Correspondence:

Prof. Dr. Heino Kienapfel

Dept. of Orthopedic Surgery

Philipps University

D-35033 Marburg

Germany

Phone: int.49-6421-283691

Fax: int.49-6421-287007

e-mail: kienapfe@mailer.uni-marburg.de
 
 

Abstract: The term osseointegration referred originally to an intimate contact of bone tissue with the surface of a titanium implant, the term bone ingrowth refers to bone formation within an irregular ( beads, wire mesh, casting voids. cut grooves) surface of an implant. The historical background informs on the development of macroporous, microporous and textured surfaces with an emphasis on the evolution of porous and textured metal surfaces. The principal requirements for osseointegration and bone ingrowth are systematically reviewed:

1. The physiology of osseointegration and bone ingrowth including biomaterial biocompatibility in respect to cellular and matrix response at the interface. 2. The implant surface geometry characteristics. 3. Implant micromotion and fixation modes. 4. The implant-bone interface distances. Based on current methods of bone ingrowth assessment this article contains a complete comparative review and discussion of the results of experimental studies with the objective to determine local and systemic factors that enhance bone ingrowth fixation.

Key words: bone ingrowth, osseointegration, implant fixation, porous coating, bone morphogenetic proteins, factor XIII, CaP-coatings.
 
 

Historical background

To the authors knowledge the first patent for the concept of fixation by bone ingrowth was issued to Greenfield(1) in December 1909. Introducing a metallic cage like framework for an artificial tooth root Greenfield suggested that " in the course of time, the bone would grow in, around, and through the frame, and the latter would therefore be held securely in position." In the 1950s the use of porous polyvinyl sponges(2,3) was investigated for the reconstruction of bone. Struthers(4) proposed their use as augmentation of autogenous grafting procedures. Other investigators(5-7) focused on a resorbable porous polyurethane foam for osteosynthesis. In two of the polyurethane studies(5,7) and in another porous teflon study(8) the effect of pore size on bone ingrowth was analyzed.

The first porous material that appeared to have adequate mechanical strength for a load bearing orthopedic application was Cerosium, a porous ceramic-plastic composite introduced by Smith(9) in 1963.

The late 1960s and the early 1970s were particularly fruitful in the evolution of porous materials for prosthetic coatings. 1n 1968 Hirschhorn and Reynolds(10) were the first to report on the fabrication of porous metal (cobalt-chromium alloy) as an implant material. In 1969 Lueck et al.(11) reported the fabrication and implantation of a porous commercially pure titanium fiber composite material. They suggested that porous metallic materials produced by powder metallurgy techniques exhibit poor strength characteristics when the degree of porosity is sufficient to permit bone ingrowth. Ever since the fiber-metal material pioneered by Rostoker and Galante has been under continuos investigation(12,13) and is currently used clinically as a coating on total hip prostheses(14,15) and total knee prostheses(14). In Europe Ducheyne et al.(16,17) developed stainless steel porous coatings with pore sizes ranging from 50-100µ and performed animal experimental studies under dynamic loading conditions.

In the 1970s research studies on porous cobalt-chromium were continued by Welsh, Pilliar and Cameron(18-22) and developed further by Bobyn(23-25) and others. They prepared specimens by sintering microspheres of the alloy either greater or less than 44µ. Based on mechanical push-out tests in a canine cortical bone model they concluded that both the small and large pore size materials were effective. This research was the basis for the porous cobalt-chromium alloy coatings currently in use(26-28).

Among the porous polymers porous polyethylene(29), porous polysulfone(30) and a composite teflon/graphite fiber (Proplast) material(31) was studied but its clinical application was discontinued.

Klawitter et al. (32) studied the effect of different pore sizes of porous calcium aluminate specimens. They experienced a hydration reaction that retarded the mineralization of osteoid adjacent to the ceramic. Porous aluminumoxide ceramics displayed a good bone ingrowth pattern in canine experimental models(33). However, the clinical application of ceramic materials(34) did not become as popular as the clinical application of metal materials with surface geometry modifications by sintered, cast and preformed structures as well as direct coatings.

Basic requirements for ingrowth.

Physiology of osseointegration and bone ingrowth
 
 

The principal requirements for osseointegration(35-37) and bone ingrowth(38,39) are the same and well understood. The term osseointegration referred originally to an intimate contact of bone tissue with the surface of a titanium implant(35,36) but is meanwhile accepted as a general term for intimate implant surface to bone contact. The term bone ingrowth refers in the literature mainly to bone formation within a porous surface structure of an implant. In the figurative sense of the word ingrowth any bone formation into the irregular depths of non smooth surfaces can analogous be called bone ingrowth. Therefore the term bone ingrowth will be used in this article for all modifcations of surface geometry including sintered(18,19,23,24) , cast(40-42) and preformed structures(12,13) and direct coatings(43).

The physiological response to an inserted porous coated implant resembles the healing cascade of cancellous defects, with the newly formed tissues occupying the void spaces of the porous material. Repair of a hole drilled within the medullary canal of a long bone is associated by the formation of a hematoma and development of mesenchymal tissue which is replaced by woven bone. Lamellar bone remodeling soon follows as does reestablishment of the bone marrow. Like in primary fracture healing with stable osteosynthesis(44) no intermediate fibrocartilaginous stage occurs. Consequently the clinical success of fixation by osseointegration and bone ingrowth depends on a stable implant - bone interface.
 
 

Biocompatibility of implant materials

In the history of total joint replacement various metallic, ceramic and polymeric implant materials have been introduced. These implant materials are known to demonstrate different patterns of biocompatibility. Based on animal experimental studies the reactive new bone formation adjacent to the material surfaces can be categorized according to Osborn(45)as distance-osteogenesis, contact-osteogenesis and bond osteogenesis subsequently classifying the extent of biocompatibility. Transmission electron microscopy studies have demonstrated that the implant/bone ultrastructure of c.p. Titanium, Ti6Al4V, CoCr alloy and stainless steel is comparable (Table1).
 
 

Cellular and matrix response
 
 

The adherence of cells to a biomaterial is a prerequisite for tissue integration. New bone formation on biomaterials depends on surface structures which promote cell proliferation and production of extracellular matrix. Wilke et al.(46) used a human bone marrow cell culture demonstrating clear differences in cell proliferation, cell differentiation and the production of extracellular matrix when the commercially available coating materials hydroxyapatite, titanium and CrCoMb alloy were compared. Cell proliferation was highest on hydroxyapatite surfaces followed by titanium and CrCoMb. There were no differences in T-cell (CD 2) and monocyte (CD14) proliferation whereas the B-cell (CD19) and granulocyte (CD15) proliferation was elevated on titanium specimens. Most of the Osteocalcin marked osteoblasts adhered to hydroxyapatite. The constituents of the ECM produced on hydroxyapatite and titanium were fibronectin, laminin and collagen II and III. Identifacation and characterization of the cell-binding domains of interface adhesive proteins has led to better understanding of cell adhesion at the molecular level. Pierschbacher(47) and colleagues used monoclonal antibiodies and proteolytic fragments of fibronectin to identify the location of the cell attachment site of the molecule. Subsequently, residue sequences within the cell binding domains of other adhesive proteins were identified and summarized by Yamada(48). The RGD sequence first isolated from fibronectin was later found present within vitronectin, osteopontin, collagens, thrombospondin and fibrinogen(49)
 
 

Surface geometry characteristics
 
 

Various modifications of surface geometry technologies were developed including macroporous metals with a pore size larger than 500µ(50), and microporous metals with a pore size up to 500 µ using titanium (11,13), cobalt-chromium-molybdenum alloy (10,18,21), stainless steel(16,51), porous polymers such as teflon, polyethylene, polysulfone and polypropylene(29,30,32,52-56), porous carbon(53,57)and porous ceramics(32,52,54,55) Only the surface geometry modifications of titanium, cobalt-chromium-molybdenum, teflon, polysulfone and polyethylene have been used clinically. Presently the surface modifications that are most commonly used in clinical trials are metal coatings. These coatings are applied by cast structures, sintered structures (i.e. Co-Cr microspheres), direct coatings (i.e.plasma spray coating of CP Ti) and by diffusion bonding of preformed structures (i.e.CP Ti-fiber metal composite). In one animal experimental study was reported that the use of a rough surface (surface roughening by grit-blasting) provided also an excellent surface to bone implant integration and implant fixation strength(58). A recent study by Friedman(59)compared arc deposited titanium surfaces with sintered one layer cobalt chromium beads, sintered three layers of cobalt chromium beads, plasma sprayed cobalt-chromium and grit blasted titanium alloy in a press fit rabbit model. After 12 weeks. The bone apposition and mechanical stability of arc deposited titanium were similar to those of a single layer of beads. There appeared to be no advantage to multiple layers of beads. The plasma sprayed cobalt-chromium and grit blasted titanium surfaces demonstrated lower shear strength and bone apposition than the other groups.

The effect of pore size on the strength of fixation has been investigated in canine models, using pore sizes ranging from less than 50 um to 800 um. In studies examining pore sizes less than 100 um the increasing pore size was associated with increasing strength of fixation(18,60). Most studies analyzing pores in the range of 150 um to 400 um have shown no relationship between pore size and strength of fixation(24,61). Whereas one study with titanium fiber metal implied that varying the pore size between 190 and 390 um had no effect on interfacial shear strength at six weeks(12) another study demonstrated a decrease of bone ingrowth and strength of fixation(62) when the pore size was increased (in the range from 175 um to 325 um).In a canine acetabular model, however, it has been reported that more bone ingrowth was observed within implants with 450 um and 200 um pores than in implants with 140 um pores(63). From these studies it can be concluded that the optimum range for pore sizes is from 100 um to 400 um. Almost all porous coated prostheses currently undergoing clinical trials have pore sizes in this range(64). The effect of additional calcium phosphate ceramic coating of the surface modified geometries will be discussed in respect to local factors influencing bone ingrowth.
 
 

Implant stability/ micromotion

There is evidence that too much relative motion between the implant and host bone leads to ingrowth of fibrous connective tissue rather than bone The extent of implant stability contributes to a reduction in relative motion between the implant and host bone. Burke(65) has demonstrated in an experimental study that micromotions of 75 µ induce fibrous tissue ingrowth. Micromotions of 40 µ allowed the formation of woven bone within a porous titanium wire surface. However there appeared to be no osseous continuity between the woven bone within the coating and the trabecular bone adherent to the implant. In a later in vivo canine study of the same author it was demonstrated that the interface formed under displacements of 40 µ comprised of a mixture of bone and fibrous tissue(66).

In another study bone ingrowth has also been observed in situations where the relative displacements were less than 28 um, but when the displacements were greater than 150 um, only mature connective tissue provided the fixation(67). In a canine THA model bone ingrowth has been observed in the femoral components that had initial micromotion of 56 µ (68). Additional HA coating demonstrated an effect on the architecture of fibrous tissue formation in a weight bearing canine gap model allowing controlled micromovements of 150µ. In this study(69) both the HA coated and the titanium porous coated implants had only fibrous tissue ingrowth. However, there was a stronger fibrous anchorage of the HA coated implants together with the presence of fibrocartilage, higher collagen concentration and radiating orientation of the collagen fibers.Relative bone implant movements of as much as 300 µ due to rigid body motion of cementless tibial trays have been documented in several reports(70-73). Finite element studies and in vitro studies have also demonstrated that the difference of the elastic modulus of the porous coating of tibial components in TKA in comparison to the underlying bone tissue can cause displacement incompatibilities of as much as 150µ. In addition, two studies of porous-coated tibial components of total knee replacements in animals and human retrievals showed that bone ingrowth was consistently found within and near the fixation pegs but was variable elsewhere(14,74). Recent RSA in vivo studies in porous coated THA and TKA components have demonstrated that in many cases the analyzed micromotions were well above the limits of bone ingrowth compatibility(74-78). Various retrieval studies of porous coated acetabular and femoral components in THA have also demonstrated a high variability in bone ingrowth (79-81). Jasty(82) suggested that due to fatigue fractures of the bridging trabeculae failure of fixation can occur in femoral stems albeit the presence of bone ingrowth.

In summary it can be concluded that the amount of bone ingrowth also depends on an optimal primary stability. From a clinical perspective this primary stability can vary depending on implant design variables (cross-sectional geometry, means of additional fixation, mismatch in implant/bone stiffness), implantation technology variables (accuracy of tools for rasping, reaming, drilling, sawing), surgical technique variables (accuracy of utilization of the implantation technology) and patient variables (bone quality, bone defects).
 
 

Interface distances

The lack of a direct and continuous interface contact between the porous surface and the host bone had a negative effect on bone ingrowth and strength of fixation in both weight bearing and non-weight bearing models. Numerous gap models with a controlled gap and a stable implant have demonstrate the inhibiting effect of gap size on bone ingrowth and strength of fixation. In a recent sheep study we used a 2 millimeter non-weight bearing gap model with a Ti-porous coated implant to analyze the effect of an additional HA coating. After an implant in situ duration of 3 weeks the amount of bone ingrowth was sixfold higher for the press-fit inserted implants when compared to the contralateral 2 mm gap control(64,83). Other studies have also demonstrated that gaps at the interface of 2mm and less impair bone ingrowth(21,23,63,84,85). In two studies bone ingrowth was impaired by a three millimeter gap (83,86). Compared to a similar press-fit model with intimate bone implant contact the amount of bone ingrowth was reduced sixfold(87). In one canine non weight bearing study gap sizes of 2mm, 1 mm and 0.5 mm were compared wit a press-fit situation. The increase of the gap size had a decreasing effect on both bone ingrowth an strength of fixation(88). Clinically these studies imply the importance of accomplishing direct implant bone contact by the surgical technique including the filling of osseous defect with graft materials.
 
 

Experimental models

The quantitative assessment of bone ingrowth is preferably done using sterelogical methods. These methods determine volume fractions of pore space within the porous surface that have bone ingrowth. Point counting of stained sections using grids and a light microscope are considered the standard method. Backscattered Electron Imaging in SEM has been introduced as a elegant, quick and accurate method(89). Numerous animal models were used to assess bone ingrowth. Models using rodents appear to have the disadvantage of a comparatively high bone formation rate. The bone formation rates of primates, canines, sheep and pigs are closer to the human bone formation rates(90). A few prospective experimental studies were done in humans(91). The experimental models can further be categorized into weight-bearing and non-weight bearing study designs, press fit and interface gap designs and weight-bearing revision model designs. The most reasonable way to classify these experimental models is to distinguish between those analyzing local factors and systemic factors. The local factors can further be subdivided in a) tissue and blood derived factors such as autogenous bone graft , allogenic bone graft, demineralized bone, bone morphogenetic proteins, transforming growth factor beta and b) CaP ceramics such as calcium phosphate granules and calcium phosphate coatings and c) electromagnetic, radiation and ultrasound factors.
 
 

Effect of local factors (excluding CaP-ceramics)

Autogenous bone graft has been investigated in numerous studies. With the exception of one weight bearing gap study(92) and one non-weight bearing press fit study(93)all other studies demonstrated bone ingrowth enhancement(84,91,94-98) (see table2). For this reason autogenous bone graft had to be considered to be the golden standard and was experimentally often used as a positive control. Compared with the untreated negative control fresh frozen allogenic bone graft(84,94,99) but not freeze dried allogenic bone graft(95) demonstrated also a positive effect. The use of fibrin adhesive systems(86,100,101), demineralized bone matrix(93,96,102) and non recombinant "bone morphogenetic protein"(103,104) led to inconsistent results. Chesmel et al.(105) were the first to report on the enhancement of osseointegration by TGF-beta. These results were later supported by Sumner et al.(106)
 
 
 
 

Effect of local factors: CaP-ceramics
 
 

Calcium phosphate granules were either composed of tricalcium phosphate (93)or hydroxyapatite(107) or a combination of the two(92,97,108,109) (see table 3). In some studies collagen or autogenous bone graft was added to the calcium phosphate granules making the analysis of the true biologic effect of the ceramic difficult(92,108). In summary the results were inconsistent with two weight-bearing gap studies finding a bone ingrowth enhancement(107,110), two weight bearing studies finding an inhibition of bone ingrowth (92,108) and one study demonstrating no effect(109). These results are in contrast to the numerous studies determining the effect of calcium phosphate coatings. With the exception of two studies(111,112)all other studies demonstrated a positive effect on bone ingrowth and the implant fixation strength(107,108,113-122). This positive effect was demonstrated not only on porous surface structures but also on grooved structures (123). One major problem wit calcium phosphate coatings is that the resulting coating will partially obstruct the original surface geometry. Gas shielded titanium arc spray is reported to solve this problem(124). Fuorapatite coatings appear to have no advantages when compared with hydroxyapatite coatings(125). The results in respect to hydroxyapatite coatings on a grit blasted surface in comparison to a porous coated surface demonstrated that the energy absorption for porous coated implants was twice that of grit blasted implants during push-out testing(126).
 
 

Electromagnetic and radiation factors, ultrasound
 
 

In the electric stimulation studies only direct electric stimulation(111,127-129) but not inductively coupled electromagnetic fields(130) and capacitively coupled electric fields(131) have shown a positive local effect on bone ingrowth (see table 4). Recently in a canine study low intensity ultrasound was reported to stimulate bone ingrowth(132). On the other hand irradiation clearly demonstrated negative effects when 1000 rad(87) and 5500 rad(133) was used but no effect when 500 rad was used(87). It can be concluded that the biologic negative effect of radiation must start somewhere between 500 and 1000 rad.
 
 

Systemic factors
 
 

In a canine transcortical plug model various drug administration protocols simulating the clinical use of indomethacin were studied. The quantitative histological analysis showed no differences among any of the treatment protocols(134). Disodium (1-hydroxythylidene) diphosphonate had a positive effect on bone ingrowth when used in a dosage of 2.5-5mg/d in a rabbit model(135). Among the hormones studied growth hormone(136)demonstrated a positive effect . Estrogen and hydrocortisone acetate caused a possible inhibition but there was no negative control(90,137). Factor XIII concentrate but not recombinant factor XIII was reported to enhance bone ingrowth. A possible explanation for this difference might be that factor XIII concentrate is derived from human placentae and thus contained many other growth factors. Warfarin demonstrated a negative effect(138) and coumadin a possible inhibition but there was no negative control(139) The chemotherapeutic drugs cisplatin(140) and methotrexate(139) have both been reported to have a negative effect on bone ingrowth.
 
 

Conclusion
 
 

Until recently autogenous bone graft appeared to be the "gold standard" of bone graft materials for enhancement of bone ingrowth. Although the mechanisms are not well defined it appears that autogenous bone combines osteoconductive properties, osteoinductive properties and the stimulation of an inflammatory response accompanied by the release of cytokines.

Osteoconduction is a phenomenon describing the ingrowth of sprouting capillaries, perivascular tissues and osteoprogenitor cells from the recipient host bed into the three-dimensional structure of an implant or graft(141). Calcium Phosphate ceramic coatings are used both on porous and non-porous implant surfaces. In respect to the latter critical questions about the long term durability have to be addressed, whereas the ideal characteristics of a calcium phosphate coating for enhancement of bone ingrowth into a modified metal surface have yet to be analyzed. As the use of calcium phosphates has demonstrated to enhance bone ingrowth the eventual long-term clinical advantage of a combined calcium phosphates-modified metal surface coating will be provided by mechanical interlocking of the ingrown bone within the modified surface. However, this has yet to be demonstrated.

Osteoinduction is a process that supports the mitogenesis of undifferentiated perivascular mesenchymal cells, leading to the formation of osteoprogenitor cells with the capacity to form new bone(142). The results of a recent study(106) have demonstrated that enhancement of bone ingrowth in implants that have been treated with a combination of a local osteoconductive (hydroxyapatite-tricalcium phosphate coating) and local osteoinductive (transforming growth factor beta 1) factor have exceeded the effect of autogenous bone graft alone. In that study transforming growth factor beta appeared to enhance the recruitment and proliferation of osteoprogenitor cells(143).

Future directions of research in this field will probably focus on the efficacy of growth factors in combination with adequate ceramic(144,145), polymeric(146) or collagenous(144) carrier systems.
 
 
 
 

Acknowledgments The authors work cited in this paper is supported by NIH Grants 16485 and 39827 and Deutsche Forschungsgemeinschaft Grant KI 354/1-1.
 
 
 
 

Table 1: Extent of biocompatibility and reactive bone formation of different biomaterials.
 
 
 

materials	extent of biocompatibility	reactive bone formation
PMMA	biotolerant	distance osteogenesis
stainless steel	biotolerant	distance osteogenesis
Al2O3 ceramic	bioinert	contact osteogenesis
Carbon	bioinert	contact osteogenesis
Ti-base alloys	bioinert	contact osteogenesis
CrCo-base alloys	bioinert	contact osteogenesis
Ca-P-Ceramics	bioactive	bond osteogenesis
surface active glass	bioactive	bond osteogenesis

abbreviations:

+	enhancement of bone ingrowth and/or strength of fixation
-	inhibition of bone ingrowth and/or strength of fixation
(-)	no enhancement or inhibition
(+)	possible enhancement but no negative control (untreated gap)
(-)	possible inhibition but no negative control
pf	press fit
ut	untreated control
rev	revision model
ABG	autogenous bone graft
TCP	tricalcium phosphate
Plsp	Plasmaspray
FA	Fluorapatite
po	porous coated surface
gr	grit blasted surface
HA	hydroxyapatite
icpemf	inductively coupled pulsed electromagnetic field
ccpemf	capacitively coupled electric field
des	direct electric stimulation
oox	oophorectomy
FXIII conc	human factor XIII concentrate (Fibrogammin, Behringwerke Marburg, FRG)
rec FXIII	recombinant factor XIII (Behringwerke Marburg)
postop. med	postoperative medication
preop. med	preoperative medication

 
 
 

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