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, BiomaterialsPresident-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 SouthWales, Australia

Guest Professor, Tsinghua University, Beijing and Visiting Professor, Shanghai Jiao TongMedical University, China

Emeritus Professor, University of Liverpool, UK

Biocompatibility and War and Peace

Biocompatibility is a war zoneAnd war is a continuumConflict resolutionMay lead to quiescenceBut peaceLike biocompatibilityIs metastableInsurgencies, just as thrombus, can occurAt any timeIf defences are let downNew technologiesMaybe WMD at the nanoscaleLead to changes, andNew strategies of defence.

BiocompatibilityCan never be wonIt can be tamedAnd watched over, for ever

© D.F.Williams 2010

Williams D.F. On the mechanisms of biocompatibilityBiomaterials, 2008, 29, 2941

Williams D.F. On the nature of biomaterialsBiomaterials, 2009, 30, 5897

The Williams Definition ofBiocompatibility

‘The ability of a material toperform with an appropriate hostresponse in a specific application’

The Williams Dictionary of BiomaterialsLiverpool University Press, 1999

The Williams Definition of a Biomaterial

2009

A biomaterial is a substance that has been engineeredto take a form which, alone or as part of a complex system,

is used to direct, by control of interactions with components ofliving systems, the course of any therapeutic or diagnostic

procedure.

Implantable Medical Devices

Implantable Medical Devices•Long term biocompatibility and toxicology of metallic

systems are reasonably well known; do we need new alloys?

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 isreasonably well known; do we need new polymers?

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 isreasonably well known; do we need new polymers?•Long term response of bone to biomaterials is well

understood; do we need new bone-contacting surfaces?

Implantable Medical Devices

•Long term biocompatibility and toxicology of metallicsystems are reasonably well known; do we need new alloys?

•Long term biocompatibility of biostable polymers isreasonably 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

Biomaterial Performance

Always remember with the biocompatibility of medical devices, thethree 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

Implantable Degradable Systems

Implantable Device – Drug Combinations

Implantable Device – Drug Combinations

Drug – eluting stentsBMP releasing devices in the spine

Bisphosphonates in bone

Do we know sufficient about pharmacokinetics andpharmacodynamics in these systems to be sure of

mechanisms of action, efficacy and safety?

The ability of a material to perform with an appropriate hostresponse in a specific application

The scientific basis of biocompatibility involves theidentification of the causal relationships

between materials and host tissue such thatmaterials can be designed to elicit the

most appropriate response

This implies that it is possible to determineunequivocally the way in which material parameter X

influences host response Yand that knowing this, we can modify X in order to modulate Y

This is how we should determine the specifications for biomaterials

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

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

The Reality for Implantable Devices

• The host response, involving both humoral and cellularcomponents is extremely complex,

• Several of these components involve amplification or cascadeevents,

• There is often a two-way relationship between the materialvariable and the host response e.g. a degradation process ispro-inflammatory and the products of inflammation enhance thedegradation process,

• Mechanical stability influences the host response, and in manysituations 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, pharmacologicalstatus, lifestyle, etc.,

• Biocompatibility is species specific - testing materials in youngrats in Liverpool or Winston-Salem may be of no relevance tosenior citizens in Atlanta.

The Reality;Long-term Implantable Devices

It has proved impossible in virtually all situations topositively modulate the host response by

manipulation of the material variables.

In almost all situations, the practical consequence isthat we select devices that irritate the host the least,through the choice of the most inert and least toxic

materials and the most appropriate mechanicaldesign,

The Reality;Long-term Implantable Devices

• HIPS PE, Co-Cr, Al2O3, PMMA

• VALVES Ti, C, PTFE• ARTERIES PTFE, POLYESTER• TEETH Ti• ELECTRODES PGM• EYES PMMA, PDMS

The Laws of Biomaterials Selection

When selecting materials for long term implantabledevices, choose the material that optimises the

functional properties of the device, consistent withmaximum chemical and biological inertness

The biocompatibility of a long term implantablemedical device refers to the ability of the deviceto perform its intended function, with the desired

degree of incorporation in the host, withouteliciting any undesirable local or systemic effects

in that host.

Tissue Engineering

Tissue engineering is the creation of new tissue for thetherapeutic reconstruction of the human body, by the

deliberate and controlled stimulation of selectedtarget cells through a systematic combination of

molecular and mechanical signals

The Changing Nature of Biomaterials andMethods for their Evaluation

Tissue Engineering ProductsWe 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 10993 is not a valid basis for testing new biomaterialsWe 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?

Biocompatibility of Tissue EngineeringScaffolds and Matrices

The biocompatibility of a scaffold or matrix for a tissueengineering product refers to the ability to perform asa substrate that will support the appropriate cellularactivity, including the facilitation of molecular and

mechanical signalling systems, in order to optimisetissue 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 anappropriate specification for a tissue engineering scaffold or matrix material

•Biocompatibility has to be determined in the context of theintended function of the product

•We need better systems for the determination of biologicalsafety

•We may have to re-define ‘surfaces’ in the new world ofnanostructured biomaterials

•We have to take the determination of biocompatibility out ofthe courtroom

peggy@morgan-masterson.com