Elsevier

Biomaterials

Volume 24, Issue 24, November 2003, Pages 4385-4415
Biomaterials

RGD modified polymers: biomaterials for stimulated cell adhesion and beyond

https://doi.org/10.1016/S0142-9612(03)00343-0Get rights and content

Abstract

Since RGD peptides (R: arginine; G: glycine; D: aspartic acid) have been found to promote cell adhesion in 1984 (Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule, Nature 309 (1984) 30), numerous materials have been RGD functionalized for academic studies or medical applications. This review gives an overview of RGD modified polymers, that have been used for cell adhesion, and provides information about technical aspects of RGD immobilization on polymers. The impacts of RGD peptide surface density, spatial arrangement as well as integrin affinity and selectivity on cell responses like adhesion and migration are discussed.

Introduction

These days a large number of synthetic polymeric materials with various different properties are available for medical applications like prostheses, implants and tissue engineering matrices. Most of the common materials have sufficient mechanical stability and elasticity as well as desired stability towards degradation, and are non-toxic. One important remaining problem is inadequate interaction between polymer and cells, leading in vivo to foreign body reactions, such as inflammation, infections, aseptic loosening, local tissue waste, and implant encapsulation as well as thrombosis and embolization [1], [2]. Approaches to improve biomaterials include reduction of unspecific protein adsorption, known as non-fouling properties, enhancement of adsorption of specific proteins, and material modification by immobilization of cell recognition motives to obtain controlled interaction between cells and synthetic substrates [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].

In this review we focus on the modification of synthetic polymers with peptides containing the cell recognition motif RGD. RGD peptides do not only trigger cell adhesion effectively but can also be used to address selectively certain cell lines and elicit specific cell responses.

Section snippets

Proteins or peptides?

In the last decades scientists from the fields of material science, surface engineering, chemistry, physics, biology, biochemistry and medicine attempted to functionalize polymers to obtain specific cell surface interactions. In the beginning these materials were coated with cell adhesive proteins like fibronectin, collagen, or laminin [13], [14], [15], [16], [17], [18], [19]. The use of proteins, however, bears some disadvantages in the view of medical applications. At first the proteins have

Functionalization of polymers using RGD peptides

Stable linking of RGD peptides to a surface is essential to promote strong cell adhesion, because formation of focal adhesions only occurs, if the ligands withstand the cells contractile forces [74], [75], [76]. These forces are able to redistribute weakly adsorbed ligands on a surface, which leads only to weak fibrillar adhesions later on [49], [74], [77], [78]. Furthermore cells can remove mobile integrin ligands by internalization [79], [80].

In vitro evaluation of RGD functionalized polymers

The peptide-polymer materials described above have to be characterized further by in vitro studies to test their effectiveness for cell adhesion, their influence on cell behavior and to prove their applicability for medical use. These studies include investigations of cell attachment, cell spreading, cytoskeletal reorganization and formation of focal adhesions as well as proliferation and cell motility. Specific cell functionalities can be investigated by analyzing e.g. calcium content,

Design and arrangement of RGD peptides for cell adhesion

Next to proper peptide immobilization on the different materials, the design of the RGD peptide itself as well as its density and arrangement on surfaces contribute to successful cell attachment. Moreover they can even tune a certain cell behavior.

Other materials and other cell recognition motifs

Besides synthetic polymers, other materials have been modified with RGD peptides. These include natural and nature-alike polymers: collagen [267], [282], [283], [284], [285], silk fibroin [286], fibrin [287], [288], [289], bovine serum albumin (BSA) [39], [147], [171], [217], [234], [290], [291], [292], avidin and streptavidin [293], [294], [295], hyaluronic acid [12], [296], [297], [298], alginate [280], [299], [300], [301], [302], [303], [304], starch [290], [209], [305], dextran [204], [198]

In vivo evaluation of RGD functionalized polymers

The encouraging results of in vitro cell adhesion and proliferation on RGD modified polymers led to in vivo studies to determine possible biological effects and medical applications of these materials [117], [147], [148], [174], [190], [191], [194], [203], [212].

Here we focus on a few examples to demonstrate the success of RGD modified polymers in promotion of CNS tissue replacement and bone regeneration, as well as undesired results of subcutaneous implants.

One example deals with GGRGD

Conclusion

In many cases RGD peptides were proven to serve as a useful tool to stimulate cell adhesion on various materials. A great wealth of knowledge has been gained about the biology of integrin mediated cell adhesion on two-dimensional surfaces [36], [63].

Techniques to immobilize and detect RGD peptides on polymer surfaces are established, as well as in vitro evaluation of adhered cells. Therefore RGD mediated cell adhesion is tested often on new polymers to prove their applicability as bioactive

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