COATING MEDICAL DEVICE SURFACES CONTACTING GAS-SUPERSATURATED FLUIDS

Abstract: A method is provided of using biocompatible surface-active agents to impart improved characteristics to a surface contacting a gas-supersaturated fluid, advantageously by forming on the surface a coating including an adsorbed biocompatible surface-active agent promoting surface charge neutralization or surface energy reduction, and of providing a surface contacting a gas-supersaturated fluid, the surface having such improved characteristics.

Description: COATING MEDICAL DEVICE SURFACES CONTACTING GAS-SUPERSATURATED FLUIDS FIELD OF THE INVENTION The present invention relates generally to the coating of medical device surfaces contacting gas-enriched fluids, and more particularly, to the coating of medical device surfaces forming fluid conduits (e.g , catheters, infusion guidewires. tubing, capillaries and the like) to impart improved characteπstics to the surfaces contacting oxygen-supersaturated fluids duπng deliver.' BACKGROUND OF THE INVENTION This section is intended to introduce the reader to various aspects of art that may be related to \ aπous aspects of the present invention which are descπbed and/or claimed below This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the vaπous aspects of the present invention Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of pπor art Adverse biological reactions, such as thrombosis, inflammation and infection, are thought to result from tissues and fluids contacting or otherwise interacting with the surfaces of medical devices Thus, for many years, there has been significant interest on the part of physicians and the medical industry to develop, manufacture and use clinically medical devices that do not tend to promote adverse biological reactions As descπbed m U.S. Patent No. 5,928.916. for example, one approach used for minimizing adverse biological reactions has been to attach vaπous biomolecules to the surfaces of medical devices Numerous attachment methods, such as covalent attachment techniques and ionic attachment techniques, have been used or suggested Such attachment methods may involve the use of coupling agents to attach biomolecules to surfaces Hepaπn is a type of biomolecule often coupled to surfaces Surface hepaπmzation is thought to improve the thromboresistance of biomateπals and inhibit blood coagulation The '916 patent descπbes. inter aha. some of the history of surface hepaπmzation development and some of the methods for attaching hepaπn to surfaces There are many approaches to binding hepaπn to biomateπal surfaces, and while methods of surface hepaπmzation to minimize certain undesirable biological reactions are known, hepaπn continues to be of interest in the development of non-thrombogenic blood-contact biomateπal surfaces SUMMARY OF THE INVENTION Certain aspects commensurate m scope with the disclosed embodiments are set forth below It should be understood that these aspects are presented merely to provide the reader with a bπef summary of certain forms the invention might take and that these aspects are not intended to limit the scope of the invention Indeed, the invention may encompass a vaπety of aspects that may not be set forth below While biomolecules such as hepaπn have been used on surfaces to inhibit adverse biological reactions, one aspect of the present invention relates to methods using biomolecules to impart improved characteπstics to medical device surfaces contacting gas- supersaturated fluids More generally, one aspect of the present invention relates to methods using a biocompatible surface-active agent to impart improved characteπstics to medical device surfaces contacting gas-supersaturated fluids, e g , by forming reactive or non-reactive coatings on such surfaces Bv way of example and without limitation, the biocompatible surface-ac e agent, either alone, or in combination with other such agents or other substances [e g , undergoing surface adsorption with (e g . in competition w ith or complexed with ) such agents or such other substances], mav be covalentlv or lonicalK bonded to a surface, immobilized thereupon, or otherwise adsorbed or deposited therew ith to lorm such coatings The improved characteπstics may be imparted, for example, b\ placing one or more coatings (alone or m a multi-lavered structure) on the fluid contacting surface (e g , by dip-coating, by flushing a coating fluid from a pressuπzed source across the surface, etc ) for sufficient time for adsorption to occur The term ' biocompatible surface-active agent " appeaπng herein means a substance forming a reactive or non-reactι\ e coating on a fluid-contacting surface Examples of biocompatible surface-active agents which may be used according to certain aspects of this invention include, by way of example and without limitation, a negatively charged moiety , a positively charged moiety, both a negatively charged moiety and a positivelv charged moιet\ any biocompatible molecular entity that mitigates a high surface energy of a gas- supersaturated fluid delivery path (e g . by promoting charge neutralization or surface free energy reduction), a protein, a globular protein, a structural protein, a membrane protein, a cell attachment protein; a glycoprotem; dipalmitoyl phosphatidylchohne (DPPC), a DPPC deπvative; phosphorylchohne (PC), a mucous agent; a glycolated mucm; a polysacchaπde, a surfactant, a nonproteolytic surfactant; a biocompatible surfactant; a glycosammoglycan (GAG), a quaternary ammonium salt; stearalkonium: tπdodecylmethyl ammonium chloπde (TDMAC), benzalkomum; a biomolecule; hepaπn; a hepaπn salt; a water-soluble hepaπn salt, a water-insoluble hepaπn salt; cetyl tπmethyl ammonium bromide (CTAB), and polyvinylpyrro done (PVP) In general, as used in the specification and claims, the term "biomolecule " means a mateπal that is capable of engaging in a biological activity or that is capable of modulating a biological activity, either alone or in combination w ith different biomolecules. and combinations thereof An example of a reactive coating including a biomolecule is a hepaπn coating An example of a non-reacm e coating is a PVP coating The term "gas-supersaturated fluid" appeanng herein means a fluid in which the dissolved gas content would occupy a volume of between about 0 5 and about 3 times the volume of the solvent normalized to standard temperature and pressure Examples of solvents which may be used include physiologic saline, lactated Ringer ' s, and other aqueous physiologic solutions For medical applications, particularly advantageous gas-supersaturated fluids include oxygen-supersaturated fluids, although fluids including dissolved gases other than oxygen also may be used Compared to the fluids typically used clinically toda\ , gas-supersaturated fluids are gas-enriched fluids including increased amounts of a dissolved gas It is thought that gas- supersaturated fluids are "metastable" in that, as compared to clinically-used fluids, there is an increased potential for dissolved gas to come out of solution For example, panicles such as dust, debπs. etc. generally do not affect the dissolved gas of clmicallv-used fluids as the gas remains in a dissolved state in the presence of such particles However with gas- supersaturated fluids, such particles may mterefεre with, disrupt, create or otherwise intereact with gas nuclei that seed bubble formation, growth or coalescence For example, one wav of de veπng gas-supersaturated fluids is v ia a glass capillary How ever, borosilicate glasses contain negatively charged groups that impart a high surface energy to the surface contacting the gas-supersaturated fluid It is thought that this high surface energy tends to attract and bind particles such as dust, debπs. etc that ma\ promote bubble formation w hen gas-supersaturated fluids are passed through the capillan In applications where gas-supersaturated fluids are infused directh into a patient, and in applications where such fluids first are mixed with other fluids for such mlusion. it is desirable to minimize, inhibit or eliminate physicochemical transitions (e g , the emergence or grow th of gas bubbles in the infused fluid) that might possiblv result in undesirable phy siologic responses bv the patient Such responses may be immediate or delayed depenαing upon the circumstances involved in the ph sicochemical event(s) ( e g the rate at which gas bubbles grow or coalesce) Accordingly a simple and convenient w ay ol minimizing, inhibiting, or eliminating undesirable physicochemical activity, particularlv non- reactiv e phvsiochemical activitv . associated with surfaces contacting gas-supersaturated fluids mav be desirable The present invention mav address one or more of the problems set forth abov e Certain possible aspects of the present invention are set forth below as examples It snould be understood that these aspects are presented merely to provide the reader with a bπef summary of certain forms the invention might take and that these aspects are not intended to limit the scope of the invention Indeed, the invention may encompass a vaπety of aspects that may not be set forth below The present invention may include within its scope methods including the step of using biocompatible surface-activ e agents to impart improved characteπstics to a surface contacting a gas-supersaturated fluid The present invention also may include, bv w ay of example and without limitation, methods including the step of forming a coating on a surface contacting gas-supersaturated fluids to impart improved characteπstics to the surface, the coating including a biocompatible surface-active agent, methods including the step of providing a surface contacting gas-supersaturated fluids including a biomolecule coating imparting improved characteπstics to the surface for such contacting, and methods including the step of coating a surface with hepaπn to impart improved characteπstics to the surface for i ς contacting gas-supersaturated fluids As used in the specification and claims, the term ' medical device " means a device including a surface contacting gas-supersaturated fluid in the course of its operation, which fluid is used in a patient diagnostic or therapeutic procedure This definition includes within 20 its scope both blood contact and non-blood contact surfaces This definition also includes within its scope devices for intravascular use, such as catheters, guidewires, and the like which may be placed into blood vessels or the heart, or proximate the heart, the brain, oi other organs or tissues, and other devices, such as oxygenators pumps, sensors, tubing accumulators, capillaπes. etc.. which may be used either alone or in combination with such devices, advantageously for diagnostic or therapeutic purposes The present invention may be susceptible to vaπous modifications and alternative forms Specific embodiments of the present invention are descπbed herein in detail It should be understood, however, that the descπption set forth herein of specific embodiments is not intended to limit the present invention to the particular forms disclosed Rather, all modifications, alternatives, and equivalents falling within the spiπt and scope of the invention as defined by the appended claims are intended to be covered DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS The descπption below discusses exemplary embodiments of the present invention For the sake of claπty, not all features of an actual implementation of the present invention are descπbed in this specification It should be appreciated that in connection with developing any actual embodiment of the present invention manv application-specific decisions must be made to achiev e specific goals, which may v ary from one application to another Further, it should be appreciated that any such development effort might be complex and time-consuming, but would still be routine for those of ordinary skill in the art having the benefit of this disclosure A method is provided for coating medical device surfaces contacting gas- supersaturated fluids One such medical device having such a surface compπses a capillarv assembly , advantageously including a single fused silica capillary having a 100 μm inner diameter and a 350 μm outer diameter. Alternately, the capillary assembly may compπse a plurality of captllaπes having inner diameters in the range of about 20 μm to about 1000 μm, with an inner diameter of about 100 μm to about 125 urn being particularly advantageous The capillaπes advantageously may be potted together or otherwise joined at their outer surfaces to form a single capillary bundle The capillaπes also may be formed of glass, PEEK (poly ether ether ketone) or another biocompatible mateπal To coat the inteπor surface of a capillary assembly (e g , one or more silica glass capillaπes having a 100 μm inner diameter ( commercially available from Polvmicro. California), a commercial preparation of benzalkonium chloride (BKC) and porcine intestine hepaπn (H) may be used at an 80 units/ml concentration in isopropyl alcohol (IPA ) The capillary assembly advantageously is cleaned pπor to being coated with the BKH solution Cleaning may include the steps of flushing the capillary assembly with filtered w ater, ethanol or other solvents to remove debπs and contaminants Advantageously, the capillary assembly is polished and maintained in a particle-free environment To coat the capillary assembly, approximately forty tube volumes ol ethanol are flushed through the capillary assembly, advantageously wetting the inner surface of each tubule A solution of approximately 80 units/ml BKH in 99 99% pure IPA then is flushed through the capillary in an amount comparable with forty tube volumes The IPA then is evaporated by filtered air flush Silica capillaπes coated with BKH exhibited an increased ability to deliver oxygen- supersaturated fluids without bubble formation or growth as compared to clean but uncoated capillaries and to cleaned capillaries coated only with BKC. As shown in Table 1, no bubbles were observed when oxygen-supersaturated fluid was delivered at a flow rate of 2.0 ml/min through BKH coated capillaries into a beaker of still water. Uncoated capillaries, and capillaries coated with BKC only, did not exhibit such performance, and had a much higher incidence of failure, defined bv the observance ofmicrobubbles duπng testing. TABLE 1 Surface Preparation No. Tested No. Bubble-Free » Not Bubble-Free BKH 10 10 ! 0 BKC 15 12 20 None 10 7 30 The present invention has been described in terms of exemplary embodiments. In accordance with the present invention, the parameters for the methods disclosed may be varied, typically for a specific desired clinical indication. Further, it is contemplated that other embodiments, which may be devised readily by persons of ordinary skill in the art based on the teachings set forth herein, may be within the scope of the invention which is defined by the appended claims. The present invention may be modified and practiced in different but equivalent manners that will be apparent to those skilled in the art having the benefit of the teachings set forth herein. No limitations are intended to the details shown herein, other than as described in the claims appended hereto. Thus, it should be clear that the specific embodiments disclosed above may be altered and modified, and that all such variations and modifications are within the spirit and scope of the present invention as set forth in the claims appended hereto.

Claims: CLAIMS WHAT IS CLAIMED IS 1 A method compπsmg the step of using a biocompatible surface-active agent to impart improved characteπstics to a surface contacting a gas-supersaturated fluid 2 A method compπsing the step of forming a coating on a surface contacting gas-supersaturated fluids to impart improved characteπstics to the surface, the coating including a biocompatible surface-active agent 3 A method compπsing the step of providing a surface including a biocompatible surface-active agent coating imparting improved characteπstics to the surface for contacting gas-supersaturated fluids 4 A method compπsing the step of coating a surface with a biocompatible surface-active agent to impart improved characteπstics to the surface for contacting gas-supersaturated fluids 5 The method of claim 1 , wherein the biocompatible surface-activ e agent neutralizes a surface charge of the surface 6 The method of claim 1, wherein the biocompatible surface-active agent reduces surface energy of the surface 7 The method of claim 1, wherein the surface has a net negative surface charge 8 The method of claim 1, wherein the surface compπses borosilicate glass 9 The method of claim 1 , wherein the biocompatible surface-active agent compnses a biomolecule 10 The method of claim 9, wherein the biomolecule is immobilized 11 The method of claim 9, wherein the biomolecule compπses hepaπn 12 The method of claim 11, compπsing the step of binding the hepaπn by a moietv to the surface through an ionic bond 13 The method of claim 1 1, compπsmg the step of binding the hepaπn by a moiety to the surface through a covalent bond 14 The method of claim 12, wherein the moiety compπses benzalkonium chloπde 15 The method of claim 1 , wherein a portion of the surface forms a tube 16 The method of claim 1. wherein a portion of the surface forms a capillary 17 The method of claim 1, wherein the surface forms a portion of a medical device 18 The method of claim 17. wherein the medical device compπses an assembly for supplying a gas-supersaturated fluid 19 The method of claiml 7, wherein the medical device compπses an assembly for supplying an oxygen-supersaturated fluid 20 The method of claim 19, wherein the oxygen-supersaturated fluid compπses physiologic saline 21 The method of claim 1 , wherein the biocompatible surface-active agent compπses a quaternary ammonium salt 22 The method of claim 1, wherein the biocompatible surface-active agent compπses benzalkonium hepaπn 23 A method of de veπng gas-supersaturated fluid, the method compπsing the acts of (a) providing a delivery device, a portion of the delivery device having a surface compπsing a biocompatible surface-active agent; and (b) passing the gas-supersaturated fluid across the surface 24 The method of claim 23. wherein act (a) compπses the act of coating the portion of the delivery device with the biocompatible surface-active agent to form the surface 25 The method of claim 23. wherein the portion of the delivery device compπses a capillary 26 The method of claim 23, wherein the delivery device compπses a catheter 27 The method of claim 23, wherein the delivery device compπses a guidewire. 28 The method of claim 23, wherein the delivery device compπses a tube. 29 The method of claim 23, wherein the biocompatible surface-active agent facilitates delivery of the gas-supersaturated fluid in a bubble-free manner. 30 The method of claim 23, wherein the biocompatible surface-active agent compπses hepaπn. 31 The method of claim 23, wherein the biocompatible surface-active agent compπses benzalkonium hepaπn. 32. The method of claim 23, wherein the gas-supersaturated fluid comprises an oxygen-supersaturated fluid. 33. The method of claim 23, wherein the gas-supersaturated fluid comprises fluid isotonic to blood. 34. A method of delivering gas-supersaturated fluid, the method comprising the act of: passing the gas-supersaturated fluid through a portion of a delivery device having a surface comprising a biocompatible surface-active agent. 35. A method of delivering gas-supersaturated fluid, the method comprising the act of: passing the gas-supersaturated fluid through a portion of a delivery device having a surface comprising a coating which facilitates delivery of the gas- supersaturated fluid in a bubble-free manner.

Inventors: CREECH JEFFREY L, PATTERSON WILLIAM R, CREECH, JEFFREY, L., PATTERSON, WILLIAM, R.
Applicants: THEROX INC, THEROX, INC.
Application year: 2000
Main classification: A61L33
IPC codes: A61L29, A61L31, A61L33