The development of reliable experimental models for the clinical use of biomaterials and in predicting implant success or failure is becoming increasingly important in attaining adequate health and safety conditions. This paper summarizes the main benefits and limits of in vitro and in vivo biological tests taking into account general pathophysiological considerations regarding the skeletal tissue. Current findings demonstrate the need to adopt both in vitro and in vivo methodologies and to improve test quality with particular attention to the ethical issues associated with in vivo experiments.
Lavos-ValeretoI.C., WolynecS., DeboniM.C.Z., KönigB.Jr.. In vitro and in vivo biocompatibility testing of Ti-6Al-7Nb alloy with and without Plasma-Sprayed Hydroxyapatite Coating. J Biomed Mater Res2001; 58: 727–33.
2.
AnselmeK.Osteoblast adhesion on biomaterials. Biomaterials2000; 21: 667–81.
3.
OlivaA., Della RagioneF., SalernoA.. Biocompatibility studies on glass ionomeric cements by primary cultures of human osteoblasts. Biomaterials1996; 17: 1351–6.
4.
RahnB.A.Bone healing: histological and physiological concepts. In: Sumner-SmithG. ed. Bone in clinical orthopaedics.Stuttgard: Thieme2002; 287–325.
5.
KienapfelH., SpreyC., WilkeA., GrissP.Implant fixation by bone ingrowth. J Arthroplasty1999; 14: 355–68.
6.
SumnerD.R., TurnerT.M., UrbanR.M.Animal models of bone ingrowth and joint replacement. In: AnY.H., FriedmanR.J. eds. Animal models in orthopaedic research.Boca Raton: CRC Press1999; 407–25.
7.
DaviesJ.E., HosseiniM.M.Histodynamics of endosseous wound healing. In: Bone Engineering.Toronto: Rainbow Graphic and Printing Ltd1999; 1–14.
8.
BarnesG.L., KostenuikP.J., GerstenfeldL.C., EinhornT.A.Growth factor regulation of fracture repair. J Bone Miner Res1999; 14: 1805–15.
9.
MauzinO., SoballeK., BechtoldJ.E.Loading improves anchorage of hydroxyapatite implants more than titanium implants. J Biomed Mater Res2001; 58: 61–8.
10.
SimmonsC.A., ValiquetteN., PilliarR.M.Osseointegration of sintered porous-surfaced and plasma spray-coated implants: an animal model study of early postimplantation healing response and mechanical stability. J Biomed Mater Res1999; 47: 127–38.
11.
LiJ.K., ChangW.H., LinJ.C., RuaanR.C., LiuH.C., SunJ.S.Cytokine release from osteoblasts in response to ultrasound stimulation. Biomaterials2003; 24: 237–85.
12.
WeytsF.A., BosmansB., NiesingR., LeeuwenJ.P., WeinansH.Mechanical control of human osteoblast apoptosis and proliferation in relation to differentiation. Calcif Tissue Int2003; 72: 505–12.
13.
MuschlerG.F., LaneM.J.Orthopaedic Surgery. In: HabalM.B., and ReddiH.A. eds. Bone grafts and bone substitutes.Philadelphia: W.B. Saunders1992; 375–347.
14.
PuleoD.A., NanciA.Understanding and controlling the bone-implant interface. Biomaterials1999; 20: 2311–21.
15.
RoccaM., OrientiL., SteaS., MoroniA., FiniM., GiardinoR.Comparison among three different biocoatings for orthopedic prostheses. An experimental animal study. Int J Artif Organs1998; 21: 553–8.
16.
GiavaresiG., FiniM., ChiesaR.. Osseointegration of sandblasted or anodized hydrothermally-treated titanium implants: mechanical, histomorphometrical and bone hardness measurements. Int J Artif Organs2002; 25: 806–13.
17.
BelangerM.C., MaroisY.Hemocompatibility, biocompatibility, inflammatory and in vivo studies of primary reference materials low-density polyethylene and poly-dimethylsiloxane: a review. J Biomed Mater Res2001; 58: 467–77.
18.
BotchweyE.A., PollackS.R., LevineE.M., LaurencinC.T.Bone tissue engineering in a rotating bioreactor using a microcarrier matrix system. J Biomed Mater Res2001; 55: 242–53.
19.
BischoffU.W., FreemanM.A.R., SmithD., TukeM.A., GregsonP.J.Wear induced by motion between bone and titanium or cobalt-chrome alloys. J Bone Joint Surg1994; 76-B: 713–6.
20.
McDonaldD.J., EnnekingW.F., SundaramM.Metal-associated angiosarcoma of bone: report of two cases and review of the literature. Clin Orthop2002; 396: 206–14.
21.
SwiontkowskiM.F., AgelJ., Schwappach, McNairP., WelchM.Cutaneous metal sensitivity in patients with orthopaedic injuries. J Orthop Trauma2001; 2: 86–9.
22.
JacobsJ.J., GilbertJ.L., UrbanR.M.Corrosion of metal orthopaedic implants. J Bone Joint Surg1998; 80A: 269–82.
23.
LugowskiS.J., SmithD.C., McHughA.D., Van LoonC.Release of metal ions from dental implant materials in vivo: determination of Al, Co, Cr, Mo, Ni, V, and Ti in organ tissue. J Biomed Mater Res1991; 25: 1443–58.
24.
LalorP.A., RevellP.A., GrayA.B., WrightS., RailtonG.T., FreemanM.A.R.Sensitivity to titanium. A cause of implant failure. J Bone Joint Surg Br1991; 73: 25–8.
25.
MichelR., NolteM., ReichM., LoerF.Systemic effects of implanted prostheses made of cobalt-chromium alloys. Arch Orthop Trauma Surg1991; 11: 61–74.
26.
Brayda BrunoM., FiniM., PieriniG., GiavaresiG., RoccaM., GiardinoR.Evaluation of systemic metal diffusion after spinal pedicular fixation with titanium alloy and stainless steel system a 36-month experimental study in sheep. Int J Artif Organs2001; 24: 41–9.
27.
ShidaJ., TrindadeM.C., GoodmanS.B., SchurmanD.J., SmithR.L.Induction of interleukin-6 release in human osteoblast-like cells exposed to titanium particles in vitro. Calcif Tissue Int2000; 67: 151–5.
28.
TakeiH., PiolettiD.P., KwonS.Y., SungK.L.Combined effect of titanium particles and TNF-alpha on the production of IL-6 by osteoblast-like cells. J Biomed Mater Res2000; 52: 382–7.
29.
PiolettiD.P., TakeiH., KwonS.Y., WoodD., SungK.L.The cytotoxic effect of titanium particles phagocytosed by osteoblasts. J Biomed Mater Res1999; 46: 399–407.
30.
WangJ.Y., WicklundB.H., GustiloR.B., TsukayamaD.T.Prosthetic metals interfere with the functions of human osteoblast cells in vitro. Clin Orthop1997; 339: 216–26.
31.
KapanenA., KinnunenA., RyhanenJ., TuukkanenJ.TGF-beta1 secretion of ROS-17/2.8 cultures on NiTi implant material. Biomaterials2002; 23: 3341–6.
32.
WatahaJ.C., HanksC.T., SunZ.L.In vitro reaction of macrophages to metal ions from dental biomaterials. Dent Mater1995; 11: 239–45.
33.
MissrlisY.S., SpiliotisA.D.Assessment of techniques used in calculating cell-material interactions. Biomol Eng2002; 19: 287–94.
34.
AllenM., MyerB., RushtonN.In vitro and in vivo investigations into the biocompatibility of diamondlike carbon (DLC) coatings for orthopaedic applications. J Biomed Mater Res2001; 58: 319–28.
35.
TorricelliP., FiniM., GiavaresiG.. Comparative interspecies investigation on osteoblast cultures: data on cell viability and synthetic activity. Biomed Pharmacother2003; 57: 57–62.
36.
KurachiT., NagaoH., NaguraH., EnomotoS.Effect of a titanium surface on bone marrow-derived osteoblastic cell in vitro. Arch Oral Biol1997; 42: 465–68.
37.
GiardinoR., FiniM., GiavaresiG.Experimental surgery in the research of artificial organs. Int J Artif Organs1998; 21: 506–8.
38.
MartiniL., FiniM., GiavaresiG., GiardinoR.Sheep model in orthopedic research: a literature review. Comp Med2001; 51: 292–9.
39.
LopesM.A., SantosJ.D., MonteriroF.J.. Push-out testing and histological evaluation of glass reinforced hydroxyapatite composites implanted in the tibia of rabbits. J Biomed Mater Res2001; 54: 463–9.
40.
WatahaJ.C., O'Dell NorrisL., SinghB.B., GhaziM., WhitfordG.M., LockwoodP.E.Relating Nickel-induced tissue inflammation to Nickel release in vivo. J Biomed Mater Res2001; 58: 537–44.
41.
LohmanC.H., AndreacchioD., KosterG.. Tissue response and osteoinduction of human bone grafts. Arch Orthop Trauma Surg2001; 121: 583–90.
42.
LuX.J., GallurA., FlautreB.. Comparative study of tissue reactions to calcium phosphate ceramics among cancellous, cortical, and medullar bone in rabbits. J Biomed Mater Res1998; 42: 357–67.
43.
SumnerD.R., KienapfelH., GalanteJ.O.Metallic implants. In: HabalM.B., and ReddiH.A. eds. Bone grafts and bone substitutes.Philadelphia: W.B. Saunders1992; 252–62.
44.
VercaigneS., WolkeJ.G.C., NaertI., JansenJ.A.Histomorphometrical and mechanical evaluation of titanium plasma-spray-coated implants placed in the cortical bone of goats. J Biomed Mater Res1998; 41: 41–8.
45.
HofmannA.A., BloebaumR.D., BachusK.N.Progression of human bone ingrowth into porous-coated implants. Acta Orthop Scand1997; 68: 161–6.
46.
SevitS.Bone repair and fracture healing.New York: Churchill Livingstone Inc1981.
47.
KleinschmidtJ.C., HollingerJ.O.Animal models in bone research. In: HabalM.B., ReddiA.H. eds. Bone grafts and bone substitutes.Philadelphia: W.B. Saunders1992; 133–46.
48.
AnY.H., FriedmanR.J.Animal selections in orthopaedic research. In: AnY.H., FriedmanR.J. eds. Animal models in orthopaedic research.Boca Raton: CRC Press1999; 39–57.
49.
SarkarM.R., WatchterN., PatkaP., KinziL.First histological observation on the incorporation of a novel calcium phosphate bone substitute material in human cancellous bone. J Biomed Mater Res2001; 58: 329–34.
50.
SquireM.W., RicciL.J., BiziosR.Analysis of osteoblast mineral deposits on orthopaedic/dental implant metals. Biomaterials1996; 17: 725–33.
51.
OrlandiniS.Z., FormigliL., BenvenutiS.. Functional and structural interactions between osteoblastic and preosteoclastic cells in vitro. Cell Tissue Res1995; 281: 33–42.
52.
LoomerP.M., EllenR.P., TenenbaumH.C.Osteogenic and osteoclastic cell interaction: development of a co-culture system. Cell Tissue Res1998; 294: 99–108.
53.
Lacombe-GleizeS., GregoireM., DemignotS., HecquetC., AdolpheM.Implication of TGF beta 1 in co-culture of chondrocytes-osteoblasts. In Vitro Cell Dev Biol Anim1995; 31: 649–52.
54.
ItoM., AzuaY., OhtaT., KomoriyaK.Effects of ultrasound and 1, 25-dihydroxyvitamin D3 on growth factor secretion in co-cultures of osteolasts and endothelial cells. Ultrasound Med Biol2000; 26: 161–6.
55.
TrindadeM.C., LindM., SunD., SchurmanD.J., GoodmanS.B., SmithR.L.In vitro reaction to orthopaedic biomaterials by macrophages and lymphocytes isolated from patients undergoing revision surgery. Biomaterials2001; 22: 253–9.
56.
GoughJ.E., ChristianP., ScotchfordC.A., RuddI.A.Synthesis, degradation, and in vitro cell responses of sodium phosphate glasses for craniofacial bone repair. J Biomed Mater Res2002; 59: 481–9.
57.
HorowitzS.M., GonzalesJ.B.Effects of polyethylene on macrophages. J Orthop Res1997; 15: 50–6.
58.
CampocciaD., ArciolaC.R., CervellatiM., MaltarelloM.C., MontanaroL.In vitro behaviour of bone-marrow derived mesenchymal cells cultured on fluoro-hydroxyapatite-coated substrata with different roughness. Biomaterials2003; 24: 587–96.
59.
SchwartzZ., BoyanB.D.Underlaying mechanisms at the bone-biomaterial interface. J Cell Biochem1994; 56: 340–7.
60.
SpadaroJ.A.Mechanical and electrical interactions in bone remodelling. Bioelectromagnetics1997; 18: 193–202.
61.
SunJ.S., TsuangY.H., LinF.H., LiuH.C., TsaiC.Z., ChangW.H.S.Bone defect healing enhanced by ultrasound stimulation: an in vitro tissue culture model. J Biomed Mater Res1999; 46: 253–61.
62.
TorricelliP., FiniM., GiavaresiG., GiardinoR.Bone tissue cultures: an in vitro model for the evaluation of bone defect healing after L-Arginine and L-Lysine administration. Art Cells Blood Substit and Immobil Biotechnol2001; 29: 325–34.
63.
GuzzardellaG.A., FiniM., TorricelliP., GiavaresiG., GiardinoR.Laser stimulation on bone defect healing: an in vitro study. Lasers Med Sci2002; 17: 216–20.
64.
ThompsonD.D., SimmonsH.A., PirieC.M., KeH.Z.FDA guidelines and animal models for osteoporosis. Bone1995; 17(Suppl 4): S125–33.
65.
TorricelliP., FiniM., RoccaM., GiavaresiG., GiardinoR.In vitro pathological model of osteopenia to test orthopaedic biomaterials. Artif Cells Blood Substit Immobil Biotechnol2000; 28: 181–92.
66.
FiniM., GiavaresiG., TorricelliP.. Biocompatibility and osseointegration in osteoporotic bone. J Bone Joint Surg Br2001; 83: 139–43.
67.
FiniM., Nicoli AldiniN., GandolfiM.G.. Biomaterials for orthopaedic surgery in osteoporotic bone: a comparative study in osteopenic rats. Int J Artif Organs1997; 20: 291–7.
68.
OkazakiA., KoshinoT., SaitoT., TagakiT.Osseous tissue reaction around hydroxyapatite block implanted into proximal metaphysic of tibia of rats with collagen-induced arthritis. Biomaterials2000; 21: 483–7.
69.
McCrackenM., LemonsJ.E., RahemtallaF., PrinceC.W., FieldmanD.Bone response to titanium alloy implants placed in diabetic rats. Int J Oal Maxillofac Implants2000; 15: 345–54.
70.
TorricelliP., VerneE., BrovaroneC.V.. Biological glass coating on ceramic materials: in vitro evaluation using osteoblast cultures from healthy and osteopenic rat bone. Biomaterials2001; 22: 2535–43.
71.
SaitoT., KinY., KoshimoT.Osteogenic response of hydroxyapatite cement implanted into the femur of rats with experimentally induced osteoporosis. Biomaterials2002; 23: 2711–6.
72.
GiavaresiG., FiniM., TorricelliP., MartiniL., GiardinoR.The ovariectomized ewe model in the evaluation of biomaterials for prosthetic devices in spinal fixation. Int J Artif Organs2001; 24: 814–20.
