professordavidwilliams - uts

Concepts in Biocompa.bility: New Biomaterials,

New Paradigms and New Tes.ng Regimes

Professor David Williams Wake Forest Ins.tute of Regenera.ve Medicine, USA

Editor-‐in-‐Chief, Biomaterials President, TERMIS

Professor Emeritus, University of Liverpool, UK

Visi.ng Professor Universi.es in Cape Town, Singapore, Shanghai, Beijing, Taipei, Sydney, Trivandrum

MINNEAPOLIS May 2013

© D.F.Williams

Biological evalua.on of medical devices Part 1: Evalua.on and tes.ng (ISO 10993-‐1:2003)

•  ISO 10993 consists of the following parts, under the general .tle Biological evalua.on of medical

devices : •  — Part 1: Evalua.on and tes.ng •  — Part 2: Animal welfare requirements •  — Part 3: Tests for genotoxicity, carcinogenicity and reproduc.ve toxicity •  — Part 4: Selec.on of tests for interac.ons with blood •  — Part 5: Tests for in vitro cytotoxicity •  — Part 6: Tests for local effects a`er implanta.on •  — Part 7: Ethylene oxide steriliza.on residuals •  — Part 8: Selec.on and qualifica.on of reference materials for biological tests •  — Part 9: Framework for iden.fica.on and quan.fica.on of poten.al degrada.on products •  — Part 10: Tests for irrita.on and delayed-‐type hypersensi.vity •  — Part 11: Tests for systemic toxicity •  — Part 12: Sample prepara.on and reference materials •  — Part 13: Iden.fica.on and quan.fica.on of degrada.on products from polymeric medical

devices •  — Part 14: Iden.fica.on and quan.fica.on of degrada.on products from ceramics •  — Part 15: Iden.fica.on and quan.fica.on of degrada.on products from metals and alloys •  — Part 16: Toxicokine.c study design for degrada.on products and leachables

Concepts in Biocompa.bility: New Biomaterials,

New Paradigms and New Tes.ng Regimes

• Biocompa.bility and biological safety: concepts and principles

• Changing perspec.ves on biomaterials

• Changing perspec.ves on biocompa.bility

• Views on in vitro tes.ng

• Challenges with animal tes.ng

• Genomics, proteomics and computer modeling

• Sugges.ons and recommenda.ons

Biocompa.bility and Biological Safety Concepts and Principles

•  Devices are placed on the market, having sa.sfactorily undergone industry-‐standard pre-‐clinical tes.ng procedures, but problems (real or apparent) are encountered, such that they have to be removed from those markets, and everyone suffers.

•  Devices are oèn used in inappropriate pa.ents, with improper techniques. Everyone knows this but we s.ll persist in promo.ng their widespread use in the interests of market size or share. Neither tes.ng procedures nor regulatory processes can take into account the fact that pa.ent selec.on and clinical skills are oèn more important than intrinsic biocompa.bility in determining clinical outcomes.

•  These difficul.es are now being compounded by the introduc.on of new biomaterials and new therapeu.c and diagnos.c concepts, which oèn have different, and perhaps contradictory, implica.ons for biological safety and product performance.

Changing Perspec.ves on Biomaterials (Williams DF On The Nature of Biomaterials, Biomaterials, 2009, p 5897)

•  Permanently (long term) implantable devices •  Short term implantable devices •  Invasive but removable devices •  External ar.ficial organs •  Organ assist devices •  Surgical and clinical accessories •  Drug, gene and vaccine delivery systems •  Tissue engineering / cell therapy systems •  In vivo diagnos.c systems •  In vitro diagnos.c systems SHOULD WE BE USING THE SAME TESTING REGIMES FOR ALL

OF THESE PRODUCTS?

Changing Perspec.ves on Biomaterials Williams DF Essen.al Biomaterials Science, Cambridge University Press, 2014

The Williams Defini?on of a Biomaterial

A biomaterial does not have to be solid, visible and tangible; it does not have to be manufactured by conven.onal top-‐down industrial processes. A biomaterial does not have to

be dead.

A biomaterial could be a suspension of nanopar.cles, or a self-‐assembling pep.de hydrogel. It could be an engineered sheet of stem-‐cells. It could be a non-‐viral gene vector or even an

engineered viral vector. It could be an an.body func.onalized nanoscale superparamagne.c, drug-‐loaded en.ty for theranos.c uses. It could be engineered re-‐cellularized ECM.

Changing Perspec.ves on Biomaterials (Williams DF On The Nature of Biomaterials, Biomaterials, 2009, p 5897)

The Williams Defini?on 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 interac?ons with components of living systems, the course of any therapeu?c or diagnos?c procedure.

DO WE NEED NEW PARADIGMS OF BIOLOGICAL SAFETY TESTING TO ACCOMPANY THESE NEW

PARADIGMS OF BIOMATERIAL DESIGN AND PERFORMANCE

Changing Perspec.ves on Biocompa.bility Williams DF Essen.al Biomaterials Science, Cambridge University Press, 2014

Significance of Nanoscale Biocompa.bility

• In vitro nanopar.cle cytotoxicity is highly dependent of cell type • In vitro behavior of nanopar.cles is dependent on par.cle size, zeta poten.al,

aggrega.on processes and protein corona characteris.cs • In vivo performance and safety of nanopar.cles is dependent on transloca.on,

biodegrada.on and biopersistence • Internaliza.on of nanopar.cles within cells partly depends on mechanical effects on

cell membranes • The role of the nanotopography of biomaterials surfaces on biocompa.bility is largely

unknown

NONE OF THESE PROCESSES ARE ADDRESSED BY STANDARD ISO 10993 TESTS

Basic concepts in regenera.ve medicine and the essen.al

.ssue engineering paradigm

Tissue Engineering

Tissue engineering is the crea?on of new ?ssue for the therapeu?c reconstruc?on of the human body, by the deliberate and controlled s?mula?on of selected target cells through a systema?c combina?on of molecular and mechanical signals

Williams D.F. To engineer is to create, Trends

in Biotechnology, 2006, 24, 4-‐8

Tissue Engineering Templates

In order to achieve spa.o-‐temporal control, we need biomaterials that can be formed into a suitable template which:

•  May be pre-‐formed or injectable / in situ selng or gelling •  Has the appropriate mechanical and biophysical proper.es •  Can incorporate and release of necessary specific biomolecules •  Degrades with the appropriate kine.cs and lack of toxicity •  Has the appropriate biocompa.bility characteris.cs. But The biomaterial alone cannot perform all of the required func.ons, it needs to be

in a form that has the appropriate architecture and morphology, and needs to convey and deliver relevant biomolecules.

A Tissue Engineering Template comprises: BIOMATERIAL + ARCHITECTURE + BIOMOLECULES

We have no procedures that are able to assess these complex templates

Specifica?ons for Template Biomaterials • The material should be capable of orchestra.ng molecular signaling to the

target cells, either by direc.ng endogenous molecules or delivering exogenous molecules,

• The material should be of a physical form that provides appropriate shape and size to the regenerated .ssue,

• The material should be capable of forming into an architecture that op.mizes cell, nutrient, gas and biomolecule transport, either or both ex

vivo or in vivo, and facilitates blood vessel and nerve development, • The material should be intrinsically non-‐cytotoxic and non-‐immunogenic,

and minimally pro-‐inflammatory,

TESTING REGIMES SHOULD ADDRESS ALL OF THESE SPECIFICATIONS; IT IS NOT ACCEPTABLE TO SIMPLY LOOK FOR CHEMICALLY-‐DRIVEN NEGATIVE EFFECTS. A FAILURE TO POSITIVELY STIMULATE CELLS YIELDS A NEGATIVE

OUTCOME

Op?ons for Template Biomaterials

Porous solids * Hybrid nano / micro-‐structured blends of synthe?c (PHB) / natural

(silk-‐elas?n) materials Hydrogels

*Engineered pep?de hydrogels Decellularized ECM materials

NOTE; Standard biodegradable synthe.c polymers prepared by standard fabrica.on routes are unlikely to provide op.mal .ssue engineering templates and prior FDA approval of materials used in medical devices is not an appropriate specifica.on for a template

Views on In Vitro Tes.ng

•  Simple, standardized, in vitro tests should mostly be considered as screening procedures that warn against significant adverse effects,

•  Since most tests have arbitrary, semi-‐quan.ta.ve, criteria for the interpreta.on of results, effec.vely giving a pass-‐fail conclusion, where repeated tests may give different outcomes, we can only use these as approximate indicators of safety

•  In vitro tests should be mul.parametric, involving different cell types, different condi.on and several types of outcome, including cell morphology, cell func.on, reac.ve oxygen species produc.on and the different parameters of cell death, including cytotoxicity and apoptosis.

Challenges with Animal Tes.ng

•  Biocompa.bility is species specific •  As with humans, the host response in animals varies with age, gender, health status, pharmacological status etc

•  There are few acceptable animal models for most clinical situa.ons, e.g. pelvic organ prolapse, spinal fusion

•  Very difficult to balance the need for sta.s.cally valid long-‐term data with the requirements for acceptable economics

Suggestions and Recommendations

•  Need a far beoer correla.on between the science of biocompa.bility and the pragma.c aspects of biological safety tes.ng.

•  Tes.ng regimes should be much more closely aligned to the characteris.cs of the product, including mode of contact between biomaterial and .ssues.

•  In vitro tes.ng should be considered as preliminary / screening procedures, in general not to be used for the defini.ve determina.on of safety.

•  For implantable devices, in vivo tes.ng should build on exis.ng ISO 10993 guidelines but should be even more consistent with the intended func.on, the precise loca.on and biomechanical variables


•  For regenera.ve medicine products, tes.ng regimes should focus on func.onality and take into account the delivery of signaling mechanisms and phenotypic changes to the target cells.

•  With nanopar.cle products, both for diagnos.c and therapeu.c purposes, tes.ng regimes should be mul.variant and should take into account factors such as aggrega.on, biopersistence, biodegrada.on, cellular uptake, biodistribu.on and systemic effects.

•  Whenever xenogeneic and allogeneic sources are used for either cells or .ssues, full account should be taken of their immunogeneic poten.al.


•  Greater aoen.on should be given to the use of ‘substan.al equivalence designa.ons’. Greater weight should be given to prior evidence of intrinsic biomaterials biocompa.bility and less weight to product similari.es.

•  There should be greater associa.on between pre-‐clinical tes.ng regimes and clinical studies. The logis.cs, economic burden and reliability of the different types of clinical studies should be re-‐evaluated.

•  Efforts should be made to integrate computer modeling, combinatorial processes and gene / protein expression profiling into biocompa.bility tests.

Incon.nence and Pelvic Organ Prolapse

This involves on-‐going li.ga.on; Essen.ally sub-‐judice. Curr Urol Rep. 2011 Oct;12(5):370-‐6. doi: 10.1007/s11934-‐011-‐0206-‐0. Epidemiology of stress urinary inconBnence in women. Reynolds WS1, Dmochowski RR, Penson DF. Stress urinary incon.nence is common and affects many women globally. About 50% of women with urinary incon.nence report symptoms of stress incon.nence, but es.mates of the prevalence and incidence are limited by inconsistent methods of measurement between epidemiologic studies in different popula.ons. Es.mates also are affected by underlying differences in the age and ethnicity of study popula.ons. Longitudinal studies assessing the incidence and natural history of stress incon.nence es.mate an annual incidence of 4% to 10%. While remission does occur, data on this remains sparse. Mul.ple risk factors have been associated with stress incon.nence and may to contribute to the development of the condi.on.

Prepared for the

World Summit on Regenerative Medicine, 2013

19–22 October 2013Sofitel Xi’an on Renmin Square, Xi’an, China

Xi’an World Summit on2013

Regenerative Medicine

THE XI’ANPAPERS

The Xi’an Protocol

There is overwhelming evidence that a powerful global mul.disciplinary community is emerging which can, even with diverse cultures, economies and poli.cs, orchestrate a

successful pathway between the legi.mate, ethical crea.on of wealth and the delivery of therapies in area of un-‐met need.

• Scalable manufacturing and control of supply chain

• Standardized disease-‐relevant animal models • New procedures for pre-‐clinical tes.ng of biomaterials

• Business models, insurers, pa.ent groups, service vs products • Use of cosme.c/veterinary markets for early revenue

• Recogni.on of lines of resistance ‘ Culture defeats Strategy’ • Convergence of progressive regulatory procedures

• Accelera.on of global approaches through co-‐opera.on

SCENIHR

SCIENTIFIC COMMITTEE ON NEWLY IDENTIFIED

AND EMERGING HEALTH RISKS

Opinion on “The Safety of Human Blood and

Organs with Regard to West Nile Virus”

2006

SCENIHR



Opinion on “The Safety of Human-‐derived Products with regard to Variant Creutzfeldt-‐Jakob Disease”

2006

SCENIHR SCIENTIFIC COMMITTEE ON NEWLY

IDENTIFIED AND EMERGING HEALTH RISKS

OPINION ON

“THE SAFETY OF MEDICAL DEVICES CONTAINING DEHP-‐ PLASTICIZED PVC OR OTHER PLASTICIZERS ON NEONATES AND

OTHER GROUPS POSSIBLY AT RISK” 2008

SCENIHR



Opinion on “The safety of dental amalgam and

alterna.ve dental restora.on materials for pa.ents and users”

2008

SCENIHR SCIENTIFIC COMMITTEE ON NEWLY IDENTIFIED


The SCENIHR opinion states: Nanotechnology is the term given to those areas of science and engineering where phenomena that take place at dimensions in the nanometre scale are

u.lised in the design, characterisa.on, produc.on and applica.on of materials, structures, devices and systems. Although in the natural world there are many

examples of structures that exist with nanometre dimensions (herea`er referred to as the nanoscale), including essen.al molecules within the human

body and components of foods, and although many technologies have incidentally involved nanoscale structures for many years, it has only been in

the last quarter of a century that it has been possible to ac.vely and inten.onally modify molecules and structures within this size range. It is this control at the nanometre scale that dis.nguishes nanotechnology from other

areas of technology.

SAT MECHANICAL TAVI DEPLOYMENT DEVICE: KEY IP FEATURES •  Self-‐homing, straight Transapical Approach independent of dimensional /

pathological characteris.cs of femoral/iliac arteries.

•  Non-‐occlusiveness makes slow deployment possible

•  Short deployment rout does not require catheter-‐skills like in TF route.

•  Back-‐flow protec.on secures diastolic pressures essen.al for coronary perfusion while protec.ng the ventricle from distending

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