Poly(ethy1ene oxide)-Grafted Thermoplastic Membranes for Use as Cellular Hybrid Bio-Artificial Organs in the Central Nervous System Molly S. Shoichet,' Shelley R. Winn,' Sushama Athavale? J. Milton Harris? and Frank T. Gentile'* zyxwvutsr ' zyxwv CytoTherapeutics, Inc., Providence, Rhode Island, and 2Shearwater Polymers, Inc., Huntsville, Alabama 3580 1 Received June 2 1, 1993/Accepted October 2 I, 1993 Poly(acrylonitri1e-co-vinyl zyxwvutsrqp chloride) (PANNC) anisotropic membranes were chemically modified with poly(ethy1- ene oxide) (PEO) zyxwvutsr (5000 and 20,00Og/mol) by one of two aqueous reactions: (a) acid hydrolysis of the nitrile group to a carboxylic acid with which amine-terminated PEO (PEO-NH2) reacted or (b) base reduction of the nitrile group to an amine with which PEO-succinimide (PEO-SC) reacted. Approximately 1.3% of the bulk material was modified with PEO-NH2 whereas 1.8 to 3.5% was modified with PEO-SC as determined by proton nuclear magnetic resonance ('H NMR) and attenuated total reflectance Fourier transform infrared (ATR FTIR) spectra. Approximately 50 to 75% less bovine serum albumin (BSA) adsorbed to PEO-grafted single skin fibers than to unmodified PANNC. Transport properties of modified and unmodified fibers were compared by passive diffusion, convective nominal molecular weight cutoff, and hydraulic permeability. Neither hydraulic permeability nor nominal molecular weight cutoff of BSA changed appreciably after surface modification with PEO indicating that pore structure was not adversely affected by the chemistry involved in grafting poly(ethylene oxide). However, in the absence of any membrane conditioning, the apparent diffusion of a-chymotrypsinogen (24,000 g/mol) was enhanced in PEO-grafted PANNC fibers possibly as a result of reduced sorption of the permeating protein. In vivo biocompatibility in the brain tissue of rats was judged by histological assessment of the host's cellular response to fibers implanted for 30 days; biocompatibility of both PANNC and PANNC-g-PEO was satisfactory but improved slightly with PEO grafting. zyxwvuts 0 1994 John Wiley & Sons, Inc. Key words: surface modification biocompatibility artificial organs biohybrid INTRODUCTION Poly(acrylonitri1e-co-vinyl chloride) (PANNC) hollow fiber membranes have been used to encapsulate living cells that release bioactive products for the treatment of serious diseases and disabilities such as type I diabetes, Parkin- son's disease, and chronic pain.',7,'7.22 Such membranes restrict passage of cytotoxic agents and are compatible with surrounding host tissue. Although investigators have * To whom zyxwvutsrqpon all correspondence should be addressed. reported good biocompatibility of PANNC the design and handling of PANNC implants are limited in versatility. For example, the composition of cell culture medium to which fibers (and devices) may be exposed prior to implant is restricted. Unlike a PANNC fiber immersed in a chemically defined medium prior to implant, a fiber immersed in a medium containing serum of a xenogeneic source evokes a host-tissue reaction in the brain and other sites. In modifying the surface of PANNC, the design and handling of such implants may be facilitated. By decreasing protein adsorption, for example, the devices may be immersed in a serum-containing medium which may extend their shelf life. Accordingly, attempts are made to enhance the biocompatibility of PANNC mem- branes by chemically grafting poly(ethy1ene oxide) (PEO) to preformed P A N P C hollow fiber membranes of two distinct morphologies. Chemically modifying the preformed membrane is more desirable than changing the membrane's formulation because the latter complicates the process of membrane fabrication and optimization of the membrane's properties such as size, configuration, and transport. Several approaches have been taken to improve the biocompatibility of implant-grade material; for example, surface modification techniques used to inhibit protein adsorption include the introduction of negative charge and coating the surface with a biologically derived compound, among others.I2 Poly(ethy1ene oxide) offers unique prop- erties for biomedical and biotechnical appli~ations.'~ In PEO-grafted materials the bulk mechanical properties of the solid material remains unchanged whereas the surface acquires the properties of PEO, thereby producing a surface that may be better suited for in vivo applications. PEO- modified surfaces resist protein adsorption likely because PEO chains exclude a volume as a result of their mo- bility and because PEO is hydrophilic and n e ~ t r a l . ~ For example, grafting PEO to poly(viny1 chloride) was reported to improve antithrombogenic properties without affecting the mechanical properties?' a similar effect was observed with PEO-copolymerized material^.^ Poly(ethy1ene oxide)- grafted polystyrene exhibits decreased adsorption of fib- rinogen relative to the unmodified material: The surface Biotechnology and Bioengineering, Vol. 43, Pp. 563-572 (1994) 0 1994 John Wiley & Sons, Inc. CCC 0006-35921941070563-10