Bioactive biomaterials

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Abstract

The most important advances in the field of biomaterials over the past few years have been in bioactive biomaterials. Materials have been developed to incorporate bioactivity through biological recognition, including incorporation of adhesion factors, polyanionic sites that mimic the electrostatics of biological regulatory polysaccharides, and cleavage sites for enzymes involved in cell migration. Materials have also been developed to be active in biological environments by undergoing phase changes in situ, including transformations from liquid precursors to solids and from soluble materials to materials that are immobilised on tissue surfaces.

Introduction

Important advances have been made in the field of biomaterials over the past few years, and most of these have been associated with rendering materials biologically active. It is as logical to develop biomaterials that are bioactive as it is to develop drugs that are bioactive. Pharmacological activity is based on the principles of biological recognition, for example, to competitively inhibit receptors or enzymes, to block binding sites, to regulate certain biological pathways, and so on. One can, in most applications, consider the function of a biomaterial-based device analogously to that of a pharmaceutical. An example could be considered in the context of the vascular graft. Certainly, the basic functions of the graft have nothing to do with biological activity: it must carry blood flow, must resist the dilatory pressures of the cardiovascular system, and must resist the compressive and kinking forces of the tissues external to the cardiovascular system. These goals can be met entirely in the absence of biological activity. Beyond these basic performance goals, however, one may be well advised to turn to bioactivity: to prevent coagulation, to encourage endothelial cell attachment and retention, to promote capillary infiltration as a source of endothelial cells, to prevent excessive smooth muscle cell proliferation and collagen matrix expression. To turn to biological recognition to accomplish these ends, for example, to incorporate biologically motivated, biomimetic adhesion-promoting sites or to incorporate growth factors, is quite logically based on the analogy of drug design. In addition to the highly biospecific biological recognition phenomena described above, some natural biological recognition proceeds by less specific physicochemical interactions, such as binding of a charged polysaccharide to a protein. One can mimic these less specific interactions as well, in this case with polyelectrolytes, in biomaterials design.

This review considers biological recognition from one additional perspective, namely enzymatically modulated material degradation. Most degradable biomaterials degrade based on chemical clocks, such as ester hydrolysis in the polymer backbone or sidechains. The rate of the hydrolysis reaction is programmed via selection of the detailed chemical environment around the ester bonds, such as side groups, crystallinity and hydrophilicity, to set the speed of the chemical clock. In this approach, the clock is set in the laboratory, based on a prediction of a biological response. An alternative approach, one involving the concept of bioactivity, is to let a degradation program proceed along a coordinate of the healing process, rather than time, by making the material sensitive to the feedback provided by the cells involved in the healing response. Indeed, this paradigm is employed naturally in tissue generation, remodelling and regeneration, as cells enzymatically degrade the extracellular matrix around them. By rendering a biomaterial sensitive to these enzymatic activities, one can pursue the goal of biomimetic material degradation.

This review also considers bioactivity from a perspective other than biological recognition, namely active material transformation from one state to another in the presence of the biological system. Materials can be designed to transform under some external stimulus, such as light, temperature or chemical composition (e.g. from liquids to elastic solids, from cell adhesive to cell non-adhesive, or from freely soluble to bound to a tissue surface). By design of materials for bioactivity, it may be possible to develop materials that enable new surgical procedures, such as closure of internal incisions by bioactive adhesives, or organ culture methods, such as culture of cell and cell aggregates within gels.

Section snippets

Bioactivity by incorporation of adhesion factors

One approach toward biological activity in biomaterials is the incorporation of adhesion-promoting oligopeptides or oligosaccharides. Cell adhesion to traditional biomaterials, such as polyethylene, polytetrafluoroethylene or silicone rubber, is based upon indirect recognition, that is, by proteins from the body fluids adsorbing nonspecifically to the material surface and some subset of these adsorbed proteins, including fibronectin, fibrinogen, and vitronectin, promoting the adhesion of cells

Bioactivity by incorporation of growth factors

Polypeptide growth factors are powerful regulators of a variety of cellular behaviours, including cell proliferation, migration, differentiation, and protein expression, and these molecules are being developed as important therapeutics in tissue regeneration (e.g. in closing bone defects and in healing chronic ulcers in the skin). Growth factors are also being explored as key components of biomaterials and biomaterial systems, as discussed in the illustrative examples below. Why is it useful to

Bioactivity by physicochemically based biological recognition

Some biological interactions are based on physicochemical interactions that are less specific than those described in the previous sections, such as adsorption due to electrostatic interactions, which can be readily mimicked and incorporated into bioactive biomaterials. Heparin’s electrostatically dominated interactions in anticoagulation present one example, and extensive work has been performed at immobilisation of heparin on biomaterials to render them bioactive [25]. Extensive work has also

Bioactivity by incorporation of enzymatic recognition sites

The two sections above, dealing with incorporated adhesion and growth factors, addressed the transmission of biological information from a biomaterial to the neighbouring cells. One can also consider the other direction, in which the biomaterial is the recipient of information produced by cells. One such form of information is enzymatic activity associated with the cell surface during cell migration. Cell migration through collagen [33] and fibrin [34] gels, both natural biomaterials involved

Bioactivity by material transformation

Biomaterials can possess biological activity (i.e. activity in a biologically relevant context) via the ability to be transformed from one state to another. Several examples have already appeared and some have already found clinical utility, and selected examples are presented below. The reader is directed elsewhere for a review exclusively on this topic [38].

Materials that undergo phase transformations have a great deal of potential for use in surgery, for example, as adhesives, sealants, and

Conclusions

Biological activity has played an important role in modern biomaterials development, employing the principles of biological recognition that are used so frequently in pharmaceutical design in addition to other more material-centric principles, for example, those that permit material to respond to external stimuli. Only recently have these novel bioactive biomaterials begun to make clinical impact, but given the relatively long cycle from concept to clinic this is to be expected. Indeed, it is

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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