Biocompatibility remains the central theme for biomaterials applications in medicine. It is generally accepted that this term means not only absence of a cytotoxic effect but also positive effects in the sense of biofunctionality, i.e. promotion of biological processes which further the intended aim of the application of a biomaterial. The national and international standards for testing regimes represent a lowest common denominator for such applications and do not necessarily ensure that optimal function will be achieved. The authors' thesis is that biocompatibility testing has scope for extensive development with respect to biofunctionality. The present paper reviews current trends in the in vitro aspects of biocompatibility testing. As well as a critical appraisal of the recent literature, future trends are also stressed, which the authors regard as essential for a meaningful integration of a modern biological approach into new developments in the material sciences. These include the application of modern techniques of cell and molecular biology, the concepts of tissue remodelling, hybrid organ development and encapsulated cell technology.
WilliamsD. F.Progress in Biomedical Engineering, Definitions in Biomaterials, Vol. 4, 1987, pp. 54 (Elsevier, Amsterdam).
2.
KirkpatrickC. J.MittermayerCh.Theoretical and practical aspects of testing potential biomaterials in-vitro. J. Mater. Sci., Mater. Medicine, 1990, 1, 9–13.
3.
KirkpatrickC. J.DekkerA.Quantitative evaluation of cell interaction with biomaterials in-vitro. Adv. Biomater., 1992, 10, 31–41.
4.
KirkpatrickC. J.A critical view of current and proposed methodologies for biocompatibility testing: Cytotoxicity in-vitro. Regulatory Affairs, 1992, 4, 13–32.
5.
DekkerA.PanfilC.ValdorM.PennartzG.RichterH.MittermayerCh.KirkpatrickC. J.Quantitative methods for in vitro cytotoxicity testing of biomaterials. Cells and Mater., 1994, 4, 101–112.
6.
CliffordC. J.DownesS.A comparative study of the use of colorimetric assays in the assessment of biocompatibility. J. Mater. Sci., Mater. Medicine, 1996, 7, 637–643.
7.
MacnairR.RodgersE. H.MacdonaldC.WykmanA.GoldieI.GrantM. H.The response of primary rat and human osteoblasts and an immortalized rat osteoblast cell line to orthopaedic materials: Comparative sensitivity of several toxicity indices. J. Mater. Sci., Mater. Medicine, 1997, 8, 105–111.
8.
GratznerH. G.Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication. Science, 1982, 218, 474–475.
9.
DuvalJ. L.Warocquier-CléroutR.Sigot-LuizardM. F.Comparative assessment of the cytotoxicity of various substrates in organ culture and cell culture: A scanning electron microscopy study. Cells and Mater., 1992, 2, 179–192.
10.
Warocquier-CléroutR.Hachom-NitcheuG. C.Sigot-LuizardM. F.Reliability of human fresh and frozen gingiva explant culture in assessing dental materials cyto-compatibility. Cells and Mater., 1995, 5, 1–14.
11.
AmesB. N.DurstanW. E.YamasakiE.LeeF. D.Carcinogens are mutagens; a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl Acad. Sci. USA, 1975, 70, 2281–2285.
12.
KirkpatrickC. J.WagnerM.KöhlerH.BittingerF.OttoM.KleinC. L.The cell and molecular biological approach to biomaterial research: A perspective. J. Mater. Sci., Mater. Medicines, 1997, 8, 131–141.
13.
PurchaseI. F. H.Current knowledge of mechanisms of carcinogenicity: Genotoxins versus non-genotoxins. Human and Expl Toxicol., 1994, 13, 17–28.
14.
HarrisC. C.p53: At the crossroads of molecular carcinogenesis and risk assessment. Science, 1993, 262, 1980–1981.
15.
SmithM. L.FornaceA. J.Jr.The two faces of tumor suppressor p53. Am. J. Pathol., 1996, 148, 1019–1022.
16.
KleinC. L.KoehlerH.KirkpatrickC. J.Increased adhesion and activation of polymorphonuclear neutrophil granulocytes to endothelial cells under heavy metal exposure in-vitro. Pathobiology, 1994, 62, 90–98.
17.
KirkpatrickC. J.BittingerF.KleinC. L.DekkerA.Adhesion of human mesothelial and endothelial cells to vascular prostheses. Colloids and Surf., B: Biointerfaces, 1994, 2, 251–263.
18.
ClarkP.ConnollyP.CurtisA. S. G.DowJ. A.T.WilkinsonC. D. W.Topographical control of cell behaviour: II. Multiple grooved substrata. Development, 1990, 198, 635–644.
19.
MeyleJ.GültigK.BrichM.HämmerleH.NischW.Contact guidance of fibroblasts on biomaterial surfaces. J. Mater. Sci., Mater. Medicine, 1994, 5, 463–466.
20.
den BraberE. T.de RuijterJ.E.GinselL. A.von RecumA. F.JansenJ. A.Quantitative analysis of fibroblast morphology on microgrooved surfaces with various groove and ridge dimensions. Biomaterials, 1996, 17, 2037–2044.
21.
WanH.WilliamsR. L.DohertyP. J.WilliamsD. F.A study of cell behaviour on the surfaces of multifilament materials. J. Mater. Sci., Mater. Medicine, 1997, 8, 45–51.
22.
RichterE.FuhrG.MüllerT.ShirleyS.RogaschewskiS.ReimerK.DellC.Growth of anchorage-dependent mammalian cells on microstructures and microperforated silicon membranes. J. Mater. Sci., Mater. Medicine, 1996, 7, 85–97.
23.
KirkpatrickC. J.OtterbachT.AnderheidenD.SchieferJ.RichterH.HöckerH.MittermayerC.DekkerA.Quantitative scanning electron microscopy (SEM) to study the adhesion and spreading of human endothelial cells to surface-modified poly(carbonate urethane)s. Cells and Mater., 1992, 2, 169–177.
24.
LabatB.ChamsonA.FreyJ.Effects of gammaalumina and hydroxyapatite coatings on the growth and metabolism of human osteoblasts. J. Mater. Sci., Mater. Medicine, 1995, 29, 1397–1401.
25.
GranchiD.SteaS.CiapettiG.CavedagnaD.SteaS.PizzoferratoA.Endodontic cements induce alterations in the cell cycle of in vitro cultured obsteoblasts. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 1995, 79, 359–366.
26.
KirkpatrickC. J.Mueller-SchulteD.RoyéM.HollwegG.GossenC.RichterH.MittermayerC.Surface modification of polymers to permit endothelial cell growth. Cells and Mater., 1991, 2, 93–108.
27.
DoyleV.PearsonR.LeeD.WolowaczS.McTaggartS.An investigation of the growth of human dermal fibroblasts on poly-L-lactic acid in-vitro. J. Mater. Sci., Mater. Medicine, 1996, 7, 381–385.
28.
KirkpatrickC. J.MohrW.HaferkampO.The effects of nickel ions on articular chondrocyte growth in monolayer culture. Res. Expl Medicine, 1982, 181, 259–264.
29.
YangJ.ShanbhagA.LilienJ.BlackJ.Human neutrophil response to short-term exposure to F-75 cobalt based alloy. J. Mater. Sci., Mater. Medicine, 1990, 26, 1217–1230.
30.
FukuchiN.AkaoM.SatoA.Effect of hydroxyapatite microcrystals on macrophage activity. Biomed. Mater. Engng, 1995, 5, 219–231.
31.
CharissouxJ. L.NajidA.MoreauJ. C.SettonD.RigaudM.Development of in vitro biocompatibility assays for surgical material. Clin. Orthop., 1996, 326, 259–269.
32.
ISO-10993–4 Biological evaluation of medical devices, Part 4: Selection of tests for interactions with blood, 1992, pp. 3, Subsection 6.1.6 (International Standardization Organization, Geneva).
33.
KleinC. L.OttoM.KoehlerH.van KootenT. G.Sliwa-TomczokW.TomczokJ.KirkpatrickC. J.Adhesion of platelets and neutrophilic granulocytes on glass and FEP teflon during exposure to shear stress in a parallel plate flow chamber system. Colloids and Surf., B: Biointerfaces, 1994, 3, 229–239.
34.
OttoM.KleinC. L.KöhlerH.WagnerM.RöhrigO.KirkpatrickC. J.Dynamic blood cell contact with biomaterials: Validation of a flow chamber system according to international standards. J. Mater. Sci., Mater. Medicine, 1997, 8, 119–129.
35.
BittingerF.MühlbayerS.SalihV.GrauM.RichterH. A.KleinC. L.KirkpatrickC. J.Experimental studies on the suitability of human mesothelial cells for seeding vascular prostheses: Shear stress resistance in-vitro. J. Mater. Sci., Mater. Medicine, 1996, 7, 543–550.
36.
ThoumineO.NeremR. M.GirardP. R.Changes in organization and composition of the extracellular matrix underlying cultured endothelial cells exposed to laminar steady shear stress. Lab. Invest., 1995, 73, 565–576.
KleinC. L.NiederP.WagnerM.KöhlerH.BittingerF.LewisJ. C.KirkpatrickC. J.The role of metal corrosion in inflammatory processes: Induction of adhesion molecules by heavy metal ions. J. Mater. Sci., Mater. Medicine, 1994, 5, 798–807.
40.
CenniE.GranchiD.ArciolaC. R.CiapettiG.SavarinoL.SteaS.CavedagnaD.Di LeoA.PizzoferratoA.Adhesive protein expression on endothelial cells after contact in vitro with polyethylene terephthalate coated with pyrolytic carbon. Biomaterials, 1995, 16, 1223–1227.
41.
CohenM. C.CohenS.Cytokine function: A study in biologic diversity. Am. J. Clin. Pathol., 1996, 105, 589–598.
42.
LilesW. C.van VoorhisW. C.Review: Nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J. Infect. Dis., 1995, 172, 1573–1580.
43.
MiossecP.Pro- and antiinflammatory cytokine balance in rheumatoid arthritis. Clin. Expl Rheumatol., 1995, 13 (Supplement 12), S13–S16.
44.
IsomakiP.LuukkainenR.SaarioR.ToivanenP.PunnonenJ.Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthr. Rheum., 1996, 39, 386–395.
45.
MillerK. M.AndersonJ. M.Human monocyte/macrophage activation and interleukin 1 generation by biomedical polymers. J. Biomed. Mater. Res., 1988, 22, 713–731.
46.
CardonaM. A.SimmonsR. L.KaplanS. S.TNF and IL-1 generation by human monocytes in response to biomaterials. J. Biomed. Mater. Res., 1992, 26, 851–859.
47.
BernatchezS. F.ParksP. J.GibbonsD. F.Interaction of macrophages with fibrous materials in-vitro. Biomaterials, 1996, 17, 2077–2086.
48.
CenniE.GranchiD.CiapettiG.VerriE.CavedagnaD.GamberiniS.Di LeoA.PizzoferratoA.Cytokine production and adhesive protein expression by endothelial cells after contact with polyethylene terephthalate. Biomaterials, 1996, 17, 2071–2076.
49.
JohnsonL. N.NobleM. E.M.OwenD. J.Active and inactive protein kinases: Structural basis for regulation. Cell, 1996, 85, 149–158.
50.
TonksN. K.NeelB. G.From form to function: Signalling by protein tyrosine phosphatases. Cell, 1996, 87, 365–368.
51.
KornbergL. J.EarpH. S.TurnerC. E.ProckopC.JulianoR. L.Signal transduction by integrins: Increased protein tyrosine phosphorylation caused by clustering of β1 integrins. Proc. Natl Acad. Sci. USA, 1991, 88, 8392–8396.
52.
GiancottiF. G.Signal transduction by the α6β4 integrin: Charting the path between laminin binding and nuclear events. J. Cell Sci., 1996, 109, 1165–1172.
53.
CaryL. A.ChangJ. F.GuanJ.-L.Stimulation of cell migration by overexpression of focal adhesion kinase and its association with src and fyn. J. Cell Sci., 1996, 109, 1787–1794.
54.
GrothT.AltankovG.Studies on cell-biomaterial interaction: Role of tyrosine phosphorylation during fibro-blast spreading on surfaces varying in wettability. Biomaterials, 1996, 17, 1227–1234.
55.
ZhangZ.VuoriK.WangH.-G.ReedJ. C.RuoslahtiE.Integrin activation by R-ras. Cell, 1996, 85, 61–69.
56.
Chrzanowska-WodnickaM.BurridgeK.Rho-stimulated contractility drives the formation of stress fibres and focal adhesions. J. Cell. Biol., 1996, 133, 1403–1415.
KoyamaH.RainesE. W.BornfeldtK. E.RobertsJ.M.RossR.Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of cdk2 inhibitors. Cell, 1996, 87, 1069–1078.
61.
FolkmanJ.ShingY.Angiogenesis. J. Biol. Chem., 1992, 267, 10931–10934.
62.
KochA. E.PolveriniP. J.KunkelS. L.HarlowL. A.DiPietroL. A.ElnerV. M.ElnerS. G.StrieterR.Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science, 1992, 258, 1798–1801.
63.
MontesanoR.KumarS.OrciL.PepperM. S.Synergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in-vitro. Lab. Invest., 1996, 75, 249–262.
64.
PolveriniP. J.Cellular adhesion molecules. Newly identified mediators of angiogenesis. Am. J. Pathol., 1996, 148, 1023–1029.
65.
DikeL. E.IngherD. E.Integrin-dependent induction of early growth response genes in capillary endothelial cells. J. Cell Sci., 1996, 109, 2855–2863.
66.
O'ReillyM. A.HolmgrenL.ShingY.ChenC.RosenthalR. A.MosesM.LaneW. S.CaoY.SageE. H.FolkmanJ.Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma. Cell, 1994, 79, 315–328.
67.
DiPietroL. A.PolveriniP. J.Angiogenic macrophages produce the angiogenic inhibitor thrombospondin 1. Am. J. Pathol., 1993, 143, 678–684.
68.
MaioneT. E.GrayG. S.PetroJ.HuntA. J.DonnerA. L.BauerS. I.CarsonH. F.SharpeR. J.Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science, 1990, 247, 77–79.
69.
EzekowitzR. A.MullikenJ. B.FolkmanJ.Interferon-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Medicine, 1992, 326, 1456–1463.
70.
AltankovG.GrinnellF.GrothT.Studies on the biocompatibility of materials: Fibroblast reorganization of substratum-bound fibronectin on surfaces varying in wettability. J. Biomed. Mater. Res., 1996, 30, 385–391.
71.
HembryR. M.BaggaM. R.ReynoldsJ. J.HamblenD. L.Stromelysin, gelatinase A and TIMP-1 in prosthetic interface tissue: A role for macrophages in tissue remodelling. Histopathology, 1995, 27, 149–159.
72.
YokohamaY.MatsumotoT.HirakawaM.KurokiY.FujimotoN.ImaiK.OkadaY.Production of matrix metalloproteinases at the bone-implant interface in loose total hip replacements. Lab. Invest., 1995, 72, 899–911.
BerthodF.HayekD.DamourO.CollombelC.Collagen synthesis by fibroblasts cultured within a collagen sponge. Biomaterials, 1993, 14, 749–754.
76.
Von SchroederH. P.KwanM.AmielD.CouttsR. D.The use of polylactic acid matrix and periosteal grafts for the reconstruction of rabbit knee articular defects. J. Biomed. Mater. Res., 1991, 25, 329–339.
DarquyS.ReachG.Immunoisolation of pancreatic β cells by micro-encapsulation. Diabetologia, 1985, 28, 776–780.
79.
SutherlandD. E. R.GruessnerR. W.G.GoresP. F.Pancreas and islet transplantation. Transplant Rev., 1994, 8, 185–206.
80.
LanzaR. P.BeyerA. M.StarukJ. E.ChickW. L.Biohybrid artificial pancreas: Long-term function of discordant islet xenografts in streptozotocin diabetic rats. Transplantation, 1993, 56, 1067–1072.
81.
MakiT.OtsuI.O'NeillJ. J.DunleavyK.MullonC. J. P.SolomonB. A.MonacoA. P.Treatment of diabetes by xenogeneic islets without immunosuppression. Diabetes, 1996, 45, 342–347.
82.
LanzaR. P.EckerD.KühtreiberW. M.StarukJ. E.MarshJ.ChickW. L.A simple method for transplanting discordant islets into rats using alginate gel spheres. Transplantation, 1995, 59, 1486–1487.
83.
YangM. D.VacantiJ. P.IngberD. E.Hollow fibres for hepatocyte encapsulation and transplantation: Studies of survival and function in rats. Cell Transplantation, 1994, 3, 373–385.
ChangP. L.ShenN.WestcottA. J.Delivery of recombinant gene products with microencapsulated cellsin vivo. Hum. Gene Ther., 1993, 4, 433–440.
86.
CenniE.CiapettiG.CervllatiM.CavedagnaD.FalsoneG.GamberiniS.PizzoferratoA.Activation of the plasma coagulation system induced by some biomaterials. J. Biomed. Mater. Res., 1996, 31, 145–148.
87.
MollnesT. E.RiesenfeldJ.GarredP.NordstromE.HogasenK.FosseE.GotzeO.HarboeM.A new model for evaluation of biocompatibility: Combined determination of neoepitopes in blood and on artificial surfaces demonstrates reduced complement activation by immobilization of heparin. Artif. Organs, 1995, 19, 909–917.
