WO2024118297A1

WO2024118297A1 - Bioprosthetic tissue and prosthetic antimicrobial treatment

Info

Publication number: WO2024118297A1
Application number: PCT/US2023/078983
Authority: WO
Inventors: Ekaterina TKATCHOUK
Original assignee: Edwards Lifesciences Corp
Current assignee: Edwards Lifesciences Corp
Priority date: 2022-11-28
Filing date: 2023-11-07
Publication date: 2024-06-06
Anticipated expiration: 2025-05-28
Also published as: CN120322258A; EP4626496A1

Abstract

Methods for preparing bioprosthetic tissue or polymer-based leaflets are provided. In some instances, bioprosthetic tissue or polymer-based leaflets are treated with antimicrobial peptides. In some instances, prepared bioprosthetic tissues or polymer-based leaflets are incorporated into a medical device.

Description

BIOPROSTHETIC TISSUE AND PROSTHETIC ANTIMICROBIAL TREATMENT

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Patent Application No. 63/385,195, filed November 28, 2022, the entire disclosure which is incorporated by reference for all purposes.

TECHNICAL FIELD

[0002] The application is generally directed to systems and methods of preparing bioprosthetic tissue, and more specifically to antimicrobial peptide treatment of prosthetic devices and delivery systems.

BACKGROUND

[0003] Prosthetic valve endocarditis (PVE) is a serious complication of valve replacement. Prosthetic valve endocarditis is defined as an infection occurring in a prosthetic heart valve with overall incidence of 0.32 to 1.2% per patient year and cumulative risk of 5% at 10 years. In the past, surgery for infectious endocarditis was associated with a mortality of 25%-6O%.

[0004] PVE is defined as early if occurring within 12 months of valve replacement and late if greater than 12 months have elapsed. Most cases are caused by Staphylococcus epidermidis and aureus, followed by Streptococcus. Early PVE is often due to methicillin- resistant Staphylococcus epidermidis, gram-negative bacilli, fungi, and other HACEK group organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikinella, Kingella), suggesting nosocomial infection.

SUMMARY OF THE DISCLOSURE

[0005] The disclosure is generally directed to systems and methods to treat bioprosthetic tissue, polymer-based leaflets, prosthetic heart valves, and/ or delivery devices with antimicrobial peptides and polypeptides for preclinical or clinical use.

[0006] In some implementations, a method is for preparing antimicrobial tissue or polymer. The method treats bioprosthetic tissue or polymer with an antimicrobial peptide solution. The method also prepares the bioprosthetic tissue or polymer for preclinical or clinical use.

[0007] In some implementations, the antimicrobial peptide solution comprises a lysine- rich peptide, an arginine-rich peptide, a proline-rich peptide, a histidine rich peptide, or a proline rich peptide.

[0008] In some implementations, the antimicrobial peptide solution comprises a peptide that comprises at least one hydrophilic block and at least one hydrophobic block. [0009] In some implementations, the antimicrobial peptide solution comprises a peptide that comprises at least one positively charged block and at least one negatively charged block.

[0010] In some implementations, the antimicrobial peptide solution comprises a peptide selected from: gramicidin, daptomycin, and colistin.

[0011] In some implementations, the treating of the bioprosthetic tissue or polymer comprises spray coating, brush coating, or spin coating the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0012] In some implementations, the treating of the bioprosthetic tissue or polymer comprises dipping the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0013] In some implementations, the treating of the bioprosthetic tissue or polymer comprises immersing the bioprosthetic tissue or polymer in the antimicrobial peptide solution.

[0014] In some implementations, the treating of the bioprosthetic tissue or polymer comprises perfusing the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0015] In some implementations, the bioprosthetic tissue is derived from an animal source.

[0016] In some implementations, the animal source is bovine, porcine, ovine, avian, or human donor.

[0017] In some implementations, the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises utilizing the bioprosthetic tissue or polymer in an assembly of a medical device.

[0018] In some implementations, the medical device is a tissue patch, a medical vessel, a conduit, a closure device or a prosthetic heart valve.

[0019] In some implementations, the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises preparing the bioprosthetic tissue or polymer for storage.

[0020] In some implementations, the storage is a wet storage or a dry storage.

[0021] In some implementations, the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises sterilizing the bioprosthetic tissue or polymer. [0022] In some implementations, sterilizing the bioprosthetic tissue or polymer comprises a treatment with one or more of: gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/or e-beam.

[0023] In some implementations, the bioprosthetic tissue is fixed.

[0024] In some implementations, bioprosthetic tissue is treated.

[0025] In some implementations, a method is for preparing an antimicrobial medical device. The method treats one or more components of a medical device with an antimicrobial peptide solution. The method prepares the medical device for preclinical or clinical use.

[0026] In some implementations, a prosthetic heart valve is treated.

[0027] In some implementations, a delivery system for delivering a prosthetic heart valve is treated.

[0028] In some implementations, a balloon of a delivery system for delivering a tubular prosthetic.

[0029] In some implementations, a method is for treating the interior luminal wall of a tubular prosthetic. The method provides a balloon coated with AMPs on its surface. The method expands the balloon such that it contacts the interior luminal wall of a tubular prosthetic.

[0030] In some implementations, the expansion of the balloon occurs during an installation of the tubular prosthetic.

[0031] In some implementations, the expansion of the balloon occurs after an installation of the tubular prosthetic.

[0032] Additional aspects and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the various aspects described. A further understanding of the nature and advantages of the present disclosure may be realized by reference to the remaining portions of the specification and the drawings, which forms a part of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The description and claims will be more fully understood with reference to the following figures, which are presented as exemplary description and should not be construed as a complete recitation of the scope of the disclosure.

[0034] Figs. 1A to 1D provide examples of diblock copolymers that can be utilized as antimicrobial peptides. [0035] Fig- 2 provides a flow chart of an exemplary method to treat bioprosthetic tissue with antimicrobial peptides.

[0036] Fig. 3 provides an exemplary prosthetic heart valve.

[0037] Fig. 4A provides an exemplary heart valve leaflet.

[0038] Fig. 4B provides an exemplary heart valve leaflet assembly.

[0039] Fig. 5 provides an exemplary transcatheter delivery system for delivering a prosthetic heart valve.

[0040] Fig. 6 provides a flow chart of an exemplary method to treat a prosthetic or delivery system with antimicrobial peptides.

DETAILED DESCRIPTION

[0041] Turning now to the drawings and description, various methods to prepare bioprosthetic tissue, polymer-based leaflets, valvular systems, and delivery systems are described. Bioprosthetic tissue or polymer-based leaflets can be prepared for use in a valvular system. In some instances, bioprosthetic tissue or polymer-based leaflets are prepared to be incorporated into a prosthetic heart valve, including (but not limited to) an aortic, a mitral, a tricuspid, or a pulmonary heart valve.

[0042] Treatments of bioprosthetic tissue, polymer-based leaflets, a valvular system, and/or a delivery system generally comprise contacting the tissue, polymer, device, and/or system with an antimicrobial peptide (AMP). AMPs are a class of peptides, polypeptides, or peptide derivatives that widely exist throughout nature and are generally utilized as part of an organism’s innate immune response. AMPs have a wide range of inhibitory effects against bacteria, fungi, parasites, and viruses. Antimicrobial peptides are a unique and diverse group of molecules that have demonstrated antimicrobial effectiveness. In addition to naturally occurring AMPs, several designer AMPs have been synthesized and shown to exhibit robust antimicrobial activity. Accordingly, the various methods and systems described herein can be a naturally occurring AMP, a modified naturally occurring AMP, or a synthetic AMP. The AMP can be a peptide, a polypeptide, a polyethylene glycol (PEG) or an ethylene glycol (EG) grafted peptide or polypeptide, or an amphiphilic blocked co-polypeptide. Amphiphilic block copolypeptides may contain a soluble block polypeptide with one or more oligo(ethyleneglycol)-terminated amino acid residues and an insoluble block containing nonionic amino acid residues.

[0043] Some AMP classes can be defined by their amino acid constituency, and the various classes of AMPs can utilize various methods to yield antimicrobial properties. AMP classes defined by amino acid constituency include (but are not limited to) lysine-/arginine- rich AMPs, proline-rich AMPs, histidine-rich AMPs, and glycine-rich AMPs.

[0044] Lysine-/arginine-rich peptides have a net positive charge. These cationic peptides can quickly incorporate into negatively charged microbial cell membrane. Once inside the membrane, the peptide can cause disruption and rupture, yielding cytoplasmic leakage that ultimately leads to microbial cell death. Lysine-rich AMPs and Arginine-rich AMPs can comprise sequences having a plurality of lysines or a plurality arginines. In various instances, the plurality of lysines, the plurality of arginines, or the plurality of both lysines and arginines constitutes greater than 20% of amino acids of the peptide, greater than 30% of amino acids of the peptide, greater than 40% of amino acids of the peptide, greater than 50% of amino acids of the peptide, greater than 60% of amino acids of the peptide, greater than 70% of amino acids of the peptide, greater than 80% of amino acids of the peptide, or greater than 90% of amino acids of the peptide. In some instances, the AMP comprises a copolymer block wherein the copolymer comprises a lysine or arginine and another amino acid. For example, copolymer K180L20 block polypeptides have been demonstrated to be biocompatible in vivo with great antimicrobial activity.

[0045] Proline-rich AMPs typically do not deconstruct microbial membranes but instead enter the microbe via a transporter. Once inside, the AMPs can target ribosomes and block the binding of aminoacyl-tRNA to peptidyltransferase center or trap decoding release factors on the ribosome during the termination of translation to interfere with protein synthesis. Proline-rich AMPs can comprise sequences having a plurality of prolines. In various instances, the plurality of prolines constitutes greater than 20% of amino acids of the peptide, greater than 30% of amino acids of the peptide, greater than 40% of amino acids of the peptide, greater than 50% of amino acids of the peptide, greater than 60% of amino acids of the peptide, greater than 70% of amino acids of the peptide, greater than 80% of amino acids of the peptide, or greater than 90% of amino acids of the peptide. Examples of prolinerich AMPs include Baes and Bac7, each having a repeated amino acid motif of -PPXR-.

[0046] Histidine-rich AMPs can permeate into microbial membranes cause leakage and rupture, and eventually microbial cell death. In various instances, the plurality of histidines constitutes greater than 20% of amino acids of the peptide, greater than 30% of amino acids of the peptide, greater than 40% of amino acids of the peptide, greater than 50% of amino acids of the peptide, greater than 60% of amino acids of the peptide, greater than 70% of amino acids of the peptide, greater than 80% of amino acids of the peptide, or greater than 90% of amino acids of the peptide. An example of a histidine-rich AMP is HV2, which has the motif RR(XH)₂XDPGX(YH)₂RR-NH2 (where X represents I, W, V, or F). [0047] Glycine-rich AMPs typically have between 14% and 22% glycine residues in the peptide. The high concentration of glycines result in particular tertiary structure of the AMPs that can activate phagocytes to confer antimicrobial activity. Examples of proline-rich AMPs include attacin, diptericins, and GG3.

[0048] In addition to the classes of AMPs listed, various AMPs based on block polypeptides are also utilized to treat bioprosthetic tissue, polymer-based leaflets, a valvular system, and/or a delivery system. Block polypeptides comprise two or more blocks, each block consisting of a contiguously linear set of amino acids. Each block can consist of a number of amino acids, which can be any number between about 5 amino acids and up to about 200 amino acids, and in some instances, longer than 200 amino acids. In various implementations, a block within a polypeptide is about 5 amino acids, about 10 amino acids, about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, about 50 amino acids, about 60 amino acids, about 70 amino acids, about 80 amino acids, about 90 amino acids, about too amino acids, about 110 amino acids, about 120 amino acids, about 130 amino acids, about 140 amino acids, about 150 amino acids, about 160 amino acids, about 170 amino acids, about 180 amino acids, about 190 amino acids, or about 200 amino acids; where “about” is within a range of ± 10 amino acids. It should be understood, however, that molecular weight and particular amino acid constituency may be important to various biological functions, such as (for example) peptide structure self-assembly, microbial membrane integration, and antimicrobial activity. In some instances, the polypeptide has a molecular weight ratio between i.oi<Mw/Mn<i.5, where Mw/Mn=weight average molecular weight divided by number average molecular weight. The final molecular weight can vary anywhere between 1-100 kDa depending on the substrate (leaflet) materials. For example, pericardial tissue or collagen-based biological materials can use a lower molecular weight polypeptide to achieve good absorption into the biological material. Polymer leaflets ,such as polyurethane based or expanded polytetrafluoroethylene (ePTFE), can require a higher molecular weight polypetides that could have higher final density to assure good attachment with the polymer surface.

[0049] It has been found that block polypeptides comprising at least one hydrophilic block and at least one hydrophobic block is beneficial to forming hydrogel-like films on prosthetic tissues, polymers, and valvular devices. Accordingly, in various instances, an AMP comprises at least one hydrophilic block and at least one hydrophobic block. The hydrophilic block can comprise hydrophilic amino acids with polar, acidic, or basic side chains. In some instances, the hydrophilic block consists of a repeated amino acid. In some instances, the hydrophilic block consists of two or more repeated amino acids, which can be a random or a nonrandom pattern. In various instances, the hydrophilic block comprises at least 50% hydrophilic amino acids, at least 60% hydrophilic amino acids, at least 70% hydrophilic amino acids, at least 80% hydrophilic amino acids, at least 90% hydrophilic amino acids, or 100% hydrophilic amino acids. The hydrophobic block can comprise hydrophobic amino acids with nonpolar side chains. In some instances, the hydrophobic block consists of a repeated amino acid. In some instances, the hydrophobic block consists of two or more repeated amino acids, which can be a random or a nonrandom pattern. In various instances, the hydrophobic block comprises at least 50% hydrophobic amino acids, at least 60% hydrophobic amino acids, at least 70% hydrophobic amino acids, at least 80% hydrophobic amino acids, at least 90% hydrophobic amino acids, or 100% hydrophobic amino acids.

[0050] This amphiphilic nature of the polypeptides comprising at least one hydrophilic block and at least one hydrophobic provides the ability of those molecules to assemble in aqueous and organic solutions and form hydrogels. Suspending the amphiphilic block polypeptides in an aqueous or organic solution allows the polypeptide to spontaneously selfassemble into various nanostructures such as fibrils, nanotubes, vesicles or micelles, which can vary in size between about 50 nm to about 500 nm. PEGylated amphiphilic block copolypeptides can evade immunological defense mechanisms in the body, which may help prevent host immunological reaction to AMPs post implantation.

[0051] Provided in Fig. 1A is an example of an amphiphilic polypeptide 101 comprising at least one hydrophilic block and at least one hydrophobic. In this example, the amphiphilic polypeptide comprises a block of repeated lysine amino acids to yield the hydrophilic block and block of repeated leucine amino acids to yield the hydrophobic block. This results in a peptide having a tight hydrophobic coil 103 and a less-compact hydrophilic extension 105 that extends from the hydrophobic coil. As can be appreciated, a plurality of amphiphilic polypeptides can interact with the hydrophobic coils of the peptides associating with the hydrophobic coils of other peptides, forming various structures (e.g., micelle-like structures). The amino groups of the lysine amino acids extend outward to interact with and stick to collagenous tissue of a prosthetic (Fig. 1B) to provide the tissue antimicrobial properties. In instances, the hydrophilic block comprises a repeated glutamate, which can similarly form various structures with the carboxyl group of the glutamate amino acids extending outward to interact with and stick to collagenous tissue of a prosthetic (Fig. 1C) to provide the tissue antimicrobial properties.

[0052] It has been further found that antimicrobial activity can be enhanced by incorporating positively charged amino acid blocks with negatively charged amino acid blocks (e.g., zwitterionic copolypeptides). Accordingly, in some instances, an AMP can have at least one positively charged block and at least one negatively charged block. The positively charged block can comprise amino acids with basic side chains, such as (for example) lysine, arginine, and ornithine. In some instances, the positively charged block consists of a repeated basic amino acid. In some instances, the positively charged block consists of two or more repeated basic amino acids, which can be a random or a nonrandom pattern. In various instances, the positively charged block comprises at least 50% basic amino acids, at least 60% basic amino acids, at least 70% basic amino acids, at least 80% basic amino acids, at least 90% basic amino acids, or 100% basic amino acids. The negatively charged block can comprise amino acids with acidic side chains, such as (for example) glutamate and aspartate. In some instances, the negatively charged block consists of a repeated acidic amino acid. In some instances, the hydrophobic block consists of two or more repeated acidic amino acids, which can be a random or a nonrandom pattern. In various instances, the negatively charged block comprises at least 50% acidic amino acids, at least 60% acidic amino acids, at least 70% acidic amino acids, at least 80% acidic amino acids, at least 90% acidic amino acids, or 100% acidic amino acids. An example of a zwitterionic diblock copolypeptide is block-poly(L- glutamate)-block-poly(L-lysine) (Fig. 1D).

[0053] Examples of copolymer block polypeptides include (but are not limited to) block- (poly(y-benzyl-L-glutamate)-block-poly(L-lysine hydrochloride) diblock copolymer and block(e-benzyloxycarbonyl)-block-poly(c-Cbz-L-lysine)-block-poly(y-benzyl-L-glutamate) triblock copolymer. Any of the described AMPs can be PEGylated, which may help stabilize hydrogel formation. Accordingly, poly(ethylene glycol) can be linked to either terminal or to any internal amino acid.

[0054] As discussed, AMPs can be from natural sources, including biological sources such as mammals, bacterial, fungi, insects or other microorganisms. Three naturally occurring AMPs for use as antimicrobial agent are gramicidin, daptomycin, and colistin, each of which is FDA approved for use as an antibiotic.

[0055] The anti-microbial resistance of microorganisms is becoming increasingly dire with the overuse of antibiotics in medicine, agriculture and animal husbandry. The prevalence of vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) is increasing in the clinic, and thus antibiotics alone should not be relied upon for preventing PVE. It is a goal of the present disclosure to mitigate PVE by treating bioprosthetic tissue, valvular systems, and/or delivery systems with AMPs. Thus, pathogenic infection can be reduced during delivery of the treated prosthetic and after implantation.

Systems and Methods of Preparing Bioprosthetic Tissue or Polymer-based Leaflets [0056] Systems and methods prepare a bioprosthetic tissue, polymer-based leaflets, valvular prosthetics, and/or delivery systems for use in a medical application, including clinical and preclinical procedures. Bioprosthetic tissue is collagenous tissue that is to be used in a medical device and/or medical procedure. Generally, the tissue can be fixed and then treated with AMPs. Or in some instances, valvular prosthetics and/or delivery devices are treated with AMPs.

[0057] Provided in Fig. 2 is an exemplary process to prepare bioprosthetic for clinical or preclinical use with an AMP treatment. Process 200 begins by obtaining 201 bioprosthetic tissue or polymer-based leaflets. Bioprosthetic tissue can be derived from any appropriate animal source, including (but not limited to) bovine, porcine, ovine, avian, and human donor. In many instances, bioprosthetic tissue is from a nonautologous (e.g., non-self) source, but an autologous (e.g., self) source can be utilized in accordance with some applications of the method.

[0058] In some applications, a tissue is processed after retrieval from a source to remove undesirable tissue. For example, adipose, venous, cartilaginous, and/or any other undesirable tissue may be removed.

[0059] Polymers to be utilized in polymer-based leaflets can be fluorocarbon-based polymers, thermoplastic polyurethanes (TPUs), polyethers, polyimides, polysiloxanes, polysulfides, biodegradeable polyesters, polyethylene terephthalate (PET), poly(butylene terephthalate) (PBT), or polycarbonate (PC). Examples of fluorocarbon-based polymers include (but are not limited to) PTFE (polytetrafluoroethylene), ePTFE( expanded PTFE), FEP (fluorinated ethylene propylene), PFA (perfluoroalkoxy alkane), MFA (methylfluoroalkoxy alkane), ETFE (ethylene tetrafluoroethylene), ECTFE (ethylene chlorotrifluoroethylene ethylene, a copolymer of ethylene and chlorotrifluoroethylene), PCTFE (polychlorotrifluoroethylene), copolymers containing PVDF (polyvinyledenefluoride), or partially fluorinated polymers containing a carbon-carbon double bond. Examples of TPUs include (but are not limited to) polyester TPUs, polyether TPUs, and polycaprolactone TPUs, which can aromatic or aliphatic based. Polyesters or polyethers can be aliphatic or semi-aromatic. Examples of biodegradable polyesters include (but are not limited to) polyglycolic acid (PGA), polylactic acid (PLA), poly-2-hydroxy butyrate (PHB), and polycaprolactone (PCL), and copolymers thereof. Examples of polyethers include (but are not limited to) polyoxymethylene (POM) or polyphenylene oxide (PPO) polyetherketone (PEK), polyetheretherketone (PEEK), and epoxy resins. An example of a polysulfide is polyphenylene sulfide (PPS).

[0060] Polymer-based leaflets can be composed of random fibers (e.g., as made by electrospinning) or structured yarns (textiles) produced from any of the mentioned materials, composites. Polymer-based leaflets can be made into a foam. Polymer-based leaflets can be also made out of biological materials such as (for example) cellulose, alginates, chitosan, and decellularized collagen-based materials (e.g. pericardium or small intestinal submucosa).

[0061] When bioprosthetic tissue is utilized, process 200 also fixes 203 and/or preserves bioprosthetic tissue. A number of methodologies and reagents can be utilized to fix and preserve bioprosthetic tissue. In several instances, tissue is fixed by perfusion, immersion, freezing, drying, or a combination thereof. A number of fixative reagents can be utilized, including crosslinking reagents and precipitating reagents. Crosslinking reagents include (but are not limited to) formaldehyde, glutaraldehyde, paraformaldehyde, formalin, other aldehydes, genipin, i-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and enzymatic crosslinkers. In some instances, an amine crosslinking reagent is utilized, such as (for example) formaldehyde, glutaraldehyde, paraformaldehyde, formalin or genipin. In some instances, a carboxy crosslinking reagent is utilized, such as (for example) EDC, which may reduce calcification of free carboxy groups. In some instances, an amine and a carboxy crosslinking are each utilized, which can be utilized concurrently or in tandem.

[0062] In some instances, bioprosthetic tissue is fixed utilizing a biodegradable crosslinker, such as (for example) an enzymatic crosslinker, which can increase biocompatibility of the tissue. Enzymatic crosslinkers include transglutaminases (e.g., factor XIII) and oxidoreductases (e.g., tyrosinases, laccases with peroxidases, and lysyl oxidases with amine oxidases). For more examples of enzymatic crosslinkers, see J. C. Schense and J. A. Hubbell, Bioconjug Chem. 1999;IO(I):75-8I; and T. Heck, et al, Appl Microbiol Biotechnol. 2O13;97(2):46I-75; the disclosures of which are each incorporated herein by reference for all purposes. In some instances, a biodegradable crosslinker is used instead of chemical crosslinking reagents allows the crosslinked tissue to remain biodegradable. In some applications, biodegradable tissue is used as a temporary implant and allows native tissue to grow in and replace the biodegradable tissue. In some instances, crosslinking is performed utilizing bio-orthogonal anchor and difunctional linking compounds, such as those described in in U.S. Patent No. 9,925,303 by Benton, the disclosure of which is incorporated herein by reference for all purposes.

[0063] In some instances, a precipitating reagent is utilized. Precipitating reagents include (but are not limited to) methanol, ethanol, propanol, and acetone. The appropriate fixation methodology and reagents utilized can vary and are often dependent on the endproduct. For instance, when fixed (or cross-linked) tissues are to be utilized for a clinical application, it may be desired to use a less toxic fixative or a fixative that can be rendered less toxic with a post-fixation procedure.

[0064] Process 200 also treats (205) bioprosthetic tissue or polymer-based leaflets with AMPs. The bioprosthetic tissue or polymer-based leaflets can be coated with AMPs and/or

- io - emerged in an AMP solution. AMP solutions for coating or emersion can have a concentration between about 0.01% to 20%w/w. In some instances, the bioprosthetic tissue or polymer is perfused with an AMP solution. Any appropriate treatment can be utilized. In some instances, the bioprosthetic tissue or polymer is spray coated, brush coated, and/or spin coated with AMPs. In some instances, spray coating is performed with ultrasonic nozzles, allowing for better control of the AMP properties in the coating. In some instances, the bioprosthetic tissue or polymer is dipped or immersed in an AMP solution.

[0065] In many instances, AMP treatment of tissue or polymer is performed in a solution. In some instances, the AMP solution comprises glycerol, ethanol, and water. In some instances, an AMP solution is buffered to maintain a pH between and 6.5 and 8.0, and in some instances a pH between about 7.0 and 7.5, which may confer a benefit to stabilize the aqueous environment and the bioprosthetic tissue. Polypeptides form long range interactions with pericardium collagen molecules since their chemistries are similar therefore delamination of the coating was never observed. Any appropriate buffer salt may be utilized, including (but not limited to) phosphate buffered solution (PBS), potassium chloride (KCL), monobasic potassium phosphate (KH₂PO₄), dibasic potassium phosphate (K2HPO4), sodium chloride (NaCl) including isotonic saline, potassium bromide (KBr), sodium bromide (NaBr), calcium chloride (CaCl₂), HEPES, MES, MOPS, HEPPs, HEPBS, and Tris-HCl. Treatment of bioprosthetic tissue can be performed in any appropriate temperature to confer appropriate activity including (but not limited to) room temperature (~25 °C), and body temperature (~37 °C). The duration of treatment can be performed to the needs of the application, depending on the reagents utilized, temperature, and desired results. In some instances, bioprosthetic tissue is treated with an AMP solution for about: 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or greater than 72 hours. Non-ionic biocompatible surfactants can be used to stabilize polypeptide selfassembly and formation of hydrogel -like coating. Examples of biocompatible surfactants include (but are not limited to) polyol esters (e.g., fatty acid esters of sorbitan), Polyoxyethylene esters (e.g., polysorbates), poloxamers (e.g., poloxamer 188). A surfactant can be included in any AMP solution at any concentration ranging between about 0.01-1%.

[0066] Process 200 also treats 207 bioprosthetic tissue or polymer-based leaflets for clinical or preclinical use. The exact preparation depends on the clinical or preclinical application. In some instances, bioprosthetic tissue or polymer-based leaflets are utilized in the manufacture of a medical device. In some particular instances, bioprosthetic tissue or polymer-based leaflets are utilized to in the manufacture of heart valve. In some instances, bioprosthetic tissue is utilized in a grafting procedure. In some instances, bioprosthetic tissue is utilized in a vasculature prosthesis. In some instances, bioprosthetic tissue or polymer-based leaflets are used in treatment of patient. In some instances, bioprosthetic tissue or polymer-based leaflets are used in preclinical applications, such as (for example) training procedures on cadavers, animal models, or anthropomorphic phantoms.

[0067] A number of measures can be taken to prepare bioprosthetic tissue or polymer- based leaflets are for clinical or preclinical use. In some instances, bioprosthetic tissue is washed and/or perfused to remove harmful fixatives and other chemicals. In some instances, bioprosthetic tissue or polymer-based leaflets are cut, folded, and/or formed into the desired shape. In some instances, free aldehydes within bioprosthetic tissue are capped (e.g., a chemical procedure to modify free aldehydes to prevent them from binding calcium in a host recipient).

[0068] In some instances, prosthetic tissue or polymer-based leaflets are prepared for storage, which may help with long-term preservation. Storage can be dry storage or wet storage. Wet storage methods include storing the tissue or polymer within a solution, such as (for example) a fixation buffer (e.g., glutaraldehyde buffer) or propylene oxide in water. Dry storage methods include treating a tissue or polymer with a solution inclusive of a biocompatible molecule for a period of time, which can allow the components of the solution to equilibrate within the tissue or polymer. The tissue or polymer is then stored free of liquids, except for the components of the aqueous solution equilibrated therein.

Biocompatible molecules to be included within a solution for dry storage include (but are not limited to) glycerol, propylene glycol, polyethylene glycol, and saccharides. Solvents for dry storage include (but are not limited) aqueous based solvents, alcohol-based solvents, any other biocompatible solvent, and any solvent mixture thereof. For more description of dry storage methods, see U.S. Patent No. 6,534,004 by Chen et al., U.S. Patent No. 8,007,992 by Tian et al., and U.S. Patent No. 10,383,978 by Dong et al., the disclosures of which are each incorporated herein by reference for all purposes. In some instances, prosthetic tissue is sterilized, which can be performed using gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/or e-beam.

[0069] A number of tissue preparation procedures have been described, including the descriptions within the following publications: U.S. Patent No. 7,972,376 by Dove et al., U.S. Patent No. 8,748,490 by Dove et al., U.S. Patent No. 9,029,418 by Dove et al., U.S. Patent No. 9,320,830 by Dove et al., U.S. Patent No. 10,722,613 by Ashworth et al., U.S. Pub. No. 2017/0173214 by Wang, et al., and U.S. Pub. No. 2019/0374680 by Lehenberger, etal., the disclosures of which are each incorporated herein by reference for all purposes.

[0070] While specific examples of AMP treatment and preparation of bioprosthetic tissue or polymer-based leaflets are described above, one of ordinary skill in the art can appreciate that various steps of the process can be performed in different orders and that certain steps may be optional according to some aspects of the description. As such, it should be clear that the various steps of the process could be used as appropriate to the requirements of specific applications. Furthermore, any of a variety of processes for AMP treatment and preparation of bioprosthetic tissue or polymer-based leaflets appropriate to the requirements of a given application can be utilized in accordance with various aspects of the description.

Methods to Assemble and Prepare Medical Devices

[0071] Various methods utilize AMP treated bioprosthetic tissue within medical devices. In many instances, a medical device is any prosthetic device for the purpose of implanting into a recipient. Recipients include (but are not limited to) patients, animal models, cadavers, or anthropomorphic phantoms. A medical device can be a tissue patch, a medical vessel, a conduit, a closure device, a prosthetic heart valve including (but not limited to) aortic, mitral, tricuspid and pulmonary prosthetic valves, or a delivery system. A number of treatments can be performed on bioprosthetic tissue to prepare it for clinical or preclinical use, including (but not limited to) tissue fixation, tissue stabilization, bioburden reduction, AMP treatment, cutting and shaping of tissue, assembly into a medical device, preservation, sterilization, and any set of combinations thereof.

[0072] Provided in Fig. 3 is an exemplary valvular prosthetic 301 for replacing a heart valve. The heart valve 301 can be a transcatheter heart valve that can be crimped into a confined profile such that it can be used in a transcatheter delivery system to implant the valve. Generally, heart valve 301 comprises a set of leaflets 303 to perform the valve function, a frame 305 for supporting the leaflets, and an inner cover 307 to ensure proper blood flow through the valve. The heart valve can further comprise an outer skirt to mitigate perivalvular leakage and/or protect the frame from the surrounding tissue or protect the surrounding tissue from the frame. The valve can further comprise an anchor or other means for securing the valve at the site of implantation.

[0073] Valvular prosthetics can be assembled with AMP treated bioprosthetic tissue or polymer-based leaflets. Any methods for assembly of a prosthetic valve can be utilized. Generally, AMP treated bioprosthetic tissue or polymer can be shaped into a leaflet via cutting, laser ablation, or any method to formulate a leaflet 401 having have an extended cusp edge 403 and an attachment edge 405 (Fig. 4A). The attachment edge can be utilized to attach leaflets together into a leaflet assembly 410 (Fig. 4B) and/or attach the leaflets to an inner wall of a valvular conduit (e.g., inner cover). The assembled leaflets, along with the inner wall of the conduit, provided a means for unidirectional blood flow. When the valve is closed, the cusp edges come together and form a seal, preventing retrograde blood flow.

[0074] Assembled transcatheter heart valve prosthetics can be utilized with a delivery system to deliver a heart valve to the site of implantation. An exemplary delivery system is provided in Fig. 5. Delivery system 501 is adapted to deliver a prosthetic heart valve 503, which is secured to the system. Delivery system 501 includes a steerable flex catheter 505 for guiding the distal end of the delivery system and an inner catheter 507 for assisting with extraction and installation of the prosthetic heart valve. Inner catheter 507 can be a balloon catheter for expanding the prosthetic heart valve at the site of implantation. It should be understood, however, that self-expanding prosthetic heart valves (e.g., nitinol-based heart valves) can be utilized and thus an expanding balloon would not be necessary. As shown, prosthetic heart valve 503 is in a crimped state to reduce the profile of the prosthetic such that it can traverse through the vasculature of the recipient. Further, a nose piece 509 can be provided at the proximal end of delivery system 501, which can have a tapered contour to better traverse through the vasculature and facilitate advancement of the delivery system.

[0075] Delivery system 501 can further include a handle 511 and shaft extending from the handle and in connection with flex catheter 505 and inner catheter 507. Handle 511 can include a side arm 513 having an internal passage for fluidic communication with one or more internal lumens, which can provide fluidic connection to expand a balloon or provide other capabilities for valve installation. Handle 511 can also include a rotatable member 515 or other means for advancing flex catheter 505 and inner catheter 507.

[0076] Various components of prosthetics and/ or delivery systems can be treated with

AMPs, especially components that come into contact or enter within the recipient. Accordingly, various components can be spray coated and/or dipped with AMPs and then assembled into the prosthetic. Components that can be treated can include any component of the prosthetic or delivery system.

[0077] In regards to heart valves, in some instance the frame of the valve is treated with AMPs. In some instances, the inner wall conduit (e.g., inner cover) is treated with AMPs. In some instances, the outer skirt is treated with AMPs. In some instances, an anchor is treated with AMPs. In some instances, components for securing the various components together are treated with AMPs, such as sutures which can be used to attach leaflets, a cover and/or a skirt to one another and/or to the frame of the valve.

[0078] It should also be understood that partially assembled or assembled prosthetics and/or delivery systems can be treated with AMPs. Accordingly, components of a prosthetic can be assembled together and then spray coated, dipped, immersed, and/or perfused with AMPs. In some instances, AMP treatment is performed directly before, concurrently with, or immediately after sterilization as part of the sterilization process. In some instances, particular components of a delivery system are treated with AMPs to provide particular benefits. For instance, components that would come in contact with the vasculature (e.g, nose cone, flex catheter, inner catheter, etc.) are treated with AMPs. In some instances, a balloon for expanding a heart valve prosthetic or other tubular prosthetic is treated with AMPs. When a balloon is coated with AMPs, the balloon can be used as a means to treat the interior luminal walls of a tubular prosthetic (e.g., heart valve). To do so, when the balloon is expanded and pressed upon the luminal walls of tubular prosthetic, the AMPs can be transferred onto the walls. This procedure can be done during or after installation of the tubular prosthetic.

[0079] Provided in Fig. 6 is an exemplary process for treating a prosthetic or system. Process 600 can begin by obtaining (601) a prosthetic or delivery system. In some instances, the prosthetic or delivery system is fully assembled. In some instances, the prosthetic or the delivery system is partially assembled. The prosthetic can be a medical vessel, a conduit, a closure device, or a prosthetic heart valve including (but not limited to) aortic, mitral, tricuspid and pulmonary prosthetic valves. The delivery system can be a system for delivering a prosthetic to the implantation site within the recipient.

[0080] Process 600 also treats (603) the prosthetic or delivery system (or a component thereof) with AMPs. The prosthetic or the delivery system can be spray coated, dipped, immersed, and/or perfused utilizing an AMP solution. Any appropriate treatment can be utilized. In some instances, the prosthetic or the delivery system is spray coated with AMPs. In some instances, the prosthetic or the delivery system is dipped in an AMP solution. In some instances, the prosthetic or the delivery system is immersed in an AMP solution. In some instances, the prosthetic or delivery system is perfused with an AMP solution.

[0081] In many instances, AMP treatment of the prosthetic or the delivery system is performed in an aqueous solution. In some instances, an aqueous solution is buffered to maintain a pH below about 8.5, and in some instances a pH between about 7.5 and 8.5, which may confer a benefit to stabilize the aqueous environment and the bioprosthetic tissue. Any appropriate buffer salt may be utilized, including (but not limited to) phosphate buffered solution (PBS), potassium chloride (KC1), monobasic potassium phosphate (KH2PO4), dibasic potassium phosphate (K₂HPO₄), sodium chloride (NaCl) including isotonic saline, potassium bromide (KBr), sodium bromide (NaBr), calcium chloride (CaCl₂), HEPES, MES, MOPS, HEPPs, HEPBS, and Tris-HCl. AMP treatment can be performed in any appropriate temperature to confer appropriate activity including (but not limited to) room temperature (~25 °C), and body temperature (~37 °C). The duration of treatment can be performed to the needs of the application, depending on the reagents utilized, temperature, and desired results. In some instances, bioprosthetic tissue is treated with an AMP solution for about: 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or greater than 72 hours. [0082] Process 600 also prepares 605 the prosthetic or the delivery system for clinical or preclinical use. The exact preparation depends on the clinical or preclinical application. In some instances, the prosthetic or the delivery system is used in treatment of patient. In some instances, the prosthetic or the delivery system used in preclinical applications, such as (for example) training procedures on cadavers, animal models, or anthropomorphic phantoms.

[0083] A number of measures can be taken to prepare the prosthetic or the delivery system for clinical or preclinical use. In some instances, the prosthetic or the delivery system is prepared for storage, which may help with long-term preservation. Storage can be dry storage or wet storage. Wet storage methods include storing the prosthetic or the delivery system within a solution, such as (for example) a fixation buffer (e.g., glutaraldehyde buffer) or propylene oxide in water. Dry storage methods include treating the prosthetic or the delivery system with a solution inclusive of a biocompatible molecule for a period of time, which can allow the components of the solution to equilibrate within the prosthetic or the delivery system. The prosthetic or the delivery system is then stored free of liquids, except for the components of the aqueous solution equilibrated therein. Biocompatible molecules to be included within a solution for dry storage include (but are not limited to) glycerol, propylene glycol, polyethylene glycol, and saccharides. Solvents for dry storage include (but are not limited) aqueous based solvents, alcohol-based solvents, any other biocompatible solvent, and any solvent mixture thereof. For more description of dry storage methods, see U.S. Patent No. 6,534,004 by Chen et al., U.S. Patent No. 8,007,992 by Tian et al., and U.S.

Patent No. 10,383,978 by Dong et al., the disclosures of which are each incorporated herein by reference for all purposes. In some instances, the prosthetic or the delivery system is sterilized, which can be performed using gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/or e-beam. After preparation, the prosthetic or the delivery system can be stored within a container, which can be hermetically sealed or otherwise kept sterile.

[0084] While specific examples of AMP treatment and preparation of a prosthetic or a delivery system are described above, one of ordinary skill in the art can appreciate that various steps of the process can be performed in different orders and that certain steps may be optional according to some aspects of the description. As such, it should be clear that the various steps of the process could be used as appropriate to the requirements of specific applications. Furthermore, any of a variety of processes for AMP treatment and preparation of a prosthetic or a delivery system appropriate to the requirements of a given application can be utilized in accordance with various aspects of the description.

Doctrine of equivalents and other considerations

[0085] While the above description contains many specific examples of the disclosure, these should not be construed as limitations on the scope of the disclosure. As such, the described methods, systems, and apparatus should not be construed as limiting in anyway. Instead, the present disclosure is directed toward all novel and nonobvious features and aspects of the various disclosed examples, alone and in various combinations and subcombinations with one another. The disclosed methods, systems, and apparatus are not limited to any specific aspect, feature, or combination thereof, nor do the disclosed methods, systems, and apparatus require that any one or more specific advantages be present or problems be solved. Accordingly, the scope of the disclosure should be determined not by the aspects illustrated, but by the appended claims and their equivalents.

[0086] Various examples of prosthetic valves or delivery systems are disclosed herein, and any combination of these options can be made unless specifically excluded. For example, any of the methods disclosed, can be used with any type of valve, and/or any delivery system, even if a specific combination is not explicitly described. Likewise, the different constructions and features of prosthetics and delivery systems can be mixed and matched, such as by combining any feature even if not explicitly disclosed. In short, individual components of the disclosed systems can be combined unless mutually exclusive or physically impossible.

[0087] Although the operations of some of the disclosed methods are described in a particular, sequential order for convenient presentation, it should be understood that this manner of description encompasses rearrangement, unless a particular ordering is required by specific language. For example, operations described sequentially may in some cases be rearranged or performed concurrently. Moreover, for the sake of simplicity, the attached figures may not show the various ways in which the disclosed methods, systems, and apparatus can be used in conjunction with other systems, methods, and apparatus.

[0088] It is specifically noted that several processes described herein can vary, as would be understood by those skilled in the art. For instance, equivalent (or near-equivalent) processes, reagents, concentrations, temperatures, buffer salt solutions, solution pH, and treatment durations that yield a similar result, as would be anticipated by those skilled in the art, are to be covered in various aspects of the disclosure.

Experimentation and Data

[0089] To test applicability of AMPs, Gramicidin A and a synthetic polypeptide were each assessed to determine their ability to associate with bovine pericardium. Gramicidin A was incorporated into bovine pericardium by spray coating with (0.025 mg / mL) concentration. The coating did not affect the chemical or mechanical properties of collagen or bovine pericardium, as assessed by Differential Scanning Calorimetry (DSC) and Tensile testing.

Additionally, concentrated solutions of (poly(l-lysine) and Poly-L-leucine-1,3- diaminopropane (Sigma Aldrich) at concentrations of o.oi-i%wt was spray-coated onto bovine pericardium. Thermal testing indicated no impact on collagen structure. FTIR-ATR testing of the wash solutions indicated polypeptide incorporation and attachment into the collagen matrix of bovine pericardial tissue.

[0090] Example 1. A method for preparing antimicrobial tissue or polymer, comprising: treating bioprosthetic tissue or polymer with an antimicrobial peptide solution; and preparing the bioprosthetic tissue or polymer for preclinical or clinical use.

[0091] Example 2. The method of example 1, wherein the antimicrobial peptide solution comprises a lysine-rich peptide, an arginine-rich peptide, a proline-rich peptide, a histidine rich peptide, or a proline rich peptide.

[0092] Example 3. The method of example 1, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one hydrophilic block and at least one hydrophobic block.

[0093] Example 4. The method of example 1, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one positively charged block and at least one negatively charged block.

[0094] Example 5. The method of example 1, wherein the antimicrobial peptide solution comprises a peptide selected from: gramicidin, daptomycin, and colistin.

[0095] Example 6. The method of any one of examples 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises spray coating, brush coating, or spin coating the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0096] Example 7. The method of any one of examples 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises dipping the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0097] Example 8. The method of any one of examples 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises immersing the bioprosthetic tissue or polymer in the antimicrobial peptide solution.

[0098] Example 9. The method of any one of examples 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises perfusing the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

[0099] Example 10. The method of any one of examples 1 to 9, wherein the bioprosthetic tissue is derived from an animal source.

[0100] Example 11. The method of example 9, wherein the animal source is bovine, porcine, ovine, avian, or human donor. [0101] Example 12. The method of any one of examples 1 to 11, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises utilizing the bioprosthetic tissue or polymer in an assembly of a medical device.

[0102] Example 13. The method of example 12, wherein the medical device is a tissue patch, a medical vessel, a conduit, a closure device or a prosthetic heart valve.

[0103] Example 14. The method of any one of examples 1 to 13, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises preparing the bioprosthetic tissue or polymer for storage.

[0104] Example 15. The method of example 14, wherein the storage is a wet storage or a dry storage.

[0105] Example 16. The method of any one of examples 1 to 15, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises sterilizing the bioprosthetic tissue or polymer.

[0106] Example 17. The method of example 16, wherein sterilizing the bioprosthetic tissue or polymer comprises a treatment with one or more of: gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/ or e-beam.

[0107] Example 18. The method of any one of examples 1 to 17 further comprising fixing the bioprosthetic tissue.

[0108] Example 19. The method of example 18, wherein fixing the bioprosthetic tissue comprises crosslinking the bioprosthetic tissue or precipitating the bioprosthetic tissue.

[0109] Example 20. A bioprosthetic tissue treated by any one of methods of examples 1 to 19.

[0110] Example 21. A method for preparing an antimicrobial medical device, comprising: treating one or more components of a medical device with an antimicrobial peptide solution; and preparing the medical device for preclinical or clinical use.

[0111] Example 22. The method of example 21, wherein the antimicrobial peptide solution comprises a lysine-rich peptide, an arginine-rich peptide, a proline-rich peptide, a histidine rich peptide, or a proline rich peptide.

[0112] Example 23. The method of example 21, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one hydrophilic block and at least one hydrophobic block. [0113] Example 24. The method of example 21, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one positively charged block and at least one negatively charged block.

[0114] Example 25. The method of example 21, wherein the antimicrobial peptide solution comprises a peptide selected from: gramicidin, daptomycin, and colistin.

[0115] Example 26. The method of any one of examples 21 to 25, wherein the treating of the one or more components of the medical device comprises spray coating, brush coating, or spin coating the one or more components with the antimicrobial peptide solution.

[0116] Example 27. The method of any one of examples 21 to 25, wherein the treating of the one or more components of the medical device comprises dipping the one or more components with the antimicrobial peptide solution.

[0117] Example 28. The method of any one of examples 21 to 25, wherein the treating of the one or more components of the medical device comprises immersing the one or more components in the antimicrobial peptide solution.

[0118] Example 29. The method of any one of examples 21 to 25, wherein the treating of the one or more components of the medical device comprises perfusing the one or more components with the antimicrobial peptide solution.

[0119] Example 30. The method of any one of examples 21 to 29, wherein the medical device is a tissue patch, a medical vessel, a conduit, a closure device, a prosthetic heart valve, or a delivery device.

[0120] Example 30. The method of any one of examples 21 to 30, wherein the preparing the one or more components of the medical device for preclinical or clinical use comprises utilizing the one or more components in an assembly of a medical device.

[0121] Example 32. The method of any one of examples 21 to 31, wherein the one or more components of the medical device are already assembled into the medical device.

[0122] Example 33. The method of any one of examples 21 to 32, wherein the preparing the one or more components of the medical device for preclinical or clinical use comprises preparing the medical device for storage.

[0123] Example 34. The method of example 33, wherein the storage is a wet storage or a dry storage.

[0124] Example 35. The method of any one of examples 21 to 34, wherein the preparing the one or more components of the medical device for preclinical or clinical use comprises sterilizing the medical device. [0125] Example 36. The method of example 35, wherein sterilizing the medical device comprises a treatment with one or more of: gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/or e-beam.

[0126] Example 37. A prosthetic heart valve treated by the method of any one of examples 21 to 36.

[0127] Example 38. A delivery system for delivering a prosthetic heart valve treated by the method of any one of examples 21 to 36.

[0128] Example 39. A balloon of a delivery system for delivering a tubular prosthetic treated by the method of any one of examples 21 to 36.

[0129] Example 40. A method for treating an interior luminal wall of a tubular prosthetic, comprising: providing a balloon coated with AMPs on its surface; and expanding the balloon such that it contacts the interior luminal wall of a tubular prosthetic.

[0130] Example 41. The method of example 40, wherein the expansion of the balloon occurs during an installation of the tubular prosthetic.

[0131] Example 42. The method of example 40, wherein the expansion of the balloon occurs after an installation of the tubular prosthetic.

Claims

WHAT IS CLAIMED IS:

1. A method for preparing antimicrobial tissue or polymer, comprising: treating bioprosthetic tissue or polymer with an antimicrobial peptide solution; and preparing the bioprosthetic tissue or polymer for preclinical or clinical use.

2. The method of claim 1, wherein the antimicrobial peptide solution comprises a lysine-rich peptide, an arginine-rich peptide, a proline-rich peptide, a histidine rich peptide, or a proline rich peptide.

3. The method of claim 1, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one hydrophilic block and at least one hydrophobic block.

4. The method of claim 1, wherein the antimicrobial peptide solution comprises a peptide that comprises at least one positively charged block and at least one negatively charged block.

5. The method of claim 1, wherein the antimicrobial peptide solution comprises a peptide selected from: gramicidin, daptomycin, and colistin.

6. The method of any one of claims 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises spray coating, brush coating, or spin coating the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

7. The method of any one of claims 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises dipping the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

8. The method of any one of claims 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises immersing the bioprosthetic tissue or polymer in the antimicrobial peptide solution.

9. The method of any one of claims 1 to 5, wherein the treating of the bioprosthetic tissue or polymer comprises perfusing the bioprosthetic tissue or polymer with the antimicrobial peptide solution.

10. The method of any one of claims 1 to 9, wherein the bioprosthetic tissue is derived from an animal source.

11. The method of claim 9, wherein the animal source is bovine, porcine, ovine, avian, or human donor.

12. The method of any one of claims 1 to 11, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises utilizing the bioprosthetic tissue or polymer in an assembly of a medical device.

13- The method of claim 12, wherein the medical device is a tissue patch, a medical vessel, a conduit, a closure device or a prosthetic heart valve.

14. The method of any one of claims 1 to 13, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises preparing the bioprosthetic tissue or polymer for storage.

15. The method of claim 14, wherein the storage is a wet storage or a dry storage.

16. The method of any one of claims 1 to 15, wherein the preparing the bioprosthetic tissue or polymer for preclinical or clinical use comprises sterilizing the bioprosthetic tissue or polymer.

17. The method of claim 16, wherein sterilizing the bioprosthetic tissue or polymer comprises a treatment with one or more of: gamma irradiation, gas plasma, aldehydes, ethylene oxide, and/ or e-beam.

18. The method of any one of claims 1 to 17 further comprising fixing the bioprosthetic tissue.

19. The method of claim 18, wherein fixing the bioprosthetic tissue comprises crosslinking the bioprosthetic tissue or precipitating the bioprosthetic tissue.

20. A bioprosthetic tissue treated by any one of methods of claims 1 to 19.