Elsevier

Biomaterials

Volume 29, Issue 20, July 2008, Pages 2941-2953
Biomaterials

Leading Opinion
On the mechanisms of biocompatibility

https://doi.org/10.1016/j.biomaterials.2008.04.023Get rights and content

Abstract

The manner in which a mutually acceptable co-existence of biomaterials and tissues is developed and sustained has been the focus of attention in biomaterials science for many years, and forms the foundation of the subject of biocompatibility. There are many ways in which materials and tissues can be brought into contact such that this co-existence may be compromised, and the search for biomaterials that are able to provide for the best performance in devices has been based upon the understanding of all the interactions within biocompatibility phenomena. Our understanding of the mechanisms of biocompatibility has been restricted whilst the focus of attention has been long-term implantable devices. In this paper, over 50 years of experience with such devices is analysed and it is shown that, in the vast majority of circumstances, the sole requirement for biocompatibility in a medical device intended for long-term contact with the tissues of the human body is that the material shall do no harm to those tissues, achieved through chemical and biological inertness. Rarely has an attempt to introduce biological activity into a biomaterial been clinically successful in these applications. This essay then turns its attention to the use of biomaterials in tissue engineering, sophisticated cell, drug and gene delivery systems and applications in biotechnology, and shows that here the need for specific and direct interactions between biomaterials and tissue components has become necessary, and with this a new paradigm for biocompatibility has emerged. It is believed that once the need for this change is recognised, so our understanding of the mechanisms of biocompatibility will markedly improve.

Introduction

The single most important factor that distinguishes a biomaterial from any other material is its ability to exist in contact with tissues of the human body without causing an unacceptable degree of harm to that body. The manner in which the mutually acceptable co-existence of biomaterials and tissues is developed and sustained has been of interest to biomaterials scientists and users of medical devices for many years. It has become clear that there are very many different ways in which materials and tissues can interact such that this co-existence may be compromised, and the search for biomaterials that are able to provide for the best performance in devices has been based upon the acquisition of knowledge and understanding about these interactions. These are usually discussed in the broad context of the subject of biocompatibility.

Biocompatibility is a word that is used extensively within biomaterials science, but there still exists a great deal of uncertainty about what it actually means and about the mechanisms that are subsumed within the phenomena that collectively constitute biocompatibility. As biomaterials are being used in increasingly diverse and complex situations, with applications now involving tissue engineering, invasive sensors, drug delivery and gene transfection systems, the medically oriented nanotechnologies and biotechnology in general, as well as the longer established implantable medical devices, this uncertainty over the mechanisms of, and conditions for, biocompatibility is becoming a serious impediment to the development of these new techniques. This review of biocompatibility attempts to address some of these uncertainties and provides a proposal for a unified theory of biocompatibility mechanisms.

Section snippets

The evolution of current concepts of biocompatibility

Biocompatibility has traditionally been concerned with implantable devices that have been intended to remain within an individual for a long time. To those who were developing and using the first generation of implantable devices, during the years between 1940 and 1980, it was becoming increasingly obvious that the best performance biologically would be achieved with materials that were the least reactive chemically. Thus, within metallic systems the plain carbon and vanadium steels, which

The agents of biocompatibility

The paradigm of biocompatibility outlined in this paper involves the separate, but potentially interrelated, responses of the two phases of the biomaterial–tissue complex and the interfacial phenomena that come into play when they meet. Probably the most important underlying principle is that the mechanisms by which materials and human tissues respond to each other are not unique to this particular use but are merely variations of natural processes that occur within materials and biological

The long-term implantable medical device

Recognising that the most trusted data on the biocompatibility of a material must come from the actual use of that material in practical clinical examples in humans, we shall review first the generic evidence concerning some well known clinical procedures, taken from a spectrum of conditions involving both hard and soft tissues and blood contact. It is noted, of course, that data on many devices may not always be definitive with respect to materials since more than one material may be involved

Degradable implantable systems

One of the first reasons for modifying the concept of biocompatibility arose with the development of degradable implantable materials and systems, where a stable equilibrium was emphatically not desired, but where the degrading material had to perform a function before or during a process by which it was degraded and eliminated from the body. Initially the focus was on absorbable sutures where, for many years, surgical catgut had been the only clinically acceptable material but, being derived

Transient invasive intravascular devices

Large numbers of patients, such as those undergoing haemodialysis, come into contact with biomaterials through the insertion of a catheter into their venous system, either for a short term delivery of some substance for nutritional, diagnostic or therapeutic purposes, or for more long-term purposes. The intervention may be either central or peripheral. For many years it has been recognised that these interventions are not without risk, largely related to either infection or thrombosis and their

Background

Notwithstanding the routine clinical successes with many of the long-term implantable devices discussed in Section 4 above, there are significant limitations to the approach of using manufactured prosthetic devices for the treatment of chronic diseases or injuries. Biocompatibility considerations obviously provide one category of limiting factors although we have seen that, provided certain basic rules are followed, these do not constitute difficult barriers in most situations. As discussed by

The central biocompatibility paradigm

We have previously defined biocompatibility in terms of the ability of a material to perform with an appropriate host response in a specific situation. That was, at its inception, a powerful reminder that biomaterials have to perform a function, and can only do so if they invoke a response from the tissues, or tissue components, that they are in contact with, that is, at the very least, compatible with that function, or better, actively support that function. It is necessary, as originally

Conclusions

Our understanding of the mechanisms of biocompatibility has been restricted whilst the focus of attention has been long-term implantable devices. Here, over 50 years of experience has determined that, in the vast majority of circumstances, the sole requirement for biocompatibility in a medical device intended for sustained long-term contact with the tissues of the human body is that the material shall do no harm to those tissues, achieved through chemical and biological inertness. Rarely has an

Acknowledgements

This paper is based on many years experience at the University of Liverpool and I wish to acknowledge the support of many colleagues and students in Liverpool, too numerous to mention, over this time, and the financial support within UK, especially from the Research Councils EPSRC, BBSRC and MRC, and the European Commission, in particular for the STEPS project in the Framework VI Programme.

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    Editor's Note: This Leading Opinion Paper is based upon a series of presentations given by the author at the University of Washington Summer Workshop in August 2003, a keynote paper at the World Biomaterials Conference in Sydney, 2004, the Gordon Research Conference on Biomaterials, Biocompatibility and Tissue Engineering, New Hampshire, USA in 2005, the Ratner Symposium in Maui, 2006 and the Founders Award Presentation, Chicago, 2007. It forms the first of a series of essays that will be published, in different journals, on the subjects of the principles of biomaterials' selection. Since the author is Editor-in-Chief of the journal, the paper has been refereed by four of the Associate Editors and revised on the basis of their reports. The opinions expressed in the review are, however, the sole responsibility of the author. It should also be noted that the reference list cannot represent the totality of literature on biocompatibility but points to some of the more significant literature that reflect the clinical outcomes concerned with biocompatibility.

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