CA2180147A1 - Cross-linked polyethylene oxide coatings to improve the biocompatibility of implantable medical devices - Google Patents

Abstract

Polyethylene oxide (PEO) coatings providing improved biocompatibility for implantable medical devices are disclosed. The PEO coatings comprise functionalized, end-capped PEO which is attached at one end to the medical device. The PEO compounds are then cross-linked by 1) exposure to a high energy source for a time sufficient to cause the PEO compounds to form a cross-linked, insoluble network or 2) by reacting the free functionalized ends of a sufficient number of bound PEO compounds with a crosslinking agent whose functional groups are reactive toward the bound PEO chain's functionalized ends. These PEO coatings are able to survive ethylene oxide sterilization procedures with minimal loss of protein or cell repulsion ability.

Description

wo 96/14887 2 1 8 ~ 1 4 7 PCI'IUS95/1 ~912 CROSS-LINKED POLYETHYLENE OXIDE COATINGS TO IMPROVE THE
BIOCOMPATIBILITY OF IMPLANTABLE MEDICAL DEVICES

FIFI n OF THE INVF~ITION

This invention relates to implantable r"edical devices. More particularly this invention relates to cross-linked polyethylene oxide coating ",alerials and methods which preserve the bioconl~dlibility of implantable medical devices that are sterilized by ethylene oxide ste,ili~dlion procedures.
.0 BACKGROUND OF Tl IF INVENTION

The bioco"~pdlibility of implantable medical devices can be improved by a variety of known methods most notably by surface modification such as the addition 15 of a coating material. For example it is known that ophthalmic lenses may be coated with a coaling male,ial. U.S. Patent No. 4170 043 discloses intraocular lenses (lOLs) coated with a film that dissolves slowly in water. This helps prevent endothelial damage upon implantation of the IOL. The coating dissolves within about 24 hoursafter implantation.

U.S. Patent No. 4 731 080 discloses a coated IOL wherein the lens is coated with a non-smudging biologically compatible hydrophobic cross-linked vinyl-containing silicone polymer coating material.

U.S. Patent No. 5 080 924 discloses a method of modifying the surface of a sul.~l,ale using radio frequency plasma-induced grafting. In this procedure which may be used on an IOL a first biocon~patible material preferably having pendant carboxylic acid or amine groups is covalently grafted to the surface of a substrate polymer core by radio frequency plasma induction. A second biocompatible material then may be grafted to the first biocompatible material using a cross-linking agent.

W096/t4887 2~1 ~ûl 47 PCI/US95/1.1912 A series of patt,lts disclQse contact lenses which are coated by various ",alerials including polyethylene oxide (PEO). Such pate,)ls include Nos. 4,280,970;
4,871,785; 4,740,533; 5,070,166; and 5,096,626. U.S. Patent No. 4,280,970 disclQses cGalil,g a contact lens by grafting PEO thereto.
s U.S. Patent No. 5,308,641 ~;scloses an improved spacer mdl~rial for improving the biocGIll~Jdlibility of a biomaterial and a method for making it in which a polyalkylimine is covalently attached to an aminated substrate and combined with a cross-linking agent which is at least difunctional in aldehyde groups. The polyalkylimine can be, for example, polyethyleneimine and the cross-linking agent can be, for example, glutaraldehyde. Pleferably, the cross-linking agent is ap,~l.ecl in dilute solution and at a pH suitable to accG")plish light cross-linking of the polyalkylimine and also provide aldehyde linkages at the i"le,race between the bismolecule and the spacer.
~s U.S. Patent No. 5,290,548, assigned to the University of Florida, disclQses PEO
coated instruments, devices, implants, con~act lenses and the like. The PEO coating is created using gar"ma radiation to polymerize vinyl-functionalized PEO directly onto the surface of the instrument, device, etc.

U.S. Patent 4,973,493 disclQses a method for modifying a surface to improve its biocompatibility. The method employs molecules of a biocompatible agent and a cher"ical linking moiety possessing two different photochemically reactive groups, one group which reacts with the surface and one which reacts with the biocompatible 25 agent. The method comprises applying stimulus to sequentially activate the groups to covalently bind the linking moiety to the m~l~c~' es of the bioco",patible agent and to photochemically covalently bind the linking moiety to the surface of the device. In one embodiment, the molecules of the biocompatible material are joined together to form a film that is attached to the surface of the device by the linking moiety. In this 30 embodiment, the biocGIllpdlilJle agent desirably may be hyaluronic acid or albumin. A

W096/1'1887 21 ~01 47 PCI`/US95/11912 bioco",,,~dlible device having such a film attached may be an a,lificial hip joint coated with a film of hyaluronic acid. No Illelllioll is made of sterilization of the devices.

., Commonly assigned, co-pending U.S. Patent Application, Serial No.
s 08/166,033, discloses intraocular lenses coated with PEO applied through amine covalent bonding. However, when these lenses are sterilized with ethylene-oxide (EtO) ste~ili dlion and then aerated to remove residual EtO, some of the protein and cell repulsion ability of the PEO coating is lost. U.S. Serial No. 08/166,033 discloses an aqueous exl,dction step in place of the conventional aeration step to minimize the coating's loss of protein and cell repulsion ability.

What is needed are ~dditional coatings and processes for improving the biocompatibility of implantable medical devices which must survive EtO sterilization procedures.

SUMMARY OF THE INVENTION

The present invention provides PEO coatings and methods for improving the biocompatibility of implantable medical devices. The PEO coatings of the presentinvention comprise PEO which is capped with functionalized groups on at least one end, wherein the PEO coatings are formed by attaching one functionalized end of the PEO compounds to the implantable medical device and then cross-linking the PEO
compounds. Cross-linking can be achieved by either 1 ) exposing the PEO
compounds to a high energy source (hereinafter referred to as the "high-energy method") or 2) alternatively, in the case where the PEO compounds have at least two or more functionalized end groups, at least one or more of the opposite or free functionalized ends of a sufficient number of bound PEO compounds may be crosslinked with other bound PEO compounds by means of a cross-linking compound (hereinafter referred to as the "cross-linker method").

WO 96/14887 ` 2 1 8 3 1 4 7 PCI~/US9~ 912 Among other factors, the present invention is based on the finding that cross-linking PEO c~dting compounds reduces the codlinys loss of protein and/or cell repulsion ability that the coating suffers when subjected to EtO ster;li~alion procedures.
s DFT~II Fn DF~:CRIPTION OF THE INVENTION

As used herein, implantable medical device means any article, derived from s~",ll,elic or semi-synthetic ",aterial, that when placed in the appropriate biological .0 locdlio" serves to replace or enhance or monitor the performance of a target tissue/
organ. These include but are not limited to substitute blood vessels, catheters,int,~ocul~r lenses, contact lenses, electrodes, hydrocephalus and abdominal shunts, etc.

~s As used herein, "biocGmpatible" or"biocGmpdliL,ility" means being compatible with b ological tissue/ fluids either in a living organism or a system consisting of a mixture of biological co",pol)ents (protein and/or cell based), not eliciting any changes in the structure or function of any of the biological components that will ultimately compromise or negatively affect the biological system or organism.

As used herein, "high energy source" means a source which results in the formation of free radicals, ions, electluns, protons, neutrons, alpha particles, beta particles, gamma radiation, X-ray radiation and ultraviolet radiation. These energy sources include but are not limited to radio-frequency glow discharge plasma (rf-25 plasma), electron beam, gamma, and ultraviolet sources.

The coatings of the present invention may be applied to the surface of anyimplantable medical device on which it may be desirable to minimize protein adsorption and cellular deposition. For purposes of illustration, examples relating to 30 lOLs will be presented; however, one skilled in the art will readily appreciate that the coatings of the present invention may be applied to any implantable medical device.

2 1 8 0 1 4 7 PCI/US95/1.1912 In the case where the implantable ~,edical device is an IOL, the improved coalings of the present invention may be applied to any of the well known hard lOLs, such as those rc"",ed from polymethylmethacrylate (PMMA). The improved coatings s of the presel)l invention may also be applied to soft acrylic lenses, such as those di~cîosed in U.S. Patent Nos. 4,834,750; 5,290,892; and 5,331,073; the entire contents of each of these three (~rt:r~nces are hereby incorporated into this rlisclosure. Additionally, as one skilled in the art would readily appreciate, the improved coatings of the present invention may be applied to other types of lens10 materials, for example silicone "~alerials. In a preferred embodiment, improved codLi"gs of the present invention are appl.ed to lenses formed from a copolymer with an elongdliGn of at least 150% wherein the copolymer is formed from two monomers, the first of which is 2-phenylethyl acrylate and the second of which is 2-phenylethyl methacrylate, and a copol~",eri~able cross-linking monomer having a plurality of15 polymerizable ethylenically unsaturated groups such as 1,4-butanediol diacrylate.
The first monomer may be present at a concentration about 65 wt.% and the secondmonomer may be prese"l at a concenlldlioil of about 30 wt.%. An ultraviolet absorbing r"dlerial such as 2-(3'-methallyl'-2-hydroxy-5'-methyl-phenyl) ben~ol,ia~ole may also be included.

According to the present invention, the biocompatibility of lOLs or other implantable medical devices is subsl~lially improved by coating them with a PEO
coating which is cross-linked prior to sterilization. In particular, the PEO-coated lenses or other devices have improved resistance to protein adsorption. This results in a lens 25 or other device which is "non-fouling" and resistant to cell deposition.

The PEO codlings of the present invention are first tethered to the suLslldte surface. There are a number of known methods for attaching PEO chains to substrate surfaces. One skilled in the art will readily recognize that these known methods30 include, for example, wet chemical methods, such as those providing electlostalic W0 96/14887 2 1 ~ 0 1 4 7 PCr/US95/1.1912 interactions or covalent bon-li"g, and dry ",etl,ods such as high energy plas",a d~positiG~).

In a preferred embodi"~ent, the PEO c~dlillg is allacl,ed to the IOL or suL.~ ate s surface through covalent bol)di,~g. The subsl,dte surface is first provided with an active codli"g or layer. rleferably, the active layer is a polymer coating containing a primary amine. However, other active layers which function to tie PEO compounds to suLslldle surfaces may also be used.

.0 The primary amine layer is plt:fer~bly rol",ed by contacting the substrate surface with an allyl amine or a lower alkyl amine of the formula RNH2, wherein R is an alkyl or allyl group of about 3-12 carbon atoms. P~eferably the alkyl or allyl amine is one of i"tel",ediale chain-length wherein R is an alkyl group of 5-8 car6OI)s. Most pr~ferdbly, the alkyl or allyl amine is n-heptyl amine.
~s The alkyl or allyl amine may be applied to the sub~lldte surface in any desired manner; however, it is preferred to create the active primary amine layer by plasma deposition of the alkyl or allyl amine. Plasma deposition in general is known in the art as shown for exal"ple in U.S. Patel)l:j 4,312,575 and 4,656,083, the disclosures of 20 which are incorporated by reference.

Plasma deposition of the primary amine layer on the subsl,dte surface is preferably carried out in two steps. In the case of an IOL, the lens is first placed in an electrical glow discharge apparatus, preferably oriented with the optical surfaces 25 parallel to direction of gas flow. A gaseous atmosphere is provided, (e.g., argon), and then the gaseous atmosphere is subjected to an electrical glow discharge to clean the surface. The gas is then removed. In the second step, plasma ignition is carried out in the presence of the vapor of the primary amine under conditions to cause the amine to deposit or forrn a plas,na and produce an ultrathin coating of about 5-300 30 Ang~llu",s on the surFace of the lens.

WO 96/14887 2 1 8 3 1 4 7 PCI/US95/1 ~912 Aftert,~dt",entwith the amine, the subsl,dte surface conlaillil,g the amine layer is then reacted with fun.;tiollalized end-carped PEO in the presence of a reducing agent to give a stable PEO COdlillg covalently bound to the sub~l~dle surface. The PEO should have terrninal groups or caps which are reactive with the amine codling.
If the high-energy method of cross-linking is to be utilized, it is not necessary that both ends of the PEO chains have reactive terrninal groups. Nevertheless, a pr~f~r,edPEO utilized in the present invention is an a,c~-aldehyde-terminated PEO having a mo'ec~ weight in the range of 200 to 100,000, preferably 1500-15,000. Most plefe"ed in the case of the high-energy method is an a,~-aldehyde-capped PEO
having a molecular weight of about 8000. Most p~efer,ed in the case of the cross-linker Ill~thod is an a,cD-aldehyde-capped PEO having a molecular weight of about 3400. Mono- and di-aldehyde-capped polyethylene oxides are known in the art, e.g., Harris, US Pat. No. 5,252,714.

If the cross-linker method of cross-linking is to be utilized, the PEO which is reacted with the suL,sl,dte surface conlai"ing the amine layer is multi-functionalized, end-capped PEO. As used herein, "multi-functionalized, end-capped PEO" means PEO which has at least two functionalized end groups, one of which is reactive with the subsl,dte surface or active coating, and the other of which can be crosslinked with other PEO compounds attached to the subsl,dle surface. Suitable PEO compounds for use in the present invention include, for example, straight chain PEO, branched chain PEO, and star-shaped PEO molEcules (such as those described in U.S. PatentNo. 5,275,838) which have at least two functiollalized end groups as described above.
Straight chain PEO compounds are prefer,ed.
2s A preferred straight chain PEO utilized in the present invention is an a,~-aldehyde-terminated PEO which has a molecular weight in the range of 200 to 100,000, preferably 1500-10,000. Most preferred is an a,~-aldehyde-capped PEO
having a molecular weight of about 3400. Such a,c3-aldehyde- capped polyethyleneoxides are known in the art; see, for exd",ple, U.S. Patent No. 5,252,714.

W096/14887 21 ~01 47 PCr/US95/1~912 In a pr~:fe,led procedure, the IOL or subglldle surface is first etched prior toamine deposition for best results. Plererdbly, etcl,i"g of the surface is conducted by conlact with an argon ~lasl"a. An argon flow rate in the range of 60-120 cm3/min, and a chal,lber pressure of 200-300 mTorr is s~1is~ctory. In conducting the deposition, s the IOL or other implantable ",edical device is placed in a holder and centered in a plas",a chal"ber with the desired argon-plasl"a flow rate to argon etch prior to amine ~eposition. A cGnlai,~er for the amine is connected to the plasma chamber unit. The plasma chamber is then ev~cu~ted to its baseline pressure and, while under the argon flow rate, is ignited for a short period, for example, 60W for six minutes. After the .0 argon-plas",a etch, the plasma chamber is ev~cllated to its baseline pressure, the amine vapor is ev~cu~ted into the chamber, the plasma ignited, and the deposition pe""itled to be maintained until a tl~i~,hr~ess in the range of 5-500, pr~ferdbly 100-300 Ang~l,ums, is achieved. After the plasma is extinguished, the chamber conditions are maintained for a short period, for example, 1-5 minutes. The chamber is then brought ~s to atmospheric conditions and the sample removed to a sealed CGn~ ,er.

PEO, e.g., a,c~-aldehyde-carped polyethylene oxide, is dissolved in a buffer solution in a concer,ll~liol1 in the range of 5-50 mg/ml. This solution is then added to each container with the amine-plasma coated IOL or other device. Stabilization of the 20 coating is then carried out, for example, by treating the IOL or other device with a stabilizing agent, such as an alkali metal borohydride, dissolved in a buffer in a concenl,dlion of 10-50 mg/ml. The reaction is then carried out at a low temperature, for example, 25-50 C for about ten to thirty hours. Low temperatures are used in order to avoid thermal degradation of the PEO compounds.

The preferred stabilizing agent is sodium cyanoborohydride of the formula NaCNBH3, a co,r""ercially available material. Reduction of the PEO-imine bond with the alkali metal borohydride will provide a stable PEO coating of about 5-500 Ang~l,ul"s, preferably 100-300 Angsl,u",s. In a preferred procedure, stabilization is 30 repeated and the lOLs or other implantable medical devices are again heated. Each IOL or other device is then washed in deionized water and the water removed.

W096/14887 21 8û1 47 PCI/US95/11912 The ~rucedure desc,ibed above is only one ",ell,od of tethering h"ctionalized end-capped PEO chains to subsl,dte surfaces. Any aller"ali,/e procedure which tethers a functionalized end-capped PEO chain to sul,~lldte surfaces may also bes used.

An illlpG,ldl1t aspect of the invention concer"s sterilization of the lOLs or other devices after plepardliol1. As used herein "EtO slerili~dliol1" co""~rises contacting the IOL or other device with 5-100% ethylene oxide in a fluorinated solvent for 14 hours .0 at 10-40 psi and 40-60 C. preferably after preconditioning in a humid al"~osphere followed by aeration to remove residual ethylene oxide. IOLs or other implantable Illedicdl devices coated in the above manner which are sterilized using EtO
steril;~dlion lose some of their protein and cell repulsion ability.

In the cross-linker method if PEO compounds having more than two functionalized end groups are used it is not necessary that all of the free functionalized end groups be crossli"ked together. One or more of the free functionalized ends of a sufFicient number of the bound PEO chains are crosslinked with functionalized end groups of other bound PEO chains to decrease the coating's 20 loss of protein and/or cell repulsion ability caused by EtO sterili,dlion procedures.
Crosslinking can be achieved by reaction of the free end-groups of the bound PEOwith a crosslinking agent whose functional groups are reactive toward the bound PEO
chain's free end groups.

In the pl~ferlt:d case where the PEO is an a~-aldehyde-capped PEO the preferred crosslinking agent is a polyether diamine which is based on a predominately polyethylene oxide backbone. Such amine-terminated polyethers with molecular weighl~ in the range 200-10000 are preferred; a molecular weight range of 900-2000 is more preferred. In the most preferred case where the functionalized end-capped PEO tethered to the subsl~dte surface is a c3-aldehyde-capped PEO having a molecular weight of about 3400 the amine-terminated predominately PEO-backbone W096/14887 2~1 801 47 PCIIUS95/1-~912 polymer should have a mc'ecul~r weight of at least 900, and preferdbly about 2000.
The most prert:r,ed crossl;,1ki"9 agent is Jeffamine ED 2001~ available from Texaco Cher"ical Co.

s The crosslinking reaction conditions will depend on the particular functionalized end-capped PEO chains tethered to the suL,sl~dLe surface and the particular crosslinking agent cl1osen. In the pr~r,~d case where the a,~-aldehyde-capped PEO is crosslinked with a polyether diamine having a predor"i"dlely PEO backbone, the polyether diamine is dissolved in a buffer in a concenl,dliG" range of 5-50 mg/ml, 0 prefe,ably at a conce, Illdlion of about 20 mg/ml. The PEO-coated IOL or other device is plaoed in this solution for a time surficie.,l for It:actioll bet~ccn the tethered PEO
chains and the polyether diamine. The resulting crosslinks are then stabilized with a buffered solution of alkali metal borohydride, most preferably sodium cyanoborohydride of the formula NaCNBH3. The resulting IOL or other device will have the indic~ted improved biocol"pdlil,ility including increased resislance to protein adsorption which makes the IOL or other device non-fouling and resistant to celldeposition.

Without wishing to be bound by theory, it is hypothesized that the PEO chains must be able to achieve a fully extended conroll,,dlion~ through solvent-polymerinteraction, and to be able to have free rotation about the single bonds of its backbone, i.e., for the chains to have a "flagella-like" motion, creating a dynamic barrier on the surface of the sub~l,dte to which it is immobilized so as to provide maximum resistance against protein adsorption or cell deposition. Driven by interfacial forces, native PEO ~l~ands, immobilized through one terminal, may become wholly or partially buried beneath the substrate surface during EtO sterilization procedures, thereby losing their ability to resist fouling. Though cross-linking may reduce the fl~g~ I;ke motion of the PEO ~lldnds~ it may serve to prevent burial of the PEO
strands beneath the sul)slldte surface.

The following examples are pr~senled to illustrate the invention but are not intel1ded to limit it in any way.

Example 1:
s A. Surface A").naliol1:

lOLs made of PMMA or a soft acrylic ~"alerial, held in position by a polyethylene lens holder placed in small glass-rack, are centered in a plasma chamber on a glass rack. The rack is positioned with the optic surface oriented parallel to the mono,ner flow. Any plasma chamber capable of holding the device to be coated canbe used. In this case, the plas")a chamber was made of a glass cylinder approximately 25 cm in diarileter and 55 cm long, wrapped in four quadrants with four copper ele.;t,odes (two hot and two ground) each 49 cm x 1 7cm.
~s n-Heptylamine (5g) is placed in a 250 ml round-bottom~flask which is connected to the plasma chamber via a metering-valve. With this valve closed, the plasma chamber is evacuated to its baseline pressure for 30 minutes. Prior to heptylamine deposition, the lOLs are argon-plasma etched. Wlth an argon flow rate of 90 cm3/ min 20 and a chamber pressure of 250 mTorr, the chamber is equilibrated for ten minutes. A
plasma is then ignited at 60 W for 6 minutes. After the argon-plasma is extinguished, the chamber is returned to its baseline pressure.

With the plasma chamber's vacuum pump speed on a low setting (baffle 25 position to approximately 5; 90 represents maximum pump rate) heptylamine vapor is evacuated into the chamber. The chamber is allowed to equilibrate for ten minutes.
At a rf power of 60 watts a plasma is ignited, and the thickness gauge activated to record deposition. The plasma is maintained until a thickness of approximately 200 A
is achieved. After the plasma is extinguished the chamber conditions are maintained 30 for 2 minutes. Following this the vacuum pump speed is returned to maximum and these conditions are maintained for ten minutes. The chamber is then brought up to WO 96/14887 2 1 ~ 3 1 4 7 PCI/US95/1 1912 al")ospheric collditiGIls by back-filling with argon and the samples removed from their respective holders. Each is placed in a labeled micro-centrifuge tube.

B. pFO lmmobiliz~
s Dithiolaldehyde-derivatized PEO, which can be synthesized following methods described by Harris et al., US Pat. No. 5,252,714, is dissolved in a 0.0042 M sodium phosphate (dib~sic) - 0.45M poPssium sulphate buffer (pH 8.5 - 9.0) at a concel,l,dliol) of 10 mg/mL. 900 ~L of this solution is added to each micro-centrifuge .0 tube co, lldil 1il 19 plasma-coated IOL. Sodium cyanoborohydride (NaCNBH3) isdissolved in buffer at a concentration of 20 mg/mL. 100 ~L of this solution is added to each micro-centrifuge tube, and after gentle mixing the sa~,lples are heated at 35 C
overnight. Note that the NaCNBH3 solution is prepared just prior to its addition to the reaction solution. A second l,~dt",ent with NaCNBH3 solution is then applied and~s sal,lples heated at 35 C for another four hours. The samples are then removed from the reaction solution, washed extensively in deionized water, and air dried.

C. Crosslinking:

High-energy method: Each salllplE is mounted in a lens holder and placed in a glass rack. This rack is centered in the plasma chamber used in Step A and thesystem evacuated to baseline pressure for ten minutes. The chamber is equilibrated for five minutes with argon at 250 mtorr and a flow rate of 90 cm3/min. A plasma is ignited at 60 watts for 20 seconds. After the plasma is extinguished, the chamber is 2s maintained at 250 mtorr with argon for five minutes. Each sample is then packaged in a sterilization pouch.

Cross-linker method: Each sample is briefly washed with deionized water and placed in a new micro-centrifuge tube containing 0.05M phosphate buffer (pH 8.0).
Samples are equilibrated for approxilllately 15 minutes. The buffer is then removed and replaced by 900 ~L of crosslinking solution. This solution is prepared by dissolving 21~3~147 WO 96/1~1887 PCI/US95/1 1912 a diamino PEO in 0.05M phosphate buffer to a final concenl,dliol) of 20 mg/mL. 100 L of NaCNBH3 solution (20 mg/mL in 0.05M phosphate buffer) is added to the reactio" mixture which is gently agitated. Salllpl~s are then heated at 35 C overnight.
The l,edl"~en~ with NaCNBH3 is repe~ted and the sampl_s are heated for another four 5 hours. Each IOL is spray washed in deionized water, and then sonicated three times each for 5 minutes in approxil,)dl~ly 3 mL deio~ ed water. Each is then dried and packaged in a sterilization pouch.

D. FtO Sttr;~

Samples are placed in a sterilization chamber which is then ev~cu~ted to about 2 psia. While maintaining this pressure the relative humidity in the chamber is raised to 60% and the temperature to 46 C. These conditions are maintained for one hour. The chamber is then charged with ethylene oxide, 12% in freon, to a final pressure of 22 -s 23 psia. After two hours the chamber is ev~cll~te~ to about 2 psia and then thesystem is brought up to al"~osphere. The lens samples are then removed to the aeration chamber and aerated at elevated temperatures for a time sufficient to remove residual EtO levels of less than 25 ppm.

20 Example 2:

Protein Adsorption:

Human fibrinogen radiolabelled with ~251Odine was used to ~.ssess the protein 25 repelling capability of the cross-linked codli,lgs following EtO slerili~dlion. Samples are incubated in Balanced Salt Solution (BSS) at 37 C for one hour. This solution is then removed and repl~ced by a BSS solution coll~illi,lg 50 ~g/mL ~251-fibrinogen. After incubating the sa,l~ s at 37 C for two hours they are removed, washed with BSS
and their individual radioactivity levels determined.

WO 96114887 2 1 û O 1 4 7 PCI/US9~/lS912 The amount of adsorbed protein is repo, led in Tables 1 & 2 as a fraction of that on ~I"coated control surfaces. The results show that PEO c~dlil,~ s which have been cross-linked accor~i"g to the present invention are very effective in reducing protein adso"~lioll even after EtO st~rili~dlion.

T~RI F 1 NORMALIZED FIBRINOGEN ADSORPTION LEVELS
ON UNCROSS-LINKED AND CROSS-LINKED (HIGH-ENERGY METHOD) PEO-COATED LENSES
.0 BEFORE AND AFTER ETHYLENE OXIDE STERILIZATION

ADSORBED FIBRINOGEN (NORMALIZED) IOLUNCROSS-LINKED COATING CROSS-LINKED COATING
Material (HIGH-ENERGY METHOD) PRE-STERILIZATION POST-STERILIZATION PRE-STERILIZATION POST-STERILIZATION
PMMA0.07 + 0.04 (n =12)t 0.27 i 0.07 (n =12) 0.08 + 0.01(n =12) 0 15 ~ 0.03 (n =12) t Values in pd,~nUIeses are the number of Sdlll, 1~, determined from the num~er of runs each pe,~ur",ed in lli 'i- . Forexample n=12 ,eprese,)~sfourruns. each pe~to-" ed In l"~

WO 96/I4887 PCr/US95/1-1912 T~RI F 2 NORMALIZED FIBRINOGEN ADSORPTION LEVELS
ON UNCROSS-LINKEI~ AND CROSS-LINKED (CROSS-LINKER METHOD) PEO-COATED LENSES
s BEFORE AND AFTER ETHYLENE OXIDE STERILIZATION

ADSORBED FIBRINOGEN (NORMALIZED) IOL UNCROSSLINKED COATING CROSS-LINKED COATING
Material (CROSS-LINKER METHOD) PRE-STERILIZATION POST-STERILI~ATION PRE-STERILIZATION POST-STERILIZATION
PMMA 0.05 + 0.01 (n = 18)t 0.62 + 0.18 (n = 15) 0.05 + 0.02 (n =39) 0.14 + 0.06 (n =21) SoRAcryc 0.07+0.01(n=12) 0.64~o17(n=1s) 0.06+0.02(n=27) 0.15~0.11(n=21) t Values in pd,t:,ltl,eses are the number of Sdlll, 'es, determined from the number of runs, each pe" ro""ed in triplicate. For exd",, 'e, n=15 I~,ul~se,,ls five runs, each pel ~u,,,,ed in lli, ' ~ ~t-.o 65% 2-phenylethylacrylate, 30% 2-phenylethylmethylacrylate, 3.2% butanediol diacrylate, 1.8%
(2-(3'-methallyl-2'-hydroxy-5'-methyl phenyl) ber,~u~ E

The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodled In other specific forms or variations thereof without departing from its spint or essentlal characteristics. The embodiments described above are therefore consldered to be illustrative in all respects and not restrictive, the scope of the invention being indicated 20 by the appended claims rather than the foregoing description.

Claims (32)

We Claim:

1. A method of improving and preserving the biocompatibility of an implantable medical device which comprises coating the device by attaching at least one functionalized end of PEO compounds to the device, cross-linking a sufficient number of bound PEO compounds prior to sterilization so that the device is capable of surviving ethylene oxide sterilization without substantial loss of protein and/or cell repulsion ability, and then sterilizing the device using ethylene oxide.

2. The method of Claim 1 wherein the medical device is an intraocular lens,

3. The method of Claim 1 wherein the functionalized end-capped PEO is .alpha.,.omega.-aldehyde-terminated PEO having a molecular weight from 200 - 100,000.

4. The method of Claim 2 wherein the .alpha.,.omega.-aldehyde-terminated PEO has a molecular weight from 1,500 - 10,000.

5. The method of Claim 1 wherein the cross-linking is achieved by exposing the PEO compounds which have been attached to the device to a high energy source fora time sufficient to cause the PEO compounds to form a cross-linked, insoluble network.

6. The method of Claim 5 wherein the functionalized end-capped PEO is .alpha.,.omega.-aldehyde-terminated PEO having a molecular weight of about 8000.

7. The method of Claim 5 wherein the high energy source is a radio-frequency glow discharge plasma, electron beam, gamma or ultraviolet source.

8. The method of Claim 7 wherein the high energy source is an argon plasma.

9. A method of producing a PEO-coated implantatle medical device which can be sterilized by ethylene oxide sterilization without substantial loss of the PEO coating's protein and/or cell repulsion ability, wherein the method comprises a) modifying the surface of the medical device in an organic amine or ammonia gas plasma;
b) exposing the modified surface to a buffered solution of aldehyde terminated-PEO and a stabilizing agent for a time sufficient to covalently bind the terminal aldehyde of the PEO to the modified surface; and c) exposing the bound PEO to a high energy source for a time sufficient to cause the PEO compounds to form a cross-linked, insoluble network.

10. The method of Claim 9 wherein the organic amine in step (a) is heptylamine, the aldehyde terminated PEO in step (b) has a molecular weight of about 8000, the high energy source in step (c) is an argon plasma, and the stabilizing agent in step (b) is sodium cyanoborohydride.

11. The method of Claim 1 wherein the PEO compounds are multi-functionalized, end-capped PEO compounds, at least one functionalized end of the PEO compounds is attached to the device, and the cross-linking is accomplished by exposing the free ends of the multi-functionalized, end-capped PEO to a solution of a cross-linking agent whose functional groups are reactive toward the free ends of the functionalized end-capped PEO for a time sufficient for reaction.

12. The method of Claim 11 wherein the multi-functionalized, end-capped PEO is .alpha.,.omega.-aldehyde-terminated PEO having a molecular weight of about 3400.

13. The method of Claim 11 wherein the crosslinking agent is a polyether diaminehaving a predominately PEO backbone.

14. The method of Claim 13 wherein the polyether diamine has a molecular weight from 200 - 10,000.

15. The method of Claim 14 wherein the polyether diamine is Jeffamine ED 2001?.

16. A method of producing a PEO-coated implantable medical device which can be sterilized by ethylene oxide sterilization without substantial loss of the PEO coating's protein and/or cell repulsion ability, wherein the method comprises a) modifying the surface of the medical device in an organic amine or ammonia gas plasma;
b) exposing the modified surface to a buffered solution of .alpha.,.omega.-aldehyde terminated PEO and a stabilizing agent for a time sufficient to covalently bind one of the terminal aldehydes of the PEO to the modified surface;
and c) exposing the bound PEO to a buffered solution of a polyether diamine having a predominately PEO backbone and a stabilizing agent for a time sufficient to cross-link the free terminal aldehydes.

17. The method of Claim 16 wherein the organic amine in step (a) is heptylamine,the .alpha.,.omega.-aldehyde terminated PEO in step (b) has a molecular weight of about 3400, the polyether diamine in step (c) is Jeffamine ED 2001?, and the stabilizing agent in both step (b) & (c) is sodium cyanoborohydride.

18. A PEO-coated implantable medical device which can be sterilized by ethylene oxide sterilization without substantial loss of the PEO coating's protein and/or cell repulsion ability, wherein the PEO coating comprises cross-linked, functionalized end-capped PEO compounds, wherein at least one functionalized end of the PEO
compounds is attached to the implantable medical device and the cross-linking isachieved by exposure to a high energy source.

19. The medical device of Claim 18 wherein the functionalized end capped PEO is .alpha.,.omega.-aldehyde-terminated PEO having a molecular weight from 200 - 100,000.

20. The medical device of Claim 19 wherein the .alpha.,.omega.-aldehyde-terminated PEO has a molecular weight from 1,500 - 10,000.

21. The medical device of Claim 20 wherein the .alpha.,.omega.-aldehyde-terminated PEO has a molecular weight of about 8000.

22. The medical device of Claim 18 wherein the high energy source is a radio-frequency glow discharge plasma, electron beam, gamma beam or ultraviolet source.

23. The medical device of Claim 22 wherein the high energy source is an argon plasma.

24. The medical device of Claim 18 wherein the medical device is an intraocular lens.

25. A PEO-coated implantable medical device which can be sterilized by ethylene oxide sterilization without substantial loss of the PEO coating's protein and/or cell repulsion ability, wherein the PEO coating comprises multi-functionalized, end-capped PEO, wherein at least one functionalized end of the coating's PEO compounds is attached to the implantable medical device and at least one or more of the opposite or free functionalized ends of a sufficient number of bound PEO compounds are crosslinked with other bound PEO compounds such that the loss of protein and/or cell repulsion ability that the coating suffers when subjected to ethylene oxide sterilization procedures is substantially reduced.

26. The medical device of Claim 25 wherein the multi-functionalized PEO is .alpha.,.omega.-aldehyde-terminated PEO having a molecular weight from 200 - 100,000.

27. The medical device of Claim 26 wherein the .alpha.,.omega.-aldehyde-terminated PEO has a molecular weight from 1,500 - 10,000.

28. The medical device of Claim 27 wherein the .alpha.,.omega.-aldehyde-terminated PEO has a molecular weight of about 3400.

29. The medical device of Claim 25 wherein the crosslinked functionalized ends of the PEO are crosslinked with a polyether diamine having a predominately PEO
backbone.

30. The medical device of Claim 29 wherein the polyether diamine has a molecularweight from 200 - 10,000.

31. The medical device of Claim 30 wherein the polyether diamine is Jeffamine ED2001?.

32. The medical device of Claim 31 wherein the medical device is an intraocular lens.