Polyurethane-based resin having a biomimetic functional modifier

Abstract

A medical device may include a medical device body and / or a coating on the medical device body. The medical device body and / or the coating may be formed from a polyurethane-based resin, which may be a reaction product of ingredients including: a diisocyanate; a chain extender; a polyglycol; and a biomimetic functional modifier. The ingredients of the reaction product may further include an additional ionically-charged modifier and / or a low-surface energy modifier. The biomimetic functional modifier may aid in prevention of thrombus formation, resistance to biofilm colonization, and inhibition of adverse tissue inflammatory response to medical implants. In addition, an ionic active agent may be ionically bound to the biomimetic functional modifier and the additional ionically-charged modifier for active and controlled release. The biomimetic functional modifier may include a phosphorylcholine functional group. The biomimetic functional modifier may be glycerophosphorylcholine. The medical device body may include a catheter tube body.

Description

POLYURETHANE-BASED RESIN HAVING A BIOMIMETIC FUNCTIONAL MODIFIERBACKGROUND

[0001] Catheters are commonly used for a variety of infusion therapies. Infusion therapy is one of the most common health care procedures. Hospitalized, home care, and other patients receive fluids, pharmaceuticals, and blood products via a vascular access device inserted into the vascular system. Infusion therapy may be used to treat an infection, provide anesthesia or analgesia, provide nutritional support, treat cancerous growths, maintain blood pressure and heart rhythm, or many other clinically significant uses. For example, catheters are used for infusing fluids, such as normal saline solution, various medicaments, and total parenteral nutrition into a patient, withdrawing blood from a patient, as well as monitoring various parameters of the patient’s vascular system.

[0002] Catheters are commonly introduced into vasculature of a patient as part of an intravenous catheter assembly. The intravenous catheter assembly generally includes a catheter hub, which supports the catheter, the catheter hub being coupled to a needle assembly, including a needle hub, which supports an introducer needle. The introducer needle is extended and positioned within the catheter such that a beveled portion of the needle is exposed beyond a tip of the catheter. The beveled portion of the needle is used to pierce the skin of the patient to provide an opening whereby to insert the needle in the vasculature of the patient. Following insertion and placement of the catheter, the introducer needle is removed from the catheter thereby providing intravenous access to the patient.

[0003] Catheter-related bloodstream infections (CRB Sis) are a major concern with indwelling catheters such as peripherally inserted central catheters (PICCs) and central venous catheters (CVCs). Concern with CRB SI has also been raised with respect to peripheral intravenous catheters (PIVCs) and midline catheters.

[0004] CRBSIs are caused by the colonization of microorganisms in patients with intravascular catheters and intravascular access devices. These infections are an important cause of illness and excess medical costs, as approximately 250,000 - 400,000 cases of central venous catheter (CVC) associated bloodstream infections occur annually in U.S. hospitals. In addition to the monetary costs, these infections are associated with anywhere from 20,000 to 100,000 deaths each year. Despite guidelines to help reduce healthcare associated infections (HAIs), catheter-related bloodstream infections continue to plague our healthcare system.

[0005] Thrombosis-induced catheter occlusions also cause illness and excess medical costs. In addition, it has been reported that thrombus formation and CRBSI are closely linked; with thrombus present, microorganism colonization and infection rate would significantly increase. There is a need for anti-fouling materials that can provide protection from thrombosis, CRBSIs, and other HAIs. The subject matter claimed in the present disclosure is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate one example technology area where some implementations described in the present disclosure may be practiced.SUMMARY

[0006] The present disclosure relates generally to a medical device including a polyurethane-based resin having a biomimetic functional modifier, as well as related systems and methods. In some embodiments, the polyurethane-based resin with the biomimetic functional modifier may inhibit biofilm colonization, thrombus formation, and an adverse tissue inflammatory response.

[0007] In some embodiments, a medical device may include a medical device body and / or a coating on the medical device body. In some embodiments, the medical device body may include a catheter tube body. In some embodiments, the medical device body and / or the coating may be formed from a polyurethane-based resin, which may be a reaction product of ingredients including: a diisocyanate; a chain extender; a polyglycol; and a biomimetic functional modifier. In some embodiments, the polyurethane-based resin may have a hard segment content in a range of from 25% to 75% by weight and a soft segment content of the resin is in a range of from 75% to 25% by weight.

[0008] In some embodiments, the ingredients of the reaction product may further include a low-surface energy modifier, such as, for example, a low-surface energy modifying oligomer. In some embodiments, the low-surface energy modifier may improve passive surface properties of the medical device body and / or coating, including antifouling and / or selflubricating properties. In some embodiments, the low-surface energy modifier may be incorporated into a backbone, as a side chain, or both of the polyurethane-based resin formed by the diisocyanate, the polyglycol, the biomimetic functional modifier, and the chain extender.

[0009] In some embodiments, an ionic active agent may be ionically bound to the biomimetic functional modifier. In some embodiments, ionic bonding of the ionic active agent to the biomimetic functional modifier may be achieved by solution imbibing technique or bulk mixing (e.g., thermal compounding or solvent mixing) technique.

[0010] In some embodiments, the biomimetic functional modifier may include a biomimetic functional group, such as, for example, a phosphorylcholine functional group. In some embodiments, the biomimetic functional modifier may be incorporated into a backbone, as a side chain, or both of the polyurethane-based resin formed by the diisocyanate, the polyglycol, and the chain extender.

[0011] In some embodiments, the biomimetic functional modifier is a particular chain extender. In some embodiments, the biomimetic functional modifier may be introduced as a hard segment of the polyurethane-based resin using the particular chain extender having the biomimetic functional group. In some embodiments, a polymer chain segment (C) includes the biomimetic functional modifier shown below.

[0012] In some embodiments, the biomimetic functional modifier is a particular diisocyanate. In some embodiments, the biomimetic functional modifier may be introduced as a hard segment of the polyurethane-based resin using the particular diisocyanate having the biomimetic functional group.

[0013] In some embodiments, the biomimetic functional modifier is a particular polyglycol. In some embodiments, the biomimetic functional modifier may be introduced as a soft segment of the polyurethane-based resin using the particular polyglycol having the biomimetic functional group.

[0014] In some embodiments, the diisocyanate and / or the particular diisocyanate may be selected from the group consisting of: an aliphatic diisocyanate, alicyclic diisocyanate and an aromatic diisocyanate. In some embodiments, the diisocyanate and / or the particular diisocyanate may be selected from the group consisting of: 4,4'-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4- cyclohexylisocyanate) (HMDI), and combinations thereof.

[0015] In some embodiments, the chain extender and / or the particular chain extender may be selected from the group consisting of: ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, neopentyl glycol, and alicyclic glycols having up to 10 carbon atoms. In some embodiments, the polyglycol and / or the particular polyglycol may be selected from the group consisting of: polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof.

[0016] In some embodiments, the polyurethane-based resin may be a random copolymer including chain segments (A), (B), and (C) as follows:(A)wherein n is in the range of 3 to 40;

[0017] An example biomimetic functional modifier glycerophosphorylcholine has a molecular structure (D) as follows, which is used to form the above polyurethane chain segment(C).

[0018] In some embodiments, a hard segment content of the polyurethane-based resin is in the range of from 25% to 75% by weight and a soft segment content of the polyurethane-based resin is in the range of from 75% to 25% by weight.

[0019] The terminology used in the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used in the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The singular forms also include the plural unless the context clearly dictates otherwise. Thus, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Also, the words “including,” “has,” and “having,” as used in the present disclosure, including the claims, shall have the same meaning as the word “comprising.”

[0020] Reference throughout the present disclosure to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases “in some embodiments,” “in the embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. Additionally, while the following description refers to several embodiments and examples of the various components and processes of the present disclosure, all of the described embodiments and examples are to be considered, in all respects, as illustrative only and not as being limiting in any manner.

[0021] It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory and are not restrictive of the invention, as claimed. It should be understood that the various embodiments are not limited to the arrangements and instrumentality shown in the drawings. It should also be understood that the embodiments may be combined, or that other embodiments may be utilized and that structuralchanges, unless so claimed, may be made without departing from the scope of the various embodiments of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0022] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0023] Figure 1A is an upper perspective view of an example catheter system having a catheter tube body formed from a polyurethane-based resin which is a reaction product of ingredients including: a diisocyanate, a chain extender, a polyglycol, and a biomimetic functional modifier, according to some embodiments;

[0024] Figure IB is a cross-sectional view of the catheter system of Figure 1 A, illustrating an example introducer needle removed, according to some embodiments;

[0025] Figure 2A is an upper perspective view of another example catheter system having a catheter tube body with a coating formed from a polyurethane-based resin which is a reaction product of ingredients including: a diisocyanate, a chain extender, a polyglycol, and a biomimetic functional modifier, according to some embodiments; and

[0026] Figure 2B is a cross-sectional view of the catheter system of Figure 2A, illustrating an example introducer needle removed, according to some embodiments;

[0027] Figure 3 is a graph illustrating chlorhexidine acetate (CHA) accumulated elution amount;

[0028] Figure 4 is a graph illustrating CHA average daily elution amount; and

[0029] Figure 5 is a photograph showing comparison of thrombosis formation (after drying) of (i) Reference PU (Control), (ii) the biomimetic BM-PU-1 without CHA imbibing, and (iii) the biomimetic BM-PU-1 with CHA imbibing, at various heparin concentrations (0.1 - 0.5 lU / mL).DESCRIPTION OF EMBODIMENTS

[0030] In some embodiments, a medical device may include a medical device body and / or a coating on the medical device body. In some embodiments, the medical device body and / or the coating may be formed from or manufactured with a polyurethane-based resin, which may be a reaction product of ingredients including: a diisocyanate; a chain extender; a polyglycol; and a biomimetic functional modifier. In some embodiments, the medical device body and / or the coating formed from the polyurethane-based resin may passively inhibit thrombus, biofilmformation, and adverse tissue inflammation due to the biomimetic functional modifier at a surface of the medical device. In some embodiments, the polyurethane-based resin may be a reaction product of the diisocyanate, the polyglycol, and multiple biomimetic functional modifiers that may be the same or different from the biomimetic functional modifier.

[0031] In some embodiments, the medical device body may include a catheter tube body. In some embodiments, the polyurethane-based resin may have a hard segment content in a range of from 25% to 75% by weight and a soft segment content of the resin is in a range of from 75% to 25% by weight.

[0032] In some embodiments, an ionic active agent may be ionically bound to the biomimetic functional modifier. In some embodiments, the ionic active agent bound to the biomimetic functional modifier may allow the medical device to actively provide antimicrobial and / or anti-fouling through release of the ionic active agent, which may occur in a controlled manner.

[0033] In some embodiments, the ingredients of the reaction product may include a low- surface energy modifier, such as, for example, a low-surface energy modifying oligomer, which may provide self-lubricating and antifouling properties. In some embodiments, the low- surface energy modifier may be incorporated into a backbone, as a side chain, or both of the polyurethane-based resin formed by the diisocyanate, the polyglycol, the biomimetic functional modifier, and the chain extender.

[0034] In some embodiments, the biomimetic functional modifier may include a biomimetic functional group, such as, for example, a phosphorylcholine functional group. The phosphorylcholine functional group includes a negatively charged phosphate group and a positively charged choline group. In some embodiments, the biomimetic functional modifier may include or correspond to glycerophosphorylcholine, which has molecular structure (D) shown below. In some embodiments, the biomimetic functional modifier may include one or more biomimetic functional groups such as a synthetic peptide, phosphorylcholine, glycocalyx, or any other suitable biomimetic moieties. In some embodiments, the biomimetic functional modifier may be incorporated into a backbone, as a side chain, or both of the polyurethane- based resin formed by the diisocyanate, the polyglycol, and the chain extender.

[0035] In some embodiments, the biomimetic functional modifier is a particular chain extender, which may be the same as or different from the chain extender. In some embodiments, the biomimetic functional modifier may be introduced as a hard segment of the polyurethane- based resin using the particular chain extender having the biomimetic functional group. In some embodiments, the particular chain extender may include a diol chain extender. In someembodiments, the diol chain extender containing the biomimetic functional group may correspond to glycerophosphorylcholine. The diol chain extender containing the phosphorylcholine functional group is shown in molecular structure (D) and the polyurethane chain segment (C) is formed after polymerization using the diol chain extender with molecular structure (D).

[0036] In some embodiments, the biomimetic functional modifier is a particular diisocyanate, which may be the same as or different from the diisocyanate. In some embodiments, the biomimetic functional modifier may be introduced as a hard segment of the polyurethane-based resin using the particular diisocyanate having the biomimetic functional group.

[0037] In some embodiments, the biomimetic functional modifier is a particular polyglycol, which may be the same as or different from the polyglycol. In some embodiments, the biomimetic functional modifier may be introduced as a soft segment of the polyurethane- based resin using the particular polyglycol having the biomimetic functional group.

[0038] In some embodiments, the diisocyanate and / or the particular diisocyanate may be selected from the group consisting of: an aliphatic diisocyanate, alicyclic diisocyanate and an aromatic diisocyanate. In some embodiments, the diisocyanate and / or the particular diisocyanate may be selected from the group consisting of: 4,4 '-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4- cyclohexylisocyanate) (HMDI), and combinations thereof.

[0039] In some embodiments, the chain extender and / or the particular chain extender may be selected from the group consisting of: ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, neopentyl glycol, and alicyclic glycols having up to 10 carbon atoms. In some embodiments, the polyglycol and / or the particular polyglycol may be selected from the group consisting of: polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof.

[0040] In some embodiments, the ingredients of the reaction product may further include an additional ionically-charged modifier, as described in U.S. Patent App. Pub. No. 2022 / 0265905, U.S. Patent App. Pub. No. 2022 / 0265906, and U.S. Patent App. Pub. No. 2022 / 0265904, which are hereby incorporated by reference in their entirety. In some embodiments, the ionically-charged modifier may be bound to an ionic active agent to further improve loading of the ionic active agent in addition to the loading that may be provided by the biomimetic functional modifier. In some embodiments, the ionically-charged modifier may include a cationic modifier, an anionic modifier, a combination of cationic and anionic modifiers, or a zwitterionic modifier.

[0041] In some embodiments, the anionic modifier may include an anionic functional moiety of — SO3 , — COO , or combinations thereof. In some embodiments, the anionic modifier may include bis-l,4-((2-hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q), 2,2-bis(hydroxymethyl)-propionic acid, 2,2-bis(hydroxymethyl)-butyric acid (BHMBA), or combinations thereof. In some embodiments, the cationic modifier may include a cationic functional moiety of quaternary ammonium. In some embodiments, the cationic modifier may include bis(2 -hydroxy ethyl) dimethylammonium chloride (BHDAC).

[0042] In some embodiments, the ionic active agent that can be bound to the ionically- charged modifier may include an antimicrobial agent. In some embodiments, the antimicrobial agent may include chlorhexidine ions. In some embodiments, the antimicrobial agent may include cetylpyridinium ions.

[0043] In some embodiments, the polyurethane-based resin may be a random copolymer including chain segments (A), (B), and (C) as follows:wherein n is in the range of 3 to 40;

[0044] An example biomimetic functional modifier glycerophosphorylcholine has a molecular structure (D) as follows, which is used to form the above chain segment (C).

[0045] In some embodiments, a hard segment content of the polyurethane-based resin is in the range of from 25% to 75% by weight and a soft segment content of the polyurethane-based resin is in the range of from 75% to 25% by weight.

[0046] The following terms shall have, for the purposes of this application, the respective meanings set forth below.

[0047] Polyglycols include but are not limited to: polyalkylene glycol, polyester glycol, and polycarbonate glycol. A nonlimiting specific example of polyalkylene glycol is poly ether glycol. A polyether glycol is a moderate molecular weight oligomer derived from an alkylene oxide, containing both ether linkages and glycol termination.

[0048] A chain extender is a short chain (low molecular weight) branched or unbranched diol, diamine or amino alcohol of up to 10 carbon atoms or mixtures thereof. Such hydroxyl - and / or amine-terminated compounds are used during polymerization to impart desired properties to a polymer.

[0049] A biomimetic functional modifier, such as glycerophosphorylcholine, is a compound containing a functional group (e.g., phosphorylcholine) that mimics the activity of a biologic object. In some embodiments, the biomimetic functional modifier may include a man-made synthetic material that replicates a biological object found in the natural world. In some instances, the biomimetic functional modifier may enhance a basic polyurethane structure of a diisocyanate, a chain extender, and a polyglycol to have properties including passive reduction of bacterial biofilm colonization and antifouling. Biomimetic functional modifiers contain one or more functional groups that replicate natural biological objects in our daily life. For example, phosphorylcholine is a functional group found in naturally occurring phospholipids, which are a major constituent of an outside surface of a cell membrane.Phosphorylcholine-based biomimetic material provides a biological “non-stick” surface that resists protein and cell adhesion, which can aid in prevention of thrombus formation, resistance to biofilm colonization, and inhibition of adverse tissue inflammatory response to medical implants.

[0050] In some embodiments, the biomimetic functional modifier may include the phosphorylcholine functional group, which is zwitterionic. In some embodiments, because the biomimetic functional modifier is zwitterionic, the ionic active agent, such as an antimicrobial or antithrombogenic agent, may be bound to the biomimetic functional modifier for active and controlled release. In some embodiments, the polyurethane-based resin may be ionically- charged, which may facilitate binding of the ionic active agent for active and controlled release, and may be an anionic polyurethane, a cationic polyurethane, a zwitterionic polyurethane, or a blend of the above.

[0051] Antimicrobial agents that may be used for bonding to the biomimetic functional modifier include any anionic antimicrobials, e.g., cioxacillin salt, cefoxitin salt, cefazolin salt, penicillin salt, or derivatives thereof. Antimicrobial agents that may be used for bonding to the biomimetic functional modifier include any cationic antimicrobials. Nonlimiting examples of cationic antimicrobials include chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, etc. In addition, cationic quaternary ammonium and guanidine containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide-mimics may also be ionically bonded with the biomimetic functional modifier of the polyurethane-based resin to provide advantages of enhanced surface properties including antimicrobial and antifouling. In some embodiments, antithrombogenic agents, e.g., heparin salt or citrate salt, may be ionically bonded with the biomimetic functional modifier to provide medical article desirable antithrombogenic properties.

[0052] A low-surface energy modifying oligomer (moderate molecular weight), as described in WO 2020 / 068617 Al and WO 2020 / 068619 Al, which is optional in embodiments herein, is a compound that enhances a basic polyurethane structure of a diisocyanate; a chain extender; a polyglycol; and a biomimetic functional modifier. Low- surface energy modifying oligomers, which are different from polyglycols, contain functional moieties (e.g., fluoroether and / or silicone) that migrate onto a surface of the polyurethane- based resin to render the resulting coating and / or medical device body with additional desirable surface properties including self-lubricating and antifouling. Modifying oligomers may have at least one, preferably two, or more than two, alcohol moieties (C-OH). The alcohol moietiesmay be located along a backbone of the oligomer. The alcohol moieties may be located at an end of the oligomer.

[0053] Isocyanate index is defined as the molar ratio of the total isocyanate groups in the diisocyanate to the total hydroxyl and / or amino groups presented in polyols and extenders. In general, polyurethane becomes harder with an increasing isocyanate index. There is, however, a point beyond which the hardness does not increase, and the other physical properties begin to deteriorate.

[0054] Incorporation of the biomimetic functional modifier into the backbone of the polyurethane-based resin means that the biomimetic functional group of the biomimetic functional modifier is directly linked to the polyurethane backbone chain; incorporation as a side chain means that there is at least one carbon chain spacer between the biomimetic functional group and the polyurethane backbone chain. The polyurethane chain segment (C) structure shows the phosphorylcholine functional group as a side chain.

[0055] Principles and embodiments of the present disclosure relate generally to thermoplastic polyurethane (TPU) materials having improved properties, and methods of preparing and using them. Provided are medical devices, including, for example, catheter tubing, that have inherent antimicrobial and anti -fouling characteristics or can easily bond ionic active agents to provide desirable material properties, including antimicrobial and / or antifouling.

[0056] Referring now to Figures 1A-2B, an example medical device is illustrated, according to some embodiments. In some embodiments, the medical device may include a catheter system 10. In some embodiments, the catheter system 10 may include a catheter adapter 12, which may include a distal end 14 and a proximal end 16. In some embodiments, the catheter system 10 may include a needle assembly 18, which may include an introducer needle 20 having a sharp distal tip 22. In some embodiments, a catheter tube 24 may extend from the distal end 14 of the catheter adapter 12. In some embodiments, the introducer needle 20 may extend beyond a distal end of the catheter 24 in an insertion configuration in order to facilitate puncturing of a patient’s skin and blood vessel to insert the catheter 24 into a blood vessel of a patient.

[0057] As illustrated in Figure IB, in some embodiments, a catheter tube body 26 forming a lumen 28 may be formed from the polyurethane-based resin, which may be a reaction product of ingredients including: the diisocyanate; the chain extender; the polyglycol; and the biomimetic functional modifier. As illustrated in Figure 2B, in some embodiments, a coating 30 on the catheter tube body 26 may include the polyurethane-based resin, which may be areaction product of ingredients including: the diisocyanate; the chain extender; the polyglycol; and the biomimetic functional modifier. In some embodiments, the coating 30 may form an outermost layer on the catheter tube 26, which may inhibit thrombus and biofilm formation during indwell of the catheter tube 26. Additionally or alternatively, in some embodiments, the coating 30 may form an innermost layer on the catheter tube 26 proximate the lumen 28, which may inhibit thrombus and biofilm formation during indwell of the catheter tube 26.

[0058] POLYURETHANES

[0059] Thermoplastic polyurethanes (TPUs) suitable for catheters and other medical devices are typically synthesized from three basic components: a diisocyanate, a polyglycol, and a chain extender, usually a low molecular weight diol, diamine, amino alcohol or water. If the chain extender is a diol, the polyurethane consists entirely of urethane linkages. If the extender is water, amino alcohol or diamine, both urethane and urea linkages are present, which results in a polyurethane urea (PUU). Inclusion of an amine-terminated polyether to the polyurethane synthesis also results in a polyurethane urea.

[0060] Polyurethane and polyurea chemistries may be based on the reactions of isocyanates with other hydrogen-containing compounds, where isocyanates are compounds having one or more isocyanate groups (-N=C=O). Isocyanate compounds can be reacted with water (H2O), alcohols (R-OH), amines (Rx-NH(3-X)), ureas (R-NH-CONH2), and amides (R-CONH2). Certain polyurethanes may be thermoplastic elastomers (TPE), whereas other compositions may be highly cross-linked.

[0061] Thermoplastic polyurethanes may include two phases or microdomains conventionally termed hard segments and soft segments, and as a result are often referred to as segmented polyurethanes. The hard segments, which are generally of high crystallinity, form by localization of the portions of the polymer molecules which include the diisocyanate and chain extender(s). The soft segments, which are generally either non-crystalline or of low crystallinity, form from the polyglycol or the optional amine-terminated polyether. The hard segment content is determined by the weight percent of diisocyanate and chain extender in the polyurethane composition, and the soft segment content is the weight percent of polyglycol or polydiamine. The thermoplastic polyurethanes may be partly crystalline and / or partly elastomeric depending on the ratio of hard to soft segments. One of the factors which determine the properties of the polymer is the ratio of hard and soft segments. In general, the hard segment contributes to hardness, tensile strength, impact resistance, stiffness and modulus while the soft segment contributes to water absorption, elongation, elasticity and softness.

[0062] In some embodiments, the thermoplastic polyurethanes, such as the polyurethane- based resin, may be produced by the reaction of: a diisocyanate, a chain extender, at least one polyglycol, a biomimetic functional modifier, and optionally, a low-surface energy modifier. The thermoplastic polyurethanes may have a hard segment content between 25 % and 75 % by weight, where a hard segment is the portion(s) of the polymer molecules which include the diisocyanate, the biomimetic functional modifier, and the extender components, which are generally highly crystalline due to dipole-dipole interactions and / or hydrogen bonding. In contrast, the soft segments are formed from the polyglycol portions and optionally the low- surface energy modifier between the diisocyanate of the polymer chains and generally are either amorphous or only partially crystalline due to the characteristics of the polyglycol(s) and modifying oligomer (s). In some embodiments, the hard segment content may be in the range of from 25 % to 75 % and the soft segment content may be in the range of from 75 % to 25 %.

[0063] In some embodiments, polymerization of the polyurethane-based resin may be a one-step or two-step copolymerization process. The process may require a catalyst, solvent, other additives, or a combination thereof. As illustrated in the example below, polymerization of the polyurethane-based resin may be a one-step process without use of a catalyst, solvent, and / or other additives. The synthesis may also be achieved by a variety of other synthesis techniques with or without catalyst / solvent understood by those skilled in the art.

[0064] In some embodiments, the diisocyanate may be selected from the group consisting of: an aliphatic diisocyanate, alicyclic diisocyanate and an aromatic diisocyanate. In various embodiments, the diisocyanate may be selected from the group consisting of: 4,4’- diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4-cyclohexylisocyanate) (HMDI), or combinations thereof.

[0065] In some embodiments, the chain extender may be selected from the group consisting of: ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, neopentyl glycol, and alicyclic glycols having up to 10 carbon atoms.

[0066] In some embodiments, the polyglycol may be selected from the group consisting of: polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof. In an embodiment, the polyglycol includes the polyalkylene glycol. In an embodiment, the polyalkylene glycol includes a polytetramethylene ether glycol (PTMEG). A further polyalkylene glycol may be polyethylene glycol (PEG) and / or polypropylene glycol (PPG). The polyurethane-based resin may further include a polyetheramine, e.g., JEFF AMINE® D4000.

[0067] BONDING OF ACTIVE AGENTS WITH POLYURETHANE-BASED RESINS

[0068] In some embodiments, the polyurethane-based resin is bound to an ionic active agent through ionic bonding with the biomimetic functional group. In some embodiments, the ionic active agent includes one or more of: a cationic antimicrobial agent, a cationic antithrombogenic agent, an anionic antimicrobial agent, and an anionic antithrombogenic agent.

[0069] In some embodiments, ionic bonding of active agents can be achieved by solution imbibing technique or bulk mixing (e.g., thermal compounding or solvent mixing) technique. As a result, ionic active agents may be ionically bonded not only on a surface of the polyurethane-based resin but also in the bulk TPU to render the resulting medical device desirable properties, including antimicrobial and antifouling.

[0070] EXAMPLE POLYURETHANE-BASED RESINS

[0071] In some embodiments, catheters are formed from the polyurethane-based resin having a biomimetic functional modifier. In some embodiments, the hard segment content of the polyurethane is in the range of from 25 % to 75 % by weight, and the soft segment content of the resin is in the range of from 75 % to 25 % by weight.

[0072] In some embodiments, the polyurethane-based resin may include the following ingredients: the diisocyanate includes 4,4 ’-diphenylmethane diisocyanate (MDI); the chain extender includes 1,4-butanediol; the polyglycols include a polytetramethylene ether glycol (PTMEG) with average MW in the range of from 250 Da to 2900 Da (n = 3 - 40); the biomimetic functional modifier includes glycerophosphorylcholine.

[0073] Other features and advantages of the present disclosure are apparent from the different example that follows. The example below illustrates different aspects and embodiments of the present disclosure and how to make and practice them. The example does not limit the claimed invention. Although methods and materials similar or equivalent to those described in the present disclosure can be used in the practice of the present disclosure, suitable methods and materials are described below. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0074] EXAMPLES

[0075] To further illustrate the embodiments of the present disclosure, the following examples are provided. These examples are not intended to limit the scope of the claimed invention, which should be determined solely on the basis of the claims.

[0076] Example 1

[0077] An experiment was performed to show that the polyglycol, the chain extender, and the biomimetic functional modifier can form a uniform reactant solution. The polyglycol included polytetramethylene ether glycol (PTMEG), the chain extender included 1,4- butanediol (BDO), and the biomimetic functional modifier included glycerophosphorylcholine. The polyglycol, the chain extender, and the glycerophosphorylcholine at a calculated ratio were charged into a beaker with a magnetic stirrer and mixed at 90 - 110 °C. As a result, the glycerophosphorylcholine solid powder was dissolved into a mixture including the polyglycol and the chain extender. Thus, it was shown that the polyglycol, the chain extender, and the glycerophosphorylcholine can form the uniform reactant solution.

[0078] Gel testing was further performed to observe a reactivity of the uniform reactant solution with the diisocyanate. The diisocyanate was 4,4’-diphenylmethane diisocyanate (MDI). A calculated amount of the uniform reactant solution (including the PTMEG, BDO, and glycerophosphorylcholine) was mixed with the diisocyanate (MDI) at about 70 °C. No catalyst or solvent was used. The uniform reactant solution reacted well with MDI resulting in a gel temperature of about 163 °C and a gel time of about 39 seconds.

[0079] Due to success in forming the uniform reactant solution and reacting the uniform reactant solution with the diisocyanate, it is shown that the polyurethanes discussed in the present disclosure may be prepared by a one-step copolymerization process, which may utilize a pilot scale polyurethane (PU) processor. The polyglycol, the chain extender, and the glycerophosphorylcholine may be added to the PU processor’s B tank with mixing and heat to form a uniform reactant mixture. The diisocyanate may be added to the PU processor’s A tank. The uniform reactant mixture of the B tank and the diisocyanate of the A tank may be injected into a mix head of the PU processor, without addition of a catalyst or solvent, to create the polyurethane-based resin of the present disclosure (See Example 2).

[0080] An amount of biomimetic functional modifier in the polyurethane-based resin may be tuned to optimize resulting material physical properties and functional performance for a specific application. In some instances, the polyurethane-based resin including the biomimetic functional modifier may be directly extruded or molded into a medical device. In some instances, the polyurethane-based resin including the biomimetic functional modifier may be used as a coating material application on one or more surfaces of the medical device.

[0081] Example 2

[0082] SYNTHESIS

[0083] Polyurethane-based resin with the biomimetic functional modifier discussed in the present disclosure was prepared by a one-step copolymerization process using a pilot-scale polyurethane (PU) processor. No catalyst or solvent was used for this reaction. The polyglycol(s) (e.g., PTMEG), biomimetic functional modifier(s) (e.g., glycerophosphorylcholine), and chain extender(s) (e.g., 1,4-butanediol) in the total amount of about 4.0 kg were charged into B tank (2.5 gallon full tank capacity with a recycle loop) of the PU processor with adequate mixing through a tank agitator at a set temperature until the biomimetic modifier (glycerophosphorylcholine, solid powder) was completely dissolved in the polyglycol / chain extender mixture; the diisocyanate (e.g., MDI, calculated amount to react out B tank diol mixture) was charged into A tank (2.5 gallon full tank capacity with a recycle loop) of the PU processor; during reaction, both B tank and A tank materials were pumped through their individual feeding lines at controlled feed rates to achieve an isocyanate index of 1.0 to 1.1 ; in one or more embodiments, the isocyanate index is 1.02; both the B and A streams were continuously injected through their respective injectors into a 8 cc mixing head with high rotor speed for adequate mixing and poured into silicone pans (covered with Teflon sheets); the entire PU processor system, including A / B tanks, fill / feed / recycle / drain lines, injectors and mixing head, was maintained at a temperature of 50 - 90 °C (various zone temperature controls) and the tanks were pulled under vacuum of < 100 mmHg during operation; the silicone pans filled with the PU reactants mixture passed through a 150 °F conveyor oven with 10 - 20 min of curing time to achieve complete reaction; the resulting white PU slab had a dimension of 7.7 in x 3.5 in x 0.3 in. The PU slabs were subsequently grinded into granulated forms. The PU granulates / chips were also extruded into ribbon sheets (thickness of 0.007 - 0.010 in.).

[0084] An example formulation (BM-PU-1 in Table 1) had MDI as an aromatic diisocyanate, a combination of polytetramethylene ether glycols (PTMEGs with average molecular weight of 500 - 1000 Da), 1,4-butanediol as the chain extender, and glycerophosphorylcholine as the biomimetic modifier according to Table 1. Reference polyurethane without a biomimetic modifier was made as well. Table 1 shows both the benchmark Reference PU and the BM-PU-1, which may be referred to as the biomimetic BM- PU-1, copolymer compositions.Table 1

[0085] Table 2 shows gel temperatures and gel times for the copolymerization reactions according to Examples in Table 1.Table 2

[0086] Comparison of syntheses of Reference PU versus BM-PU-1 shows that incorporation of the biomimetic modifier glycerophosphorylcholine (introduced as chain extender hard segment to replace part of 1,4-butanediol) during copolymerization increased the reaction rate and reduced the polymerization gel time.

[0087] Example 3

[0088] TESTING

[0089] Tensile Property Testing

[0090] Tensile properties of both the Reference PU and the biomimetic BM-PU-1 ribbons were characterized using an INSTRON tensile tester. The testing was performed at room conditions (23 °C, 50% RH, and > 40 h equilibration time), which is provided in Table 3 (mean of 10 measurements for each data).Table 3

[0091] Testing was also performed at simulated body indwell conditions (37 °C, saline solution equilibration for 4 hours), which is provided in Table 4 (mean of 10 measurements for each data).Table 4

[0092] Comparison of tensile properties of Reference PU and the biomimetic BM-PU-1 shows that with introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%)as part of the chain extender hard segment in place of 1,4-butanediol, material ultimate tensile strength and ultimate tensile strain both at room conditions and at simulated body indwell conditions did not change significantly; on the other hand, biomimetic BM-PU-1 exhibited reduced material stiffness (according to Young’s modulus) both at room conditions (42.20 vs. 92.22 MPa) and at simulated body indwell conditions (29.85 vs. 49.94 MPa) compared to the Reference PU benchmark.

[0093] Overall, after introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%), the biomimetic BM-PU-1 still exhibited desirable tensile properties for medical device applications.

[0094] Water Sorption

[0095] The Reference PU and biomimetic BM-PU-1 ribbons went through the following procedures for water sorption measurements: (i) cut ribbons (5 replicates for each group of ribbon material) into rectangular shape; (ii) dried all sample ribbon cuts in a vacuum oven at 95 °C overnight; (iii) weighed each dry ribbon cut; (iv) submerged each dry ribbon cut into 37 °C de-ionized water for 4 h; (v) immediately after taking the ribbon cut out of water, used a tissue paper to wipe off the surface free water and re-weighed the saturated ribbon cut; (vi) recorded all the pre-hydration and post-hydration weight data and calculated water sorption based on the following Equation (1):

[0096] Table 5 shows the water sorption data (mean of 5 measurements for each data).Table 5

[0097] Comparison of water sorption of Reference PU with the biomimetic BM-PU-1 shows that with introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%) as part of the chain extender hard segment in place of 1,4-butanediol, material water sorption slightly increased due to introduction of low content of biomimetic / zwitterionic functional group.

[0098] Thermogravimetric Analysis (TGA)

[0099] The Reference PU and biomimetic BM-PU-1 granulates / chips were analyzed using TA Instruments TGA Q500. For testing, 3 mg of each sample was heated from 25 °C to 800°C at 10 °C / min in Nitrogen gas. Table 6 shows the degradation temperatures (based on 1% and 5% weight losses) of both the Reference PU and the biomimetic BM-PU-1.Table 6

[0100] Table 6 shows that after introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%) as part of the chain extender hard segment in place of 1,4-butanediol, the biomimetic BM-PU-1 material showed comparable thermal degradation temperatures compared to Reference PU. This suggests that the biomimetic BM-PU-1 possesses a desirable thermal property for downstream processing, such as thermal compounding, as well as ribbon and tubing extrusions.

[0101] Melt Flow Index

[0102] The Reference PU and biomimetic BM-PU-1 granulates / chips were characterized for melt flow indexes using a Zwick / Roell extrusion plastometer. The equipment has an extrusion barrel diameter of 9.55 mm (length of 170 mm) and a piston diameter of 9.48 mm (weight of 325 g). Five (5) g of each pre-dried (dried at 95 - 110 °C for over 12 hours) sample was used to perform the test at 220 °C with 5 kg of load weight and 300 seconds of preheat time. Table 7 shows the melt mass flow rate, melt volume flow rate and melt density of both the Reference PU and the biomimetic BM-PU-1.Table 7

[0103] Table 7 shows that after introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%) as part of the chain extender hard segment in place of 1,4-butanediol, the biomimetic BM-PU-1 material showed comparable melt flow properties compared to Reference PU. This suggests that the biomimetic BM-PU-1 possesses desirablemelt flow properties for downstream processing, such as thermal compounding, as well as ribbon and tubing extrusions.

[0104] Molecular Weight

[0105] The Reference PU and biomimetic BM-PU-1 granulates / chips were characterized for molecular weight using Gel Permeation Chromatography / Multi Angle Light Scatter (GPC- MALS). Samples were dissolved in N,N-dimethylformamide, centrifuged, and diluted to 5 mg / mL. The samples were then injected (200 microliters volume) into a mobile phase of N,N- dimethylformamide with 0.1 M LiBr and run through two (2) 300 mm Agilent 5 pm PLgel Mixed-C columns to separate them by molecular weight. OPTILAB T-REX and DAWN HELEOS II detectors, manufactured by Wyatt Technology, were used to measure light scattering and differential refractive index, respectively. ASTRA software from Wyatt Technology was used to analyze the detector outputs and calculate molecular weight results. Polystyrene standards were used for calibration. Table 8 shows number average molecular weight (Mn), weight average molecular weight (Mw), and poly dispersity index (PDI) of both the Reference PU and the biomimetic BM-PU-1.Table 8

[0106] Table 8 shows that after introduction of the biomimetic modifier glycerophosphorylcholine (2.56 wt.%) as part of the chain extender hard segment in place of 1,4-butanediol, the biomimetic BM-PU-1 material showed comparable molecular weight and molecular weight distribution compared to Reference PU. The high molecular weight of the biomimetic BM-PU-1 would provide adequate material tensile strength (see data shown in previous “Tensile Property Testing” section).

[0107] Differential Scanning Calorimetry (DSC)

[0108] The Reference PU and biomimetic BM-PU-1 granulates / chips were analyzed using TA Instruments DSC Q2000. For testing, 5 mg of each sample was used for heat / cool / heat cycles; Cycle 1 = heat from 25 °C to 250 °C at 10 °C / min; Cycle 2 = cool from 250 °C to -50 °C at 10 °C / min; Cycle 3 = heat from -50 °C to 250 °C at 10 °C / min. Table 9 shows thecrystallization temperature (Tc, peak from cooling Cycle 2) and the melting temperature (Tm, peak from heating Cycle 3) of both the Reference PU and the biomimetic BM-PU-1.Table 9

[0109] The above information will be useful and can be referenced for compounding or extrusion processing of the biomimetic BM-PU-1 material.

[0110] Ionic Bonding and Elution of Cationic Antimicrobial Agent

[0111] The biomimetic PU (BM-PU-1) ribbon was used as a zwitterionic polymer substrate and chlorhexidine acetate was used as the cationic antimicrobial agent for bonding and elution studies.

[0112] Imbibing Coupon: ribbon sheets of the biomimetic BM-PU-1 were cut into rectangularly shaped coupons (rectangular area of ~ 5 cm2); the coupons were soaked in 10 mL of 400 mM of chlorhexidine acetate (CHA) in methanol solution at 37 °C for 24 hours for loading of cationic antimicrobial agent; coupons were placed on an Orbital Shaker during this loading process; after loading, the coupons were soaked in 10 mL of methanol for 1 minute at room temperature to rinse off the loading solution; finally, the coupons were dried in a fume hood at room temperature overnight to flash off residue methanol solvent.

[0113] Chlorhexidine Elution in Bovine Serum: the coupons loaded with chlorhexidine, as described above, were soaked in the elution media comprising 60 / 40 v / v% of bovine serum / phosphate buffered saline at 37 °C (on Orbital Shaker, 150 RPM) for time intervals of 24 h, 48 h, 72 h, 96 h, and 168 h. At each designated time interval, the previous elution media was removed for chlorhexidine elution analysis and quantification by high-performance liquid chromatography (HPLC) and fresh elution media was used for the next time interval. Chlorhexidine elution is defined as the mass of chlorhexidine (in terms of chlorhexidine acetate equivalence) eluted from the polymer coupon per unit area of coupon sample in the unit of pg / cm2.

[0114] Chlorhexidine Post-Elution Extraction: after 7 days of bovine serum elution testing, the remaining chlorhexidine in each coupon was completely extracted using the extraction media comprising 0.3 / 70 / 30 v / v / v% of trifluoroacetic acid / acetonitrile / water at 37 °C for 24hours (on Orbital Shaker, 150 RPM), followed by analysis and quantification of remaining chlorhexidine in each coupon by HPLC; the chlorhexidine remain is defined as the mass of chlorhexidine (in terms of chlorhexidine acetate equivalence) remaining in the polymer coupon per unit area of coupon sample in the unit of pg / cm2.

[0115] Chlorhexidine Loading Calculation: chlorhexidine initial loading on the coupon can be calculated by adding total chlorhexidine bovine serum elution (adding up all elution time points) and the chlorhexidine remain (by post-elution extraction).

[0116] Table 10 shows the chlorhexidine loading data (average of 3 replicates) of the biomimetic BM-PU-1 after imbibing.Table 10

[0117] Table 11 shows the chlorhexidine elution in bovine serum and chlorhexidine remain data (average of 3 replicates) of the biomimetic BM-PU-1.Table 11

[0118] Figure 3 shows the accumulated chlorhexidine elution and Figure 4 shows the average daily chlorhexidine elution in bovine serum over a period of 7 days of the biomimetic BM-PU-1.

[0119] Table 11, Figure 3, and Figure 4 show that the biomimetic BM-PU-1 exhibited decent chlorhexidine loading and controlled release profile even with very limited amount of biomimetic (zwitterionic) functionality. Thus, the biomimetic BM-PU-1 material can potentially be applied as a drug loading and elution system for antimicrobial as proposed.

[0120] Surface Thrombogenicity

[0121] Surface thrombogenicity of ribbon coupons (2 cm x 0.5 cm) of (i) Reference PU (Control), (ii) the biomimetic BM-PU-1 without CHA imbibing, and (iii) the biomimetic BM- PU-1 with CHA imbibing, were characterized using a thrombogenicity gradient screening method. Three different lots of fresh bovine blood were received and subsequently recalcified with calcium chloride aqueous solution; recalcified bovine blood with 5 different heparin concentrations (0.1, 0.2, 0.3, 0.4, and 0.5 lU / mL) were then prepared; each ribbon coupon (both control and other ribbon coupons) was submerged in 1 mL of the above-prepared bovine blood in an Eppendorf tube (2 mL seal top tube); these Eppendorf tubes on a rack were placed in a Shaker Oven at 15 RPM and 37 °C for 30 - 60 minutes until a thrombogenicity gradient vs. heparin concentration was observed; next, coupons were removed from the Eppendorf tube and subsequently washed with de-ionized water to wash off non-clotted blood from the surface; finally, the coupons were dried in an oven overnight; picture of the thrombogenicity gradient vs. heparin concentration was taken and the thrombus dry weight of each individual coupon (both control and other ribbon coupons) was recorded.

[0122] Figure 5 is an annotated photograph showing comparison of thrombosis formation (after drying) of (i) Reference PU (Control), (ii) the biomimetic BM-PU-1 without CHA imbibing, and (iii) the biomimetic BM-PU-1 with CHA imbibing, at various heparin concentrations (0.1 - 0.5 lU / mL).

[0123] Table 12 shows the thrombus dry weights of (i) Reference PU (Control), (ii) the biomimetic BM-PU-1 without CHA imbibing, and (iii) the biomimetic BM-PU-1 with CHA imbibing, at various heparin concentrations (0.1 - 0.5 lU / mL).Table 12

[0124] Both Figure 5 and Table 12 show that the overall trend of material surface thrombus formation, particularly at low heparin concentrations (i.e., 0.1 & 0.2 TU / mL), is the biomimetic BM-PU-1 with CHA is less than the biomimetic BM-PU-1 without CHA, which is less than the Reference PU (Control). At high heparin concentrations (i.e., 0.4 & 0.5 lU / mL), all ribbon coupons (both control and other ribbon coupons) exhibited very low thrombus formation, thus no significant differences could be observed between materials. These screening test data suggest that this biomimetic BM-PU-1 material can potentially be applied as an anti-thrombogenic material as proposed.

[0125] All examples and conditional language recited in the present disclosure are intended for pedagogical objects to aid the reader in understanding the present disclosure and the concepts contributed by the inventor to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions. Although embodiments of the present disclosure have been described in detail, the various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the present disclosure. It should be understood that the embodiments may be combined.

Claims

CLAIMS1. A medical device, comprising: a medical device body formed from a polyurethane-based resin, which is a reaction product of ingredients comprising: a diisocyanate; a chain extender; a poly glycol; and a biomimetic functional modifier.

2. The medical device of claim 1, wherein the biomimetic functional modifier comprises a phosphorylcholine functional group.

3. The medical device of claim 2, wherein the biomimetic functional modifier is glycerophosphorylcholine.

4. The medical device of claim 1, wherein the ionic active agent is ionically bound to the biomimetic functional modifier.

5. The medical device of claim 1, wherein the biomimetic functional modifier comprises the chain extender or another chain extender.

6. The medical device of claim 1, wherein the biomimetic functional modifier comprises the diisocyanate or another diisocyanate.

7. The medical device of claim 1, wherein the biomimetic functional modifier comprises the polyglycol or another polyglycol.

8. The medical device of claim 1, wherein the medical device body comprises a catheter tube.

9. The medical device of claim 1, wherein the diisocyanate is selected from the group consisting of: an aliphatic diisocyanate, alicyclic diisocyanate and an aromatic diisocyanate.

10. The medical device of claim 9, wherein the diisocyanate is selected from the group consisting of: 4,4'-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (TPDI), methylene-bis(4-cyclohexylisocyanate) (HMDI), and combinations thereof.

11. The medical device of claim 1, wherein the chain extender is selected from the group consisting of: ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, neopentyl glycol, and alicyclic glycols having up to 10 carbon atoms.

12. The medical device of claim 1, wherein the polyglycol is selected from the group consisting of: polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof.

13. A medical device, comprising: a medical device body; and a coating on the medical device body, wherein the coating is formed from a polyurethane-based resin, which is a reaction product of ingredients comprising: a diisocyanate; a chain extender; a polyglycol; and a biomimetic functional modifier.

14. The medical device of claim 13, wherein the biomimetic functional modifier comprises a phosphorylcholine functional group.

15. The medical device of claim 14, wherein the biomimetic functional modifier is glycerophosphorylcholine.

16. The medical device of claim 13, wherein the ionic active agent is ionically bound to the biomimetic functional modifier.

17. The medical device of claim 13, wherein the biomimetic functional modifier comprises the chain extender or another chain extender.

18. The medical device of claim 13, wherein the biomimetic functional modifier comprises the diisocyanate or another diisocyanate.

19. The medical device of claim 13, wherein the biomimetic functional modifier comprises the polyglycol or another poly lycol.

20. The medical device of claim 13, wherein the medical device body comprises a catheter tube.

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