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Osseointegration of porous-coated implants during revision arthroplasty procedures is often impeded due to the presence of residual granuloma, particulate debris, and a sclerotic, dysvascular bone bed. We hypothesized that local infusion of recombinant fibroblast growth factor (FGF-2) would increase bone ingrowth in an in vivo model of tissue differentiation in the rabbit tibia in the presence of phagocytosable polyethylene particles. A drug test chamber (DTC) was implanted in the proximal medial tibial metaphysis of mature rabbits unilaterally. The chamber contained a 1× 1 × 5-mm tunnel for tissue ingrowth, and was connected to an osmotic diffusion pump. FGF-2 was infused at dosages of 0, 0.5, 5, 50, or 500 ng/day for a 3-week period, with subsequent harvesting of the ingrown tissue after each 3-week treatment. The effects of ultrahigh molecular weight polyethylene particles (0.5-μm diameter) on tissue ingrowth were determined by adding particles to the chamber at concentrations of 5.8 × 1011 (low dose) or 1.7 × 1012 (high dose) particles/mL, with and without infusion of 50 ng/day of FGF for 3 weeks. The tissue forming in the chamber was harvested after each treatment for histologic processing and morphometric analysis of bone ingrowth. Statistical analysis was performed using parametric tests (ANOVA), nonparametric tests (Kruskal–Wallis test) and post hoc tests. In the absence of particles, infusion of 50 ng FGF-2 per day yielded the greatest amount of bone ingrowth. The high dose of particles suppressed bone ingrowth into the chamber, but the low dose particles did not (p = 0.0002, 95% confidence limits = 9.19–18.80). Infusion of 50 ng FGF-2 per day significantly increased net bone formation in the presence of high-dose UHMWPE particles (p = 0.039, 95% confidence limits = 1.41–6.79). There was a trend for decreased numbers of vitronectin-receptor positive (osteoclast-like) cells with the addition of FGF-2, compared to particles alone (p = 0.08). Local delivery of FGF-2 may prove useful in mitigating the adverse effects of wear debris (e.g., in treating early osteolytic lesions), and facilitating osseointegration of revision total joint replacements in situations where the bone bed is suboptimal and residual particles and granulomatous tissue are present. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 65A: 454–461, 2003

The local delivery of exogenous growth factors may help achieve a stable, long-lasting prosthetic interface around primary and revision joint replacements. This study examines the effects of local infusion of transforming growth factor beta (TGFbeta) in an in vivo model of tissue differentiation within bone. The Drug Test Chamber was implanted in the proximal medial tibial metaphysis of 8 mature rabbits unilaterally. The chamber contained a 1 x 1 x 5 mm canal for tissue ingrowth. The chamber was connected to an osmotic diffusion pump via polyvinyl tubing. 3.5 microg of recombinant TGFbeta1 was infused for 1 day or 1 week with subsequent harvesting of the ingrown tissue after 3 weeks. Each TGFbeta treatment was followed by two, 3-week infusions of carrier alone and harvesting of the ingrown tissue. TGFbeta for 1 day increased, and TGFbeta for 1 week decreased the percentage of bone in the chamber, compared to the initial control harvest after carrier alone. These changes, however, did not reach statistical significance. The number of vitronectin receptor positive cells in total, adjacent to bone and away from bone was higher after treatment with TGFbeta for 1 day, compared to 1 week. In an "unperturbed" bone ingrowth system (i.e., if bone ingrowth is not initially suppressed by other stimuli), this dose of TGFbeta did not enhance bone ingrowth using the DTC model.

Particles similar to those generated from joint replacements affect net bone formation within the Bone Harvest Chamber in rabbits. Whether these effects depend on the concentration of particulate materials is unknown. In this study, we performed a histomorphologic and morphometric analysis of net bone formation in the Bone Harvest Chamber in the presence of different concentrations of phagocytosable particles of high density polyethylene and titanium 6-aluminum 4-vanadium alloy. Chambers were implanted in 9 mature New Zealand white rabbits bilaterally. Concentrations of 10(6), 10(7) and 10(8) polyethylene particles/mL, and 10(8) and 10(9) particles/ mL of titanium alloy in 1% sodium hyaluronate carrier were implanted for 3-week periods in sequence in each of the chambers. 3-week control periods in which nothing was implanted in the chamber were included between the treatments. Increasing concentrations of polyethylene particles were associated with a more marked foreign body response and fibrosis. Net bone formation for the three polyethylene doses was reduced by 11%, 21% and 33% of controls, respectively. For titanium alloy, net bone formation was reduced by 8% and 56% of controls, for concentrations of 10(8) and 10(9) particles/mL, respectively. Our findings suggest possible adverse effects of wear debris on net bone formation and bony remodeling in the prosthetic bed, when concentrations of specific particles reach critical local levels.

The purpose of this study was to determine whether small, phagocytosable particles of titanium alloy (Ti) and high-density polyethylene (HDPE) have an adverse effect on bone ingrowth. The bone harvest chamber (BHC) was implanted bilaterally in the proximal tibial metaphysis of six mature rabbits. The BHC has a transverse 1-mm wide pore providing a continuous canal through the chamber for tissue ingrowth. After an initial 6-week period for osseointegration of the BHC, the contents of the canal were harvested repeatedly at 3 weekly intervals. This could be done with the chamber in place, without disturbing its exterior surface or the surrounding bone. The carrier solution, 1% sodium hyaluronate (Healon) was implanted first. In subsequent implantations, Healon was mixed with particles of HDPE or Ti averaging 4.7 ± 2.1 and 3.0 ± 2.6 μm, respectively. The contralateral chamber was left empty and served as a control. The chambers were harvested repeatedly, alternating experimental and control sides. The sections from the control side, and those containing Healon alone demonstrated extensive trabecular bone in a fibrovascular stroma. The sections containing Ti alloy particles were qualitatively and quantitatively similar to the control sections and those containing Healon, except for the presence of small black granules of Ti alloy, dispersed in the fibrovascular stroma or phagocytosed by scattered macrophages. The sections containing HDPE particles were infiltrated and engulfed by mononuclear and multinuclear histiocytic cells in a highly fibrous stroma. The majority of the multinucleated cells present were interpreted as being foreign body giant cells. Less trabecular bone was seen in the HDPE group compared to the other groups. Using the parameters chosen for this experiment, it would appear that small, phagocytosable HDPE particles are more deleterious to net formation of bone compared to particles of Ti alloy. © 1995 John Wiley & Sons, Inc.

Both micromotion and particulate debris have been implicated in the process of aseptic loosening of joint arthroplasties and the failure of bone ingrowth into porous coated prostheses. In the present study, we compare the histological and histomorphometric results of tissue ingrowth into titanium chambers in the presence of interfacial micromotion versus phagocytosable particles of two polymers used in orthopedic surgery. The micromotion chamber, having a 1 × 1 × 5 mm transverse canal for tissue ingrowth was implanted into the proximal right tibia of five mature male New Zealand white rabbits. In the first series, the chambers were manipulated at 40 cycles per day (cpd) at 1 Hz, using an amplitude of 0.5 mm. The tissue within the chamber was harvested after 3 weeks. In the following series, fabricated particles of bone cement or highdensity polyethylene (HDPE) were mixed with the carrier, 1% sodium hyaluronate (Healon) to obtain a concentration of 108 particles/mL; this solution was implanted in the canal of the chamber but micromotion was not instituted. Histological sections from control, nonmoved chambers, or those implanted with the carrier Healon alone contained extensive trabecular and woven bone embedded in a fibrovascular stroma. The application of 40 cpd resulted in less formation of bone and more fibrous tissue within the chamber. The sections containing particles of bone cement were infiltrated by numerous foamy, mononuclear, and multinuclear histiocytes. HDPE particles were associated with more fibrosis and a less aggressive foreign body response compared to cement particles. Chambers manipulated at 40 cpd and those containing cement or HDPE particles contained less bone compared to nonmoved chambers or those containing Healon alone. Despite evoking different histological reactions, the presence of micromotion or polymer particles appears to inhibit the formation of bone in this experimental model. © 1994 John Wiley & Sons, Inc.

In vitro models are important investigative tools in understanding the biological processes involved in wear-particle-induced chronic inflammation and periprosthetic osteolysis. In the clinical scenario, particles are produced and delivered continuously over extended periods of time. Previously, we quantified the delivery of both polystyrene and polyethylene particles over 2- and 4-week time periods using osmotic pumps and collection tubes. In the present study, we used explanted mice femora in organ culture and showed that continuous intramedullary delivery of submicron-sized polymer particles using osmotic pumps is feasible. Furthermore, infusion of 2.60 x 10(11) particles per mL (intermediate concentration) of ultrahigh molecular weight polyethylene (UHMWPE) for 2 weeks and 8.06 x 10(11) particles per mL (high concentration) UHMWPE for 4 weeks both yielded significantly higher scores for bone loss when compared with controls in which only mouse serum was infused.

Previously, small phagocytosable particles of high density polyethylene (HDPE) but not Ti6-A14-V alloy, at a concentration of 10 8 particles/mL inhibited net bone formation in vivo after 3 weeks in the bone harvest chamber (BHC). These findings reflected the effects of particles during the phase of bone ingrowth. In this study, we tested whether these effects persisted or were different during the phase of bone maturation and remodeling. BHCs were bilaterally implanted in mature male NZW rabbits. After a 6-week period for osseointegration, the contents of the chamber were harvested and discarded. One percent sodium hyaluronate, the carrier, was then placed within the canal of the chambers bilaterally and the tissue within the chambers was harvested 3 weeks later. HDPE particles were then inserted unilaterally for a 3-week period, followed by Ti6-Al4-V for 3 weeks, HDPE for 6 weeks, and Ti6-Al4-V for 6 weeks. The side chosen for each treatment was switched consecutively ; the nonimplanted, contralateral chamber served as a control. At 3 weeks the control treatments yielded trabeculae of woven bone in a fibrovascular stroma. By 6 weeks, the peripheral trabeculae were thicker, and a central marrow cavity was developing. Bone ingrowth was less with HDPE particles at 3 and 6 weeks compared to controls. Ti6-A14-V particles did not inhibit bone ingrowth at 3 weeks but showed a trend at 6 weeks. The characteristics of particles affect the differentiation, maturation, and remodeling of mesenchymal tissue differently.

Particulate wear debris from joint replacements has been implicated in the etiology of periprosthetic bone resorption. However, the effect of high-density-polyethylene or cobalt-chromium-alloy particles on osteoclastic bone resorption in vivo has not been studied previously, to our knowledge. Therefore, we examined the effect of these particles on tissue ingrowth, net bone formation (per cent trabecular bone), and osteoclastic bone resorption (osteoclasts per unit of bone surface) with use of a bone-harvest chamber that had a transverse one-millimeter channel for tissue ingrowth. After an initial six-week period for incorporation of the chamber into the proximal part of the tibia of rabbits, the contents of the channel were harvested repeatedly at three-week intervals. The carrier solution, 1 per cent sodium hyaluronate, was implanted first. In subsequent implantations, the hyaluronate was mixed with high-density-polyethylene or cobalt-chromium particles at concentrations of 10(8) particles per milliliter. The tissue harvested from the chambers that contained no particles was composed of longitudinally oriented trabecular bone in a fibrovascular stroma. Particulate high-density polyethylene evoked a moderate foreign-body reaction and a chronic inflammatory response and decreased net bone formation. When cobalt-chromium particles had been implanted, the tissue exhibited a more florid foreign-body reaction and a chronic inflammatory response, often in a nodular arrangement, in a background of dense connective tissue. Bone was sparse, and areas of cell necrosis and hyaline degeneration were noted. Histomorphometric analyses were carried out to determine the amount of net bone formation and osteoclastic bone resorption in the presence or absence of high-density-polyethylene or cobalt-chromium particles. The amount of bone was greatest in the control specimens, moderately decreased in the presence of high-density-polyethylene particles, and greatly decreased in the presence of cobalt-chromium particles. The number of osteoclasts in Howship lacunae per unit of trabecular bone surface was increased in the presence of high-density polyethylene, indicating that these particles stimulate osteoclastic bone resorption.

We performed a histomorphological and morphometric analysis of the effects of short daily periods of micromotion and phagocytosable particles of high density polyethylene (PE) on bone ingrowth into a 1 × 1 × 5 mm canal within a titanium chamber in rabbits. The micromotion chamber (MC) was implanted in the tibia of nine mature New Zealand white rabbits. After osseointegration and first harvest of tissue, 40 micromotions (amplitude = 0.5 mm) were applied daily at a rate of 1 Hz for a 3-week period. The tissue within the chamber was then harvested. For the second treatment, PE particles (108/mL) were placed within the canal. The tissue in the chamber was harvested 3 weeks later. The next treatment was a 3-week rest period, in which neither micromotion nor particles were utilized; a harvest followed. The final treatment combined PE particles and micromotion, followed by a harvest 3 weeks later. Sections from control harvests contained extensive trabecular bone arranged longitudinally throughout the canal in a fibrovascular stroma. Micromotion produced longitudinally oriented fibrous tissue within the chamber. PE particles were associated with macrophages, surrounding and engulfing the birefringent particles. The combination of particles and micromotion produced a fibrous stroma laden with macrophages. PE particles and micromotion, alone or together, produced a similar effect in inhibiting bone ingrowth, compared to nonmoved chambers without particles. In this short-term experiment, no additive or potentiating effect of these two stimuli could be demonstrated. © 1995 John Wiley & Sons, Inc.

Particles of bone cement have been shown previously to stimulate the resorption of bone. The purpose of this study was to determine whether particles of bone cement (BC) have an adverse effect on bone ingrowth. The bone harvest chamber was implanted bilaterally in the proximal tibial metaphysis of 6 mature rabbits. Both the fixed outer cylinder and the inner removable core of the chamber have a transverse 1 mm wide pore providing a continuous canal for tissue ingrowth. After an initial 6-week period for osseointegration of the outer cylinder, the contents of the inner core were harvested repeatedly at 3 weekly intervals. In the first series of rabbits, the carrier solution, 1% sodium hyaluronate (Healon) was implanted first. In subsequent implantations, Healon was mixed with small fabricated particles of BC (averaging 3.54 mm in diameter) to fill the channel of the core. The contralateral chamber was left empty and served as a control. In the second series of rabbits, implantation was carried out sequentially using the same material bilaterally. The sections from the control harvests, and those with Healon alone contained extensive trabecular bone arranged longitudinally in the canal, in a fibrovascular stroma. The sections containing BC particles were infiltrated by foamy, mononuclear and multinuclear histiocytic cells. Less trabecular bone was seen in the sections containing BC particles compared to the control sections or those containing Healon alone. Previous studies have shown that particles of bone cement stimulate bone resorption. In this study, BC particles have also been shown to diminish the formation of new bone.