irradiate the predetermined location 1015 to induce photocrosslinking at the predetermined location 1015 (rather than other locations) without the need for a photomask. It should be understood that in the absence of a crosslinking agent to initiate a crosslinking reaction, exposure to a light beam will not induce collagen crosslinking.

[0057] Additionally or alternatively, a gradient increase in crosslinking density and / or mechanical properties can be achieved (rather than just a single region with increased crosslinking density and / or mechanical properties), as referenced herein. Figures 15 to 16As discussed above, gradient increases can be achieved in various ways by controlling the exposure of the bioprosthetic tissue (and / or collagen-containing scaffold) to the light beam. For example, as discussed in previous paragraphs, multiple photomasks and / or corresponding exposures can produce multiple regions with stepwise differences in crosslink density and / or mechanical properties. Similarly, as also discussed in previous paragraphs, relatively continuous gradient increases in crosslink density and / or mechanical properties can be achieved using grayscale masks (or other gradient masks). Moreover, the exposure time of the bioprosthetic tissue (and / or collagen-containing scaffold) to the light beam can be controlled by guiding a narrow beam. For example, the beam spot can be scanned on the surface at different scan rates and / or scanned a different number of times in different portions of the bioprosthetic tissue (and / or collagen-containing scaffold) to create gradient increases in crosslink density and / or mechanical properties, wherein longer dwell times (by varying scan rates and / or by multiple scans) are expected to be associated with a greater increase in crosslink density and / or mechanical properties. Additionally or alternatively, varying amounts of crosslinking agent can be applied to corresponding regions of the bioprosthetic tissue (and / or collagen-containing scaffold) such that even uniform exposure to the light beam will result in a greater increase in crosslinking density and / or mechanical properties at locations where more crosslinking agent is present. For example, multiple concentrations of crosslinking agent can be used to apply a higher concentration of crosslinking agent at locations where higher crosslinking density and / or mechanical properties will be formed; or a larger volume of crosslinking agent can be applied to a predetermined region relative to (multiple) other (e.g., adjacent) regions. It should be understood that any of these options can be combined to create a predetermined gradient increase in crosslinking density and / or mechanical properties.

[0058] In all aspects, such as Figure 12 As shown, an opening 1211 can be formed in the biological prosthetic tissue 1201 at one or more predetermined locations 1015 before cross-linking (e.g., irradiating predetermined locations with a light beam). In another aspect, although for clarity... Figures 12 to 15 The sutures are omitted and not shown, but they can be sutured before the one or more predetermined locations are illuminated with a light beam (e.g., with multiple sutures extending through the corresponding multiple holes, see [reference]). Figure 12 (Opening 1211 in the middle). Alternatively, the plurality of holes and / or the plurality of sutures can be formed at the corresponding one or more predetermined locations after the one or more predetermined locations are irradiated with a light beam. In any case, suturing can attach the bioprosthetic tissue to the frame of the bioprosthetic device (directly or indirectly). For example, as Figure 14As shown, the bioprosthetic tissue 1401 may include collagen fibrils 1403, which are cross-linked at one or more predetermined sites without openings after being irradiated with a light beam (as indicated by asterisk 1405), and these one or more predetermined sites may then be sutured. In various respects, after irradiating the one or more predetermined sites with a light beam, the bioprosthetic tissue may be washed (e.g., with water or a buffer solution) to remove, for example, excess, most or substantially all of the cross-linking agent from the bioprosthetic tissue.

[0059] In various aspects, the one or more predetermined locations (e.g., areas of increased collagen cross-linking or other mechanical properties) may be located within the one or more leaflets 21 attached (e.g., sutured) to the frame 15. In another aspect, the one or more predetermined locations may be the locations where the one or more leaflets 21 are attached (e.g., sutured) to the seam 25. In yet another aspect, the one or more predetermined locations may be where the one or more leaflets 21 are attached to the frame 15 and / or the skirt at attachment edge 701 (e.g., Figure 7 The outer skirt 721 and / or the inner skirt 711 and / or Figure 9 The location of the skirt portion 931 shown in the overall diagram. In various respects, this one or more predetermined locations (e.g., areas of increased collagen cross-linking or other mechanical properties) may be located on one or more skirt portions (e.g., attached (e.g., sewn) to the frame. Figure 7 The outer skirt 721 and / or the inner skirt 711 and / or Figure 9 In the skirt portion 931 shown in general. In another aspect, the one or more predetermined positions in the one or more skirt portions may be located at a position separate from (e.g., independent of or away from) the one or more leaflets. Alternatively or additionally, the one or more predetermined positions may include the free edges (e.g., sides) of the one or more leaflets (e.g., locations independent of where the leaflets are attached to the frame).

[0060] Additionally or alternatively, the predetermined location may be the outer periphery of the leaflet (e.g., the farthest end of the leaflet from the suture line 801 to frame 15, shown as the closest). Figure 8 (The central part). In other aspects, as referenced above. Figure 16 As discussed, the crosslinking density and / or mechanical properties may exhibit a gradient increase toward the predetermined location. As discussed above, this gradient increase may be continuous or distributed in a stepwise manner between multiple adjacent regions. For example, refer to... Figure 8 and Figure 16 Reserved location 1605 (in Figure 16 (middle) can correspond to leaflet 21 (in Figure 8(as shown in the diagram) at the distal end (e.g., the free edge), where the gradient increases with respect to the direction from suture 801 toward leaflet 21 (in Figure 8 The radial direction corresponding to the distal end (e.g., the free edge) of the middle) in direction 1627 (in Figure 16 This occurs on the (in the middle). Additionally or alternatively, it should be understood that bioprosthetic tissue (including tissue with increased cross-linking density and / or mechanical properties (or derived from cells colonized on a collagen-containing scaffold with such properties (discussed below) or bioprosthetic tissue processed according to the methods of this disclosure) at a predetermined location) can be used independently of the frame and also with the frame (such as... Figures 1 to 2 , Figures 7 to 9 , Figure 12 and Figure 15 (As shown). For example, biological prosthetic tissues according to various aspects of this disclosure can be used as leaflets in biological prosthetic pulmonary valves, which can be sutured into place without a frame.

[0061] Furthermore, the above-described method can be applied to collagen-containing scaffolds to form regions with increased crosslink density and / or mechanical properties (and / or a gradient increase in crosslink density and / or mechanical properties). The formation of a gradient increase in crosslink density and / or mechanical properties can promote cell migration and / or colonization in regions with increased crosslink density and / or mechanical properties. Without being bound by theory, an increase in the crosslink density of a collagen-containing scaffold is associated with an increase in mechanical stiffness. Moreover, a region with increased mechanical stiffness (including a gradient increase, associated with an increase in crosslink density) adjacent to another region with relatively low mechanical stiffness can promote cell migration and / or colonization in regions with increased mechanical stiffness. Therefore, it is anticipated that providing an increase in mechanical stiffness through increased crosslink density according to the aspects and methods of this disclosure can facilitate cell migration and / or colonization in regions with increased mechanical stiffness. Furthermore, providing an increase in gradient can promote cell migration toward a predetermined location on the collagen-containing scaffold towards the maximum of this gradient increase and / or subsequently colonize at or near the predetermined location with the maximum of the gradient increase, because cells from a larger region will be able to sense this gradient increase and / or continue moving upward along it compared to a single region with substantially the same increased crosslink density and / or mechanical properties (or a collagen-containing scaffold without any region having increased crosslink density and / or mechanical properties). For example, see reference. Figure 16Cells can migrate toward a predetermined location 1605 in direction 1629 along a collagen-containing framework 1611, which can be the same direction as the gradient increase direction 1627. Therefore, the density of colonized cells can be greater closer to the predetermined location 1605 compared to farther away. Furthermore, enhanced migration of cells along the gradient increase and / or enhanced colonization at (or near) the maximum value of the gradient increase can provide further increases in the mechanical properties, biocompatibility, and / or lifespan of the resulting material (e.g., bioprosthetic tissue formed by colonization of a collagen-containing framework). In fact, bioprosthetic tissue can be formed by cell colonization of a collagen-containing framework with a gradient increase in crosslinking density and / or mechanical properties, wherein this gradient increase will still remain in the resulting bioprosthetic tissue.

[0062] This disclosure provides a bioprosthetic tissue (e.g., as part of a bioprosthetic device) having increased mechanical properties and / or crosslinking density of collagen at one or more predetermined locations, and a method for manufacturing the bioprosthetic tissue (e.g., selectively crosslinking collagen in the bioprosthetic tissue). The one or more predetermined locations may correspond to locations in the bioprosthetic tissue where pores exist, for example, where the bioprosthetic tissue is sutured to the remainder of the bioprosthetic device (e.g., a frame). Providing increased corresponding properties at and / or near the pores (e.g., corresponding to suture locations) at the one or more predetermined locations in the bioprosthetic tissue, relative to the crosslinking density, elastic modulus, shear modulus, and / or sound velocity of the bioprosthetic tissue itself, can improve the resistance of the bioprosthetic tissue and / or the corresponding bioprosthetic device to suture pull-out. In various respects, the regions at the one or more predetermined locations with enhanced properties can be surrounded by an intermediate region whose properties lie between those at the one or more predetermined locations and those of the bulk of the bioprosthetic tissue. This can further improve the resistance to suture pull-out, for example, by smoothing the transition between the properties at the one or more predetermined locations and those of the bulk of the bioprosthetic tissue. Providing enhanced mechanical properties allows the bioprosthetic tissue to closely mimic the properties of biological tissue in the bulk, while improving the resistance to suture pull-out at the one or more predetermined locations corresponding to the positions of multiple sutures. Moreover, the method of this disclosure selectively crosslinks collagen at one or more predetermined locations in the bioprosthetic tissue by applying a crosslinking agent and then activating the crosslinking agent by irradiating it with an optical wavelength to which it is sensitive.

[0063] Additionally or alternatively, a gradient increase in crosslink density and / or mechanical properties (including smooth, continuous, and / or stepwise increases) can be formed in the bioprosthetic tissue and / or collagen-containing scaffold. Providing a gradient increase in crosslink density and / or mechanical properties can promote upward migration of cells along the gradient increase in the collagen-containing scaffold and / or enhanced colonization of cells at or near the maximum of the gradient increase. Furthermore, enhanced migration of cells along the gradient increase and / or enhanced colonization at (or near) the maximum of the gradient increase can provide further increases in the mechanical properties, biocompatibility, and / or lifespan of the resulting material (e.g., bioprosthetic tissue formed by colonization of a collagen-containing scaffold with a gradient increase in crosslink density and / or mechanical properties), wherein this gradient increase will still remain in the resulting bioprosthetic tissue.

[0064] Based on this disclosure, non-limiting aspects of this disclosure will now be described. Various combinations of these aspects may be provided based on this disclosure.

[0065] Aspect 1. A biological prosthetic device, comprising: frame; A bioprosthetic tissue comprising collagen, the bioprosthetic tissue including multiple pores, the bioprosthetic tissue being attached to the framework; and Multiple sutures extend through the multiple openings. The periphery of these multiple pores has a greater collagen cross-linking density compared to the body of the bioprosthetic tissue.

[0066] Aspect 2. The bioprosthetic device as described in aspect 1, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0067] Aspect 3. The bioprosthetic device as described in any one of Aspects 1 to 2, wherein the greater crosslinking density extends from the periphery by a distance of 0.5 mm to 10 mm.

[0068] Aspect 4. The bioprosthetic device of any one of Aspects 1 to 3, further comprising an intermediate region located between the body of the bioprosthetic tissue and a peripheral region having the greater collagen crosslinking density, the peripheral region comprising the periphery of at least one of the plurality of pores, wherein the crosslinking density of the intermediate region is between the crosslinking density of the body and the greater collagen crosslinking density of the peripheral region.

[0069] Aspect 5. A biological prosthetic device, comprising: frame; A bioprosthetic tissue comprising collagen, the bioprosthetic tissue including multiple pores, the bioprosthetic tissue being attached to the framework; and Multiple sutures extend through the multiple openings. The periphery of these multiple pores has a greater elastic modulus than the body of the bioprosthetic tissue.

[0070] Aspect 6. The bioprosthetic device as described in aspect 5, wherein the periphery of the plurality of pores has a greater collagen cross-linking density compared to the body of the bioprosthetic tissue.

[0071] Aspect 7. The bioprosthetic device as described in any one of Aspects 5 to 6, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0072] Aspect 8. The bioprosthetic device as described in any one of Aspects 5 to 7, wherein the greater elastic modulus is 20% to 200% greater than the bulk elastic modulus of the body of the bioprosthetic tissue.

[0073] Aspect 9. The bioprosthetic device as described in any one of Aspects 5 to 8, wherein the greater crosslinking density extends from the periphery by a distance of 0.5 mm to 10 mm.

[0074] Aspect 10. The biological prosthesis device as described in any one of Aspects 5 to 9, wherein the suture of the biological prosthesis tissue maintains a strength of 200 g or greater.

[0075] Aspect 11. A method for selectively cross-linking biological prosthetic tissue, the method comprising: The cross-linking agent is applied to one or more predetermined sites of the bioprosthetic tissue containing collagen; and Collagen is cross-linked at one or more predetermined locations by irradiating them with a light beam, the light beam comprising an optical wavelength to which the cross-linking agent is sensitive. The surface area of ​​this bioprosthetic tissue does not contain collagen that has been cross-linked by the irradiation.

[0076] Aspect 12. The method of aspect 11, wherein the one or more predetermined locations correspond to the locations of one or more sutures in the biological prosthesis tissue.

[0077] Aspect 13. The method of any one of Aspects 11 to 12, wherein the bioprosthetic tissue is part of a prosthetic heart valve assembly.

[0078] Aspect 14. The method of any one of Aspects 11 to 13, wherein the crosslinking agent comprises riboflavin, Bengal rose red, eosin Y, or a combination thereof.

[0079] Aspect 15. The method of any one of Aspects 11 to 14, further comprising: stretching the bioprosthetic tissue during the crosslinking.

[0080] Aspect 16. The method of any one of Aspects 11 to 15, wherein the crosslinking further comprises positioning a photomask between the light source emitting the light beam and the one or more predetermined locations to confine the crosslinking to the one or more predetermined locations.

[0081] Aspect 17. The method of any one of aspects 11 to 16, further comprising: after the crosslinking, suturing the bioprosthetic tissue to form a bioprosthetic device, wherein the suturing is formed by multiple sutures extending through a plurality of holes at one or more of these predetermined locations.

[0082] Aspect 18. The method of any one of aspects 11 to 16, further comprising: prior to the crosslinking, suturing the bioprosthetic tissue to form a bioprosthetic device, wherein the suturing is formed by multiple sutures extending through a plurality of holes at one or more of these predetermined locations.

[0083] Aspect 19. The method of any one of Aspects 17 to 18, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0084] Aspect 20. The method of any one of Aspects 11 to 19, wherein the suture of the bioprosthetic tissue maintains a strength of 200 g or greater.

[0085] Aspect 21. The method of any one of aspects 11 to 20, wherein the light beam comprises primarily light of a wavelength that will activate the crosslinking agent.

[0086] Aspect 22. The method of any one of aspects 11 to 21, wherein the light beam mainly comprises light with an optical wavelength of 360 nm to 450 nm.

[0087] Aspect 23. The method of any one of aspects 11 to 21, wherein the light beam mainly comprises light with an optical wavelength of 500 nm to 570 nm.

[0088] Aspect 24. The method of any one of aspects 11 to 23, wherein the one or more predetermined locations include the attachment edge of the leaflet.

[0089] Aspect 25. The method of any one of aspects 11 to 23, wherein the one or more predetermined positions include the free edge of the leaflet.

[0090] Aspect 26. The method of any one of aspects 11 to 25, wherein the one or more predetermined positions include the position where the skirt is attached to the frame.

[0091] Aspect 27. The biological prosthesis device as described in any one of aspects 1 to 10, wherein the one or more predetermined locations include the attachment edge of the leaflet.

[0092] Aspect 28. The biological prosthetic device as described in any one of aspects 1 to 10, wherein the one or more predetermined locations include the free edge of the leaflet.

[0093] Aspect 29. The bioprosthetic device as described in any one of aspects 1 to 10, wherein the one or more predetermined locations include the location where the skirt is attached to the frame.

[0094] Aspect 30. A bioprosthetic device comprising a bioprosthetic tissue containing collagen, wherein a predetermined location on the bioprosthetic tissue has a greater elastic modulus than the elastic modulus of the bulk of the bioprosthetic tissue.

[0095] Aspect 31. The bioprosthetic device of aspect 30 further includes an intermediate region located between the body of the bioprosthetic tissue and the predetermined location having the greater collagen crosslinking density, wherein the elastic modulus of the intermediate region is between the elastic modulus of the body and the greater elastic modulus at the predetermined location.

[0096] Aspect 32. The bioprosthetic device as described in any one of Aspects 30 to 31, further comprising a gradient increase in the elastic modulus between the crosslinking density of the body of the bioprosthetic tissue and the elastic modulus at the predetermined location.

[0097] Aspect 33. A bioprosthetic device comprising a bioprosthetic tissue containing collagen, wherein a predetermined location on the bioprosthetic tissue has a collagen crosslinking density greater than that of the bulk of the bioprosthetic tissue.

[0098] Aspect 34. The bioprosthetic device of aspect 33 further includes an intermediate region located between the body of the bioprosthetic tissue and the predetermined location having the greater collagen crosslinking density, wherein the crosslinking density of the intermediate region is between the crosslinking density of the body and the greater collagen crosslinking density at the predetermined location.

[0099] Aspect 35. The bioprosthetic device as described in any one of Aspects 33 to 34, further comprising a gradient increase in crosslinking density between the crosslinking density of the body of the bioprosthetic tissue and the crosslinking density at the predetermined location.

[0100] Aspect 36. The biological prosthesis device as described in any one of Aspects 30 to 35, wherein the biological prosthesis device is a prosthetic heart valve assembly.

[0101] Aspect 37. The biological prosthetic device as described in any one of aspects 30 to 35, wherein the one or more predetermined locations include the attachment edge of the leaflet.

[0102] Aspect 38. The biological prosthesis device as described in any one of aspects 30 to 35, wherein the one or more predetermined locations include the free edge of the leaflet.

[0103] Aspect 39. The biological prosthesis device as described in any one of Aspects 30 to 38, wherein the biological prosthesis tissue further includes a plurality of pores, and the biological prosthesis device further includes a plurality of sutures extending through the plurality of pores.

[0104] Aspect 40. The bioprosthetic device as described in aspect 39 further includes a frame, wherein the bioprosthetic tissue is attached to the frame.

[0105] Aspect 41. A collagen-containing scaffold, including predetermined locations having a greater collagen cross-linking density compared to the bulk of the collagen-containing scaffold.

[0106] Aspect 42. The collagen-containing framework as described in aspect 41, further comprising an intermediate region located between the body and the predetermined position having the greater collagen crosslinking density, wherein the crosslinking density of the intermediate region is between the crosslinking density of the body and the greater collagen crosslinking density at the predetermined position.

[0107] Aspect 43. The collagen-containing backbone as described in any one of aspects 41 to 42, further comprising a gradient increase in the crosslinking density between the crosslinking density of the body and the crosslinking density at the predetermined location.

[0108] Aspect 44. A collagen-containing scaffold, including a predetermined location having a greater elastic modulus than the body due to differences in collagen crosslinking between the predetermined location and the body of the collagen-containing scaffold.

[0109] Aspect 45. The collagen-containing framework as described in aspect 44, further comprising an intermediate region located between the body and the predetermined position having the greater collagen crosslinking density, wherein the elastic modulus of the intermediate region is between the elastic modulus of the body and the greater elastic modulus at the predetermined position.

[0110] Aspect 46. The collagen-containing backbone as described in any one of aspects 44 to 45, further comprising a gradient increase in the elastic modulus between the crosslinking density of the body and the elastic modulus at the predetermined location.

[0111] Aspect 47. A biological prosthetic device comprising a collagen-containing scaffold colonized by cells, as described in any one of Aspects 41 to 46.

[0112] Aspect 48. The bioprosthetic device as described in aspect 47, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0113] Aspect 49. A method for selectively cross-linking a collagen-containing backbone, the method comprising: The cross-linking agent is applied to one or more predetermined locations on the collagen-containing backbone; and Collagen is cross-linked at one or more predetermined locations by irradiating them with a light beam, the light beam comprising an optical wavelength to which the cross-linking agent is sensitive. The surface area of ​​the collagen-containing skeleton does not contain collagen that has been cross-linked by the irradiation.

[0114] Aspect 50. The method of aspect 49, wherein the crosslinking agent comprises riboflavin, Bengal rose red, eosin Y, or a combination thereof.

[0115] Aspect 51. The method of any one of Aspects 49 to 50, further comprising: stretching the collagen-containing backbone during the crosslinking.

[0116] Aspect 52. The method of any one of aspects 49 to 51, wherein the crosslinking further comprises positioning a photomask between a light source emitting the light beam and the one or more predetermined locations to confine the crosslinking to the one or more predetermined locations.

[0117] Aspect 53. The method of any one of Aspects 49 to 52, wherein the dwell time of the light beam on the collagen-containing skeleton is increased at a location closer to the predetermined location compared to a location farther from the predetermined location on the collagen-containing skeleton.

[0118] Aspect 54. The method of any one of Aspects 49 to 53, wherein the amount of the crosslinking agent on the collagen-containing backbone increases at a location closer to the predetermined location compared to a location further away from the predetermined location on the collagen-containing backbone.

[0119] Aspect 55. The method of any one of Aspects 49 to 54, wherein the light beam comprises primarily light of a wavelength that will activate the crosslinking agent.

[0120] Aspect 56. The method of any one of aspects 49 to 55, further comprising: after the cross-linking, colonizing cells onto the collagen-containing scaffold.

[0121] Aspect 57. The method as described in aspect 56, wherein the cells in these cells migrate toward the predetermined location.

[0122] Aspect 58. A biological prosthesis device comprising a collagen-containing scaffold colonized by cells, produced by any one of aspects 56 to 57.

[0123] Aspect 59. The bioprosthetic device as described in aspect 58, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0124] Aspect 60. The method of any one of aspects 58 to 59, wherein the one or more predetermined locations include the attachment edge of the leaflet.

[0125] Aspect 61. The method of any one of Aspects 58 to 59, wherein the one or more predetermined locations include the free edge of the leaflet.

[0126] It should be understood that although various aspects have been described in detail with respect to certain illustrative and specific examples, this disclosure should not be considered as limited thereto, as many modifications and combinations of the disclosed features are possible without departing from the scope of the appended claims.

Claims

1. A biological prosthetic device, comprising: frame; A bioprosthetic tissue comprising collagen, the bioprosthetic tissue including a plurality of pores, the bioprosthetic tissue being attached to the framework; as well as Multiple sutures extend through the multiple holes. The periphery of the plurality of pores has a greater collagen cross-linking density compared to the body of the bioprosthetic tissue.

2. The biological prosthesis device as described in claim 1, wherein, The bioprosthetic device is a prosthetic heart valve assembly.

3. The biological prosthesis device according to any one of claims 1 to 2, wherein, The greater crosslinking density extends from the periphery by a distance of 0.5 mm to 10 mm.

4. The bioprosthetic device of any one of claims 1 to 3, further comprising an intermediate region located between the body of the bioprosthetic tissue and a peripheral region having the greater collagen crosslinking density, the peripheral region comprising the periphery of at least one of the plurality of pores, wherein, The cross-linking density of the intermediate region is between the cross-linking density of the body and the greater collagen cross-linking density of the peripheral region.

5. A biological prosthetic device, comprising: frame; A bioprosthetic tissue comprising collagen, the bioprosthetic tissue including a plurality of pores, the bioprosthetic tissue being attached to the framework; as well as Multiple sutures extend through the multiple holes. The periphery of the plurality of pores has a greater elastic modulus than the body of the biological prosthesis tissue.

6. The biological prosthesis device as claimed in claim 5, wherein, The periphery of the plurality of pores has a greater collagen cross-linking density compared to the body of the bioprosthetic tissue.

7. The biological prosthesis device according to any one of claims 5 to 6, wherein, The bioprosthetic device is a prosthetic heart valve assembly.

8. The biological prosthesis device according to any one of claims 5 to 7, wherein, The greater elastic modulus is 20% to 200% greater than the bulk elastic modulus of the biological prosthesis tissue.

9. The biological prosthesis device according to any one of claims 5 to 8, wherein, The greater crosslinking density extends from the periphery by a distance of 0.5 mm to 10 mm.

10. The biological prosthesis device according to any one of claims 5 to 9, wherein, The sutures of the bioprosthetic tissue maintain a strength of 200 g or greater.

11. A method for selectively cross-linking biological prosthetic tissue, the method comprising: A cross-linking agent is applied to one or more predetermined locations of the bioprosthetic tissue containing collagen; as well as Collagen is cross-linked at one or more predetermined locations by irradiating them with a light beam, the light beam comprising an optical wavelength to which the cross-linking agent is sensitive. The surface area of ​​the bioprosthetic tissue does not contain collagen that has been cross-linked by the irradiation.

12. The method of claim 11, wherein, The one or more predetermined locations correspond to the positions of one or more sutures in the biological prosthesis tissue.

13. The method according to any one of claims 11 to 12, wherein, The bioprosthetic tissue is part of a prosthetic heart valve assembly.

14. The method according to any one of claims 11 to 13, wherein, The crosslinking agent includes riboflavin, Bengal rose red, eosin Y, or a combination thereof.

15. The method of any one of claims 11 to 14, further comprising stretching the bioprosthetic tissue during the crosslinking process.

16. The method according to any one of claims 11 to 15, wherein, The crosslinking further includes positioning a photomask between the light source emitting the light beam and the one or more predetermined locations to confine the crosslinking to the one or more predetermined locations.

17. The method of any one of claims 11 to 16, further comprising, after the crosslinking, suturing the bioprosthetic tissue to form a bioprosthetic device, wherein, The sutures are formed at one or more of these predetermined locations, extending through multiple holes, with multiple suture lines.

18. The method of any one of claims 11 to 16, further comprising, prior to the crosslinking, suturing the bioprosthetic tissue to form a bioprosthetic device, wherein, The sutures are formed at one or more of these predetermined locations, extending through multiple holes, with multiple suture lines.

19. The method of any one of claims 17 to 18, wherein, The bioprosthetic device is a prosthetic heart valve assembly.

20. The method according to any one of claims 11 to 19, wherein, The sutures of the bioprosthetic tissue maintain a strength of 200 g or greater.

Images