Biocompatibility and War and Peace

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Victor Roberts
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1 Professor David Williams, D.Sc.,F.R.Eng., Professor and Director of International Affairs, Wake Forest Institute of Regenerative Medicine, North Carolina, USA Editor-in-Chief, Biomaterials President-elect, Tissue Engineering & Regenerative Medicine Society International (TERMIS) Chairman and Director, Southern Access Technologies, South Africa Visiting Professor, Christiaan Barnard Department of Cardiothoracic Surgery, Cape Town, South Africa, Visiting Professor, Graduate School of Biomedical Engineering, University of New South Wales, Australia Guest Professor, Tsinghua University, Beijing and Visiting Professor, Shanghai Jiao Tong Medical University, China Emeritus Professor, University of Liverpool, UK

3 Biocompatibility and War and Peace Biocompatibility is a war zone And war is a continuum Conflict resolution May lead to quiescence But peace Like biocompatibility Is metastable Insurgencies, just as thrombus, can occur At any time If defences are let down New technologies Maybe WMD at the nanoscale Lead to changes, and New strategies of defence. Biocompatibility Can never be won It can be tamed And watched over, for ever D.F.Williams 2010

4 Williams D.F. On the mechanisms of biocompatibility Biomaterials, 2008, 29, 2941 Williams D.F. On the nature of biomaterials Biomaterials, 2009, 30, 5897

5 The Williams Definition of Biocompatibility The ability of a material to perform with an appropriate host response in a specific application The Williams Dictionary of Biomaterials Liverpool University Press, 1999

6 The Williams Definition of a Biomaterial 2009 A biomaterial is a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure.

8 Implantable Medical Devices

10 Implantable Medical Devices Long term biocompatibility and toxicology of metallic systems are reasonably well known; do we need new alloys?

13 Implantable Medical Devices Long term biocompatibility and toxicology of metallic systems are reasonably well known; do we need new alloys? Long term biocompatibility of biostable polymers is reasonably well known; do we need new polymers?

16 Implantable Medical Devices Long term biocompatibility and toxicology of metallic systems are reasonably well known; do we need new alloys? Long term biocompatibility of biostable polymers is reasonably well known; do we need new polymers? Long term response of bone to biomaterials is well understood; do we need new bone-contacting surfaces?

18 Implantable Medical Devices Long term biocompatibility and toxicology of metallic systems are reasonably well known; do we need new alloys? Long term biocompatibility of biostable polymers is reasonably well known; do we need new polymers? Long term response of bone to biomaterials is well understood; do we need new bone-contacting surfaces? Still have some issues with xenogeneic materials Still have some uncertainties over interactions with blood endothelialization, thromboembolism etc

19 Biomaterial Performance Always remember with the biocompatibility of medical devices, the three most important mediators of clinical performance are, in this order The Quality of the Surgery The Characteristics of the Patient The Inherent Biocompatibility of the Material

20 Implantable Degradable Systems

21 Implantable Device Drug Combinations

22 Implantable Device Drug Combinations Drug eluting stents BMP releasing devices in the spine Bisphosphonates in bone Do we know sufficient about pharmacokinetics and pharmacodynamics in these systems to be sure of mechanisms of action, efficacy and safety?

23 The ability of a material to perform with an appropriate host response in a specific application The scientific basis of biocompatibility involves the identification of the causal relationships between materials and host tissue such that materials can be designed to elicit the most appropriate response This implies that it is possible to determine unequivocally the way in which material parameter X influences host response Y and that knowing this, we can modify X in order to modulate Y This is how we should determine the specifications for biomaterials

24 Material Variables Bulk material composition, microstructure, morphology, Crystallinity and crystallography, Elastic constants, compliance, Surface chemical composition, chemical gradient, molecular mobility, Surface topography and porosity Water content, hydrophobic hydrophilic balance, surface energy Corrosion parameters, ion release profile, metal ion toxicity Polymer degradation profile, degradation product toxicity Leachables, catalysts, additives, contaminants Ceramic dissolution profile Wear debris release profile, particle size Sterility and endotoxins

25 Host Response Characteristics Protein adsorption and desorption characteristics Complement activation Platelet adhesion, activation and aggregation Activation of intrinsic clotting cascade Neutrophil activation Fibroblast behaviour and fibrosis Microvascular changes Macrophage activation, foreign body giant cell production Osteoblast / osteoclast responses Endothelial proliferation Antibody production, lymphocyte behaviour Acute hypersensitivity / anaphylaxis Delayed hypersensitivity Genotoxicity, reproductive toxicity Tumour formation

26 The Reality for Implantable Devices The host response, involving both humoral and cellular components is extremely complex, Several of these components involve amplification or cascade events, There is often a two-way relationship between the material variable and the host response e.g. a degradation process is pro-inflammatory and the products of inflammation enhance the degradation process, Mechanical stability influences the host response, and in many situations the host response determines the stability The host response is time dependent, The host response is patient specific, depending on age, gender, health status / concomitant disease, pharmacological status, lifestyle, etc., Biocompatibility is species specific - testing materials in young rats in Liverpool or Winston-Salem may be of no relevance to senior citizens in Atlanta.

27 The Reality; Long-term Implantable Devices It has proved impossible in virtually all situations to positively modulate the host response by manipulation of the material variables. In almost all situations, the practical consequence is that we select devices that irritate the host the least, through the choice of the most inert and least toxic materials and the most appropriate mechanical design,

28 The Reality; Long-term Implantable Devices HIPS PE, Co-Cr, Al 2 O 3, PMMA VALVES Ti, C, PTFE ARTERIES PTFE, POLYESTER TEETH Ti ELECTRODES PGM EYES PMMA, PDMS

29 The Laws of Biomaterials Selection When selecting materials for long term implantable devices, choose the material that optimises the functional properties of the device, consistent with maximum chemical and biological inertness The biocompatibility of a long term implantable medical device refers to the ability of the device to perform its intended function, with the desired degree of incorporation in the host, without eliciting any undesirable local or systemic effects in that host.

30 Tissue Engineering Tissue engineering is the creation of new tissue for the therapeutic reconstruction of the human body, by the deliberate and controlled stimulation of selected target cells through a systematic combination of molecular and mechanical signals

31 The Changing Nature of Biomaterials and Methods for their Evaluation Tissue Engineering Products We need to assess the intrinsic level of biological risk before a device is used clinically We do not have high quality biomaterials for tissue engineering applications, and we need new test procedures The failure to produce clinical success with tissue engineering products is partly caused by the lack of standard testing and regulatory approval procedures Experience tells us the current pre-clinical test procedures are definitely not predictive of clinical performance ISO is not a valid basis for testing new biomaterials We also need effective process validation systems for ensuring continuing quality and safety Do we have the most effective procedures for quality control concerned with biological safety?

34 Biocompatibility of Tissue Engineering Scaffolds and Matrices The biocompatibility of a scaffold or matrix for a tissue engineering product refers to the ability to perform as a substrate that will support the appropriate cellular activity, including the facilitation of molecular and mechanical signalling systems, in order to optimise tissue regeneration, without eliciting any undesirable local or systemic responses in the eventual host. Previous FDA approval for the use of a biomaterial in a medical device is not an appropriate specification for a tissue engineering scaffold or matrix material

38 Biocompatibility has to be determined in the context of the intended function of the product We need better systems for the determination of biological safety We may have to re-define surfaces in the new world of nanostructured biomaterials We have to take the determination of biocompatibility out of the courtroom

ISO : A Risked Based Approach to Biological Safety

ISO : A Risked Based Approach to Biological Safety ISO 10993 : A Risked Based Approach to Biological Safety Dr Arthur Brandwood Australian Delegation Leader to ISO TC 194 Biocompatibility and Clinical Trials Previous Director Devices Registration and Assessment