Cellular Interaction with Biomaterials Modified by Arg-Gly-Asp Containing Peptides
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CELLULAR INTERACTION WITH BIOMATERIALS MODIFIED BY ARG-GLY-ASP CONTAINING PEPTIDES.
James R. Glass, William S. Craig, Ken Dickerson and Michael D. Pierschbacher Telios Pharmaceuticals, Inc., 2909 Science Park Rd., San Diego, CA. 92121
Abstract Because cells can recognize and attach to short synthetic peptides containing the tripeptide sequence, arg-gly-asp (RGD), we have designed peptides which will spontaneously bind and present an active RGD sequence on biomaterial surfaces. We have analyzed a number one which fulfills this functional criteria. This of synthetic peptides and fully characterized peptide has been named PepTite-2000 Tm. When biomaterials are placed in aqueous buffers containing PepTite-2000, the peptide rapidly binds to the surface and provides a site for cell attachment. Cell attachment occurs to PepTite-2000 coated materials by an RGD dependent mechanism using the avfl3 integrin. This coating protocol is widely applicable, and the peptide will coat and promote cell attachment to all the commonly used biomaterials we have tested including dacron, teflon, titanium and silicone. Analysis of the soft tissue response to dacron implants coated with PepTite-2000 demonstrates that the coating results in more rapid tissue ingrowth and less giant cell recruitment around the implanted materials. These data demonstrate that PepTite-2000 can be used to modify biomaterial surfaces and present a more "natural" site for cell interactions. Introduction A variety of distinct extracellular matrix (ECM) glycoproteins have been identified by their ability to promote cell attachment in tissue culture [3]. The molecular dissection of the cell attachment domains in a number of these proteins revealed that a tripeptide sequence, arg-gly-asp (RGD), comprised the cell binding region [1]. Cell adhesion proteins in which this sequence is found include, fibronectin, vitronectin, osteopontin,
collagens, thrombospondin, fibrinogens, and von Willebrand factor. Affinity chromatography using RGD-containing peptides or native proteins as ligands has been used to isolate the specific cell receptors for ECM components [4,5,6]. A family of receptors, termed integrins, have been identified, each containing transmembrane heterodimeric subunits designated a and pi. The structural conformation of RGD, in addition to different combinations of integrin subunits, provide for specific recognition of RGD in various adhesion proteins. At this time at least 14 different integrin receptors have been isolated, 6 of which bind the RGD sequence [2,4]. As a method to increase the biocompatibility of medical implant devices we have developed RGD containing peptides which will spontaneously coat a variety of materials and thus provide a site for initiating cell interactions. In this manner, the coating effectively "mimics" the native extracellular matrix. This coating would hopefully increase the rate of integration of an implant, result in decreased adverse cell reactions and inhibit potential
routes for infection. In this paper we describe the cha
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