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ARTICLE IN PRESSJ.L. Brash / Biomaterials 26 (2005) 7209–7220NSERC that have been of benefit to the biomaterialsfield have evolved over the years. These include theStrategic Grants, which are targeted to areas considered‘‘strategic’’ for Canada. A currently targeted arearelevant to biomaterials is ‘‘medical devices’’. TheCollaborative Health Research Projects where physicalscientists or engineers collaborate with biomedicalscientists on health-related projects is a recent programthat has been of benefit to biomaterials researchers.Most Canadian biomaterials researchers hold NSERCdiscovery grants and a number have been funded by theother programs as well.The other major source of Federal Governmentsupport has been the Medical Research Council ofCanada (MRC), which in 2001 became the CanadianInstitutes of Health Research (CIHR) with an expandedmandate, but retaining the committee structure of theMRC through which much of the funding is allocated.The CIHR has a standing grants committee onBiomedical Engineering where investigator-initiatedprojects on medical imaging, biomechanics, and biomaterials (among other areas) are considered for funding.The Dental Science Committee as well as the Pharmaceutical Sciences Committee have also contributed tothe funding of biomaterial-related areas. Through thesecommittees the MRC/CIHR has been a major source ofsupport for the biomaterials community in Canada formore than 30 years.Two other Federal Government programs should bementioned, namely the Canada Foundation for Innovation (CFI) and the CRCs. The CFI was set up in the late1990s to facilitate the renewal of research infrastructurein Canada, targeting mainly the universities andhospitals. Infrastructure includes facilities, equipment,building renovations, and even new buildings. The CFIhas had an enormous impact: new building has gone onat a brisk pace; many laboratories have undergonemajor facelifts and facilities upgrades. Again a significant number of biomaterials researchers have benefitedfrom the CFI.The CRC were designed to contribute to facultyrenewal in the face of a wave of retirements in the 1990sand beyond and declining university budgets (a provincial responsibility under the Canadian system). Fundingwas provided for 2000 positions allocated to eachuniversity on the basis of its historical researchperformance. Clearly this has given a tremendous boostto the Canadian academic enterprise and to research inparticular. A number of these Chairs have been awardedto individuals working in biomaterials and tissueengineering.At the provincial level, research funding has also beensignificant. In Ontario, the Centres of Excellence wereintroduced in the late 1980s, among them the OntarioCentre for Materials Research (OCMR). This Centrehad a number of thrust areas including biomaterials,7211and provided significant funding for research projectsacross the spectrum from blood-contacting to dentalbiomaterials. It also made a major contribution to theestablishment of the Centre for Biomaterials at theUniversity of Toronto, providing funding, for example,for an XPS facility dedicated to biomaterials. Morerecently the Ontario Centres have been restructured.Biomaterials is now funded through Materials andManufacturing Ontario, with an increased emphasison translation and commercialization aspects generally.In Québec, biomedical research has been fundedthrough the Fonds de la Recherche en Santé du Québec(FRSQ), the Fonds pour la Formation de Chercheurs etl’Aide à la Recherche (FCAR), and its successor theFonds Québecois de la Recherche sur la Nature et lesTechnologies. In Alberta, the Alberta Heritage Foundation for Medical Research (AHFMR) has providedsome support for biomaterials research, and the recentlyformed Alberta Ingenuity Fund (AIF) has madesignificant investments in several emerging researchlaboratories associated with biomaterials, particularlyat the University of Calgary.Non-government research foundations, for examplethe national and provincial Heart and Stroke Foundations, have also contributed significantly to the fundingof the Canadian biomaterials research effort.4. The ‘‘players’’ and their contributionsIn this section, I have attempted to highlight thecontributions of various laboratories and investigatorsacross the country. I believe I have included most of thesignificant Canadian work over the past 40 years.Inevitably, however, mainly through ignorance, I willhave omitted work that deserves to be discussed. To theresearchers whose work falls into this category I offermy apologies.The text is arranged chronologically so that the workof researchers is discussed based on the decade in whichthey became active and/or in which their work began tohave impact. This is not the only way in which thematerial could be organized, but it does give a sense ofthe development and growth of Canadian efforts overthe years. Growth has been continuous and at times, e.g.the past five or so years, extremely rapid. With theadvent of tissue engineering as a new major area ofapplication of biomaterials, it appears that such rapidgrowth will continue into the future.4.1. 1960s: the seed is sownThe first significant Canadian work was that ofDennis Smith in dental materials and Walter Zingg incardiovascular materials. These two individuals shouldbe given credit not only as the first researchers in

ARTICLE IN PRESS7212J.L. Brash / Biomaterials 26 (2005) 7209–7220Canada to devote their careers to biomaterials, but alsoas pioneer builders and promoters of the biomaterialsenterprise in this country.Dennis Smith may fairly be described as the ‘‘father’’of biomaterials in Canada. His achievements areremarkable in several respects: scientifically, administratively, and in terms of service to the broaderbiomaterials community. After a successful career inthe UK, where he established the Department of DentalMaterials at the University of Manchester, he came tothe University of Toronto in 1969. There he set up theBiomaterials Department in the School of Dentistry.The Centre for Biomaterials was established some yearslater (1986) with strong links to many other Departments and to other Canadian Universities. As mentioned above, Dennis was the prime mover inestablishing the Canadian Biomaterials Society in1971. He retired formally in 1993 but remains active inresearch and other aspects of biomaterials work; forexample he is currently the Chair of ISO/TC106Dentistry (1999–2005).In research Dennis has had a huge impact with workin a number of areas, but above all, in dentalbiomaterials. He has pointed out that biomaterials aswe now know it owes much to the study of dentalmaterials which predated the broader biomaterials field.Among his achievements in the dental area are theinvention of the polyacrylate adhesive cements [1] andcontributions to the development of other adhesivedental materials [2]. In orthopaedics, he was responsiblewith John Charnley for the development of acrylic bonecement in the period 1957–1973 [3]. In this connection itshould be noted that the Proceedings of a Symposiumon Bone Cement, which has an account of the genesis ofbone cement, was published recently in OrthopaedicClinics of North America [4]. Most recently he has beeninvolved in a series of pioneering studies (with WalterPeters) on the influence of silicon and silicones on theclinical response to breast implants (1992–2001) [5].Walter Zingg, who had a long career at the Universityof Toronto and the Toronto Hospital for Sick Children,was the first Canadian practitioner (and booster) ofbiomaterials to come from a medical background.Walter was a surgeon by original training and hadinterests in hypothermia associated with heart–lungbypass. The first Zingg paper with a clear biomaterialsconnection was published in 1960 [6]. In this paper, hereported on the use of a commercial polyurethane forthe repair of bone fractures and commented on its lackof tissue reaction, a finding that was to be repeatedmany times in the years that followed. Walter alsoworked briefly on blood rheology [7].These interests led him to collaborations withengineering colleagues Charles Ward and WilhelmNeumann, and somewhat later with Michael Albisserand Michael Sefton. With Ward he worked on the roleof gas microbubbles on blood–material interactions witha clear connection to blood oxygenators [8]. WithNeumann over a period of about 15 years (1975–1990)he worked on surface thermodynamics approaches tothe study of blood–material interactions [9,10]. Thiswork was highly productive and served to focusattention on the importance of fundamental surfacescience and the use of simple measurements such ascontact angle.Walter’s collaboration with Sefton was also productive and covered the range from cardiovascular materials [11,12] to insulin pumps [13]. Walter’s contributionswere mainly in the development of animal models forevaluation of materials and devices. The A–V shunt dogmodel for blood compatibility testing, for example, hasgenerated much valuable information [11].4.2. 1970s: the plant takes rootIn the 1970s the level of activity increased significantlywith the arrival on the scene of Robert Guidoin(Université Laval), Derek Jones (Dalhousie University),Robert Pilliar (University of Toronto), Michael Sefton(University of Toronto), and John Brash (McMasterUniversity). Guidoin, Sefton, and Brash were interestedmainly in blood contacting materials and have continued to work in this area up to the present time. Pilliarhas made seminal contributions to orthopaedic biomaterials and devices, and Jones in the dental biomaterialsarea.John Brash joined McMaster University in 1972. Overthe years his laboratory has worked extensively on thefundamentals of blood–material interactions [14–17].They were among the first to point out the primordialnature of protein adsorption in all biomaterials applications and to make the connection between proteinadsorption and cell adhesion. They have also contributed significantly in the development of biomedicalpolyurethanes [18,19]. More recently they have workedon anti-fouling surfaces based predominantly on polyethylene oxide. They have advanced the idea ofachieving biocompatibility by combining suppressionof non-specific interactions and promotion of specificinteractions [20]. An example of the latter is thepromotion of endogenous plasminogen and t-PAadsorption from blood to potentiate the dissolution ofnascent clots [21].Michael Sefton has worked on biomaterials andrelated areas at the University of Toronto since 1974.His laboratory has produced a large body of work onthe development and understanding of heparinizedmaterials for blood contact [22,23]. Other blood-relatedwork includes the development of a chronic animalmodel for the evaluation of blood compatibility [11],extensive studies of complement activation which drewattention to the role of the classical pathway in

ARTICLE IN PRESSJ.L. Brash / Biomaterials 26 (2005) 7209–7220biomaterial-complement interactions, and adaptation offluorescent activated flow cytometry to study plateletand leukocyte activation [24].More recently the Sefton laboratory has madepioneering contributions to tissue engineering, with afocus on cell encapsulation using copolymers of HEMAand MMA among others [25]. They were one of the firstlaboratories to succeed in encapsulating live cells whilemaintaining cell viability. A variety of cell types havebeen encapsulated [26] and the products of this work areexpected to have a significant impact in areas such asdiabetes, Parkinson’s disease, and gene therapy.Since the mid-1970s at l’Université Laval in QuebecCity, Robert Guidoin’s laboratory has contributedextensively to knowledge of the behaviour of vascularimplant devices clinically through retrieval studies [27].They have also worked on the development ofmembrane oxygenators [28], and blood conduits ofvarious kinds including polyester grafts impregnatedwith bioerodible scaffolds as an alternative to preclotting [29], chemically treated biological grafts (humanumbilical cord vein) [30], and cryopreservation of veinsas arterial conduits (homografts) [31]. Other contributions have been in the breast implant area, e.g. theidentification of hopeite and parascholzite in themineralization of these implants [32], and more recentlythe development of the concept of virtual biopsies fornon-metallic implants by means of MRI [33].Robert Pilliar is widely recognized as a pioneer inbiomaterials for orthopaedic applications, working sincethe early 1970s at the Ontario Research Foundation andlater at the University of Toronto. He was responsiblefor the development of orthopaedic implants (hipreplacements primarily in the early days) designed withporous coatings that gave structures suitable for boneingrowth resulting in three-dimensional interlock ofimplant with bone [34]. This work resulted in a patentthat subsequently was licensed by a major orthopaedicimplant manufacturer. Later studies drew attention tothe loss of bone due to stress shielding in well-fixedimplants and to the importance of initial implantstability and lack of relative movement at the implantbone interface to allow bone ingrowth rather thanfibrous tissue attachment [35–37]. In the 1980s, theporous coating concept was extended to dental implants[38]. This work resulted in the development of a poroussurfaced Ti alloy implant system that was licensed toInnova Corp., later Innova LifeSciences that hasmanufactured and marketed the novel implant worldwide. Most recently novel porous biodegradable inorganic structures suitable for tissue engineering applications in joint replacement have been developed [39].These structures rely on soft tissue ingrowth (articularcartilage, nucleus pulposus) into porous bone-interfacing structures that can then be stabilized in vivothrough bone ingrowth into the bone interfacing7213portions of the implants. It is of interest also to notethat in the 1980s, studies on the use of porous-coatedsurfaces demonstrated their effectiveness in cardiacpacing devices and in the metallic (titanium) components of LVADs.Derek Jones is one of the pioneers worldwide indental biomaterials. He arrived at Dalhousie Universityfrom England in 1975. There he set up a Division ofBiomaterials and an active research laboratory. Hisinitial research was in the area of silica chemistry, thecharacterization of ceramics, and the diffusion ofplasticizers in polymer systems [40,41]. He also workedextensively on the synthesis of ceramic and glassmaterials including oxide glasses (poly component ionleachable glasses) by wet chemistry [42], and studies ofthe influence of fillers on the mechanical properties ofpolymer–ceramic/glass composite materials [43]. Anotable aspect of Derek’s work was his defence of thescientific principles associated with the use of dentalamalgam as a restorative material [44].Paul Wang was also among the early Canadianbiomaterials researchers. At the University of Torontohe worked on tissue adhesives and showed thatadhesives based on synthetic polymers can adhere wellto wet biological tissues after priming with benzoylchloride [45]. In later work he developed a sustainedrelease insulin implant [46] which was commercialized(trademarked Linplant) and has been used primarily intreating diabetic research animals.The work of Irwin Feuerstein (McMaster University)on blood cell–surface interactions, particularly plateletinteractions, was initiated in the 1970s. His approach toblood–surface interactions emphasized the role ofhaemodynamics as well as the interface itself [47].Considerable insights were gained with the introductionof videomicroscopy methods for the visualization ofplatelet interactions in whole blood [48,49]. Later workwas concerned with the morphology of adherentplatelets, and with the interactions of platelets andproteins at surfaces [50].4.3. 1980s: the plant flourishesThis decade saw expansion of activity in theorthopaedic and cardiovascular areas as well as thebeginnings of tissue engineering (though the latter termdid not come into general use until the 1990s). AmongCanadian investigators beginning their work in thisperiod were John Davies (University of Toronto),Michael Lee (University of Toronto), Don Brunette(University of British Columbia), Charles Doillon(l’Université Laval), Francois Auger (l’Université Laval), Lucie Germain (l’Université Laval), and DennisBobyn (McGill University).Initially in the UK and since the late 1980s at theUniversity of Toronto, John Davies has made seminal

ARTICLE IN PRESS7214J.L. Brash / Biomaterials 26 (2005) 7209–7220contributions to the understanding of interactions at thebone–material interface and to bone tissue engineering[51]. He is responsible for two key publications in thisarea: The Bone–Biomaterial Interface, published in 1991[52], and Bone Engineering, published in 2000 [53].Michael Lee, first at the University of Toronto andmore recently at Dalhousie University in Halifax, NovaScotia, has pursued work on the mechanical propertiesof vascular tissue and its components, with importantimplications for the development of bioprosthetic heartvalves and blood vessels. Lee’s laboratory showed thathigh strain rate testing is necessary to accuratelydescribe the viscoelastic function of cardiac tissues suchas the pericardium and heart valve leaflets [54]. Theyhave also worked extensively on collagen crosslinking asit relates to bioprosthesis processing, including studiesof novel tissue processing techniques and new methodsfor mechanical and thermomechanical testing [55,56].Recently they have demonstrated synergies betweenfatigue damage, dynamic loading, and enzymolysis inthe failure of bioprosthetic vascular tissue [57].Charles Doillon, with formal training both as aphysician and a researcher, is one of the first Canadianworkers to have had an impact in tissue engineering.Working in Quebec City at l’Université Laval, his majorcontributions are in wound healing and tissue replacement by collagen-based materials (e.g., wound dressings), and more recently, in tissue engineered corneaand the problem of angiogenesis in biomaterials. Animportant idea was to combine growth factors withreconstituted extracellular matrices (ECM), thus mimicking more closely the natural tissue environment. Itwas found that fibrin is successful in maintaining growthfactor activity in vitro and in vivo and is a suitablematrix in collagen-based materials. This idea wasapplied to endothelial cell linings and wound scaffoldsusing autologous fibrin [58]. In collaboration with MayGriffith (University of Ottawa), the Doillon laboratoryalso contributed to the design of an artificial cornea/sclera by developing two interpenetrating 3-D systems[59]. The most recent work has been devoted to theproblem of angiogenesis and vasculogenesis, with theobjective of enhancing blood supply in tissue engineeredscaffolds and wound tissues [60,61].Franc- ois Auger, also at l’Université Laval, is amongthe foremost of the pioneers in tissue engineering,particularly in the areas of skin and vascular applications. As a physician researcher he established theLaboratoire d’Organogénèse Expérimentale (LOEX) atLaval in the mid-1980s. Cell biologist Lucie Germainjoined the group soon after. She holds the CanadaResearch Chair in Stem Cell and Tissue Engineering.These two investigators have developed a new andoriginal approach to tissue engineering, viz. the selfassembly method [62]. This method uses the intrinsiccapacity of cells to synthesize and organize theirextracellular matrix as a ‘‘physiological biomaterial’’(without any synthetic component), which then selfassembles into organized tissue substitutes. Using thisapproach they have been responsible for several keydevelopments in tissue engineering using only humancells: the first totally biological vascular substitute [63],the first capillary system in an organ substitute [63],and the first corneal substitute from primary culturesof normal cells [64,65]. They have also published onskin stem cells [66], and an in vitro model of woundhealing [67].Cell biologist Don Brunette and his group, working atthe University of British Columbia, have pioneered anapproach that draws attention to the effects of surfacetopography on cell behaviour. They have adaptedtechniques developed for the production of microelectronics to fabricate precisely controlled surfaces for thestudy of cell–surface behavio

tion (CFI) and the CRCs.The CFI was set up in the late 1990s to facilitate the renewal of research infrastructure in Canada, targeting mainly the universities and hospitals.Infrastructure includes facilities, equipment, building renovations, and even new buildings.The CFI has had an enormous impact: new building has gone on