Thomas M. Turner

Enhancement of bone ingrowth by transforming growth factor-beta.

Enhancement of bone ingrowth with transforming growth factor-beta was evaluated in a canine model. Ten dogs had bilateral implantation of a titanium-fiber-metal-coated rod in the proximal part of the humerus. A three-millimeter gap between the outer surface of the porous coating and the surrounding cancellous bone was created to impair bone ingrowth. All of the implants were plasma-flame-sprayed with hydroxyapatite and tricalcium phosphate. In each animal, one implant was also treated with recombinant transforming growth factor-beta 1 while the other implant, which was not so treated, served as a paired control. Two doses of transforming growth factor-beta 1 were used: 335 micrograms in five animals and 120 micrograms in the other five. At four weeks, the amount of bone ingrowth in the implants that had been treated with 120 micrograms of transforming growth factor-beta 1 was threefold higher than that in the paired controls (p = 0.009), but with the numbers available there was no significant increase in bone ingrowth with the higher dose. The amount of new-bone formation in the three-millimeter gaps adjacent to the treated implants was twice that in the gaps of the paired controls, regardless of the dose. The differences between the treated and control implants with regard to the architecture of the new bone in the gap indicate that the mechanism of action of transforming growth factor-beta 1 may include both proliferation of osteoprogenitor cells and production of matrix by committed osteoblasts. Compared with the findings in a previous study in which this canine model was used, the data from the present investigation indicate that enhancement of bone ingrowth in implants that have been treated with a combination of a hydroxyapatite-tricalcium phosphate coating and transforming growth factor-beta 1 may exceed that obtainable with grafting of the gap with autogenous cancellous bone.

Functional adaptation and ingrowth of bone vary as a function of hip implant stiffness

The purpose of the present study was to test the hypothesis that cortical bone loss, trabecular bone density and the amount of bone ingrowth vary as a function of stem stiffness in a canine cementless hip replacement model. The study was motivated by the problem of cortical bone atrophy in the proximal femur following cementless total hip replacement. Two stem stiffnesses were used and both designs were identical in external geometry and porous coating placement. The high stiffness stem caused approximately 26% cortical bone stress-shielding and the low stiffness stem caused approximately 7.5% stress-shielding, as assessed by beam theory. Each group included nine adult, male canines who received unilateral arthroplasties for a period of six months. The animals with the low stiffness stems tended to lose less proximal cortical bone than the animals with high stiffness stems (4% +/- 9 as opposed to 11% +/- 14), but the difference was not statistically significant (p = 0.251). However, the patterns of bone ingrowth into the implant and change in medullary bone density adjacent to the implant were fundamentally different as a function of stem stiffness (p < 0.01). Most importantly, while the high stiffness group had peaks in these variables at the distal end of the stem, the low stiffness group had peak values proximally. These different patterns of functional adaptation are consistent with the idea that reduced stem stiffness enhances proximal load transfer.

A comparative study of porous coatings in a weight-bearing total hip-arthroplasty model.

The purposes of this study were to compare ingrowth of bone into three types of porous coating and to determine the effect of the type of porous coating and the degree of coverage of the stem on the remodeling of bone on the femoral side in cementless hip arthroplasty. A left total hip arthroplasty was performed in forty dogs. Thirty of the dogs had a titanium-alloy femoral prosthesis that had had one of three types of commercially pure titanium porous material applied along the length of the anterior and posterior surfaces of the stem: ten with sintered fiber-metal, ten with sintered beads, and ten with plasma flame-spray coating. The remaining ten dogs had a femoral component that was circumferentially coated with commercially pure titanium that was plasma flame-sprayed along the length of the stem. In each group, five animals were killed at one month and five were killed at six months. Ingrowth of bone into all three types of porous coating was observed, indicating secure fixation of all components. By six months, there was more ingrowth of bone and new medullary bone adjacent to the proximal and distal aspects of the stems compared with the middle level of the stems in all groups. No significant difference in ingrowth of bone was observed in the beaded surface (25.2 per cent) and the fiber-metal surface (16.6 per cent) at one month, but at six months there was significantly less ingrowth into the beaded surface (23.3 per cent) than into the fiber-metal surface (37.3 per cent). In all groups, a proximal-to-distal gradient of loss of cortical bone was observed by six months. The group of dogs that had the stem with the circumferential coating experienced more severe loss of bone than did the three groups that had a stem with a partial coating. The magnitude of loss of bone was dependent on the extent rather than the type of porous coating.

Locally delivered rhBMP‐2 enhances bone ingrowth and gap healing in a canine model

The purpose of the present study was to determine if recombinant human bone morphogenetic protein‐2 (rhBMP‐2) enhances bone ingrowth into porous‐coated implants and gap healing around the implants. In the presence of a 3‐mm gap between the implant and host bone, porous‐coated implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs. In three treatment groups, the test implant was treated with HA/TCP and rhBMP‐2 in buffer at a dose of 100 μg/implant (n = 5), 400 μg/implant (n = 6), or 800 μg/implant (n = 5) and placed in the left humerus. In these same animals, an internal control implant was treated only with HA/TCP and buffer and placed in the right humerus. These groups were compared with a previously reported external control group of seven animals in which no growth factor was delivered [J. Orthop. Res. 19 (2001) 85]. The BMP treated implants in the two lower dose groups had significantly more bone ingrowth than the external controls with the greatest effect in the 100 g/implant group (a 3.5‐fold increase over the external control, p = 0.008). All three dose groups had significantly more bone formation in the 3‐mm gap surrounding the BMP treated implants than the external controls with the greatest effect in the 800 μg group (2.9‐fold increase, p < 0.001). Thus, application of rhBMP‐2 to a porous‐coated implant stimulated local bone ingrowth and gap healing. The enhancement of bone formation within the implant (bone ingrowth) was inversely related to dose.

Use of a calcium sulfate-based bone graft substitute for benign bone lesions.

Twenty-three patients with a benign bone lesion grafted with calcium sulfate, with and without demineralized bone matrix, were reviewed. At a minimum of 1 year postoperatively, 21 patients had achieved between 76% and 100% bone repair based on anteroposterior and lateral radiographs. Overall, the mean Enneking Functional Evaluation System score was 98%. Calcium sulfate is a well-tolerated, biodegradable, osteoconductive bone graft substitute. It is a reasonable alternative to autogenous bone graft for benign bone lesions.

Radiographic and histologic assessment of calcium sulfate in experimental animal models and clinical use as a resorbable bone-graft substitute, a bone-graft expander, and a method for local antibiotic delivery. One institution's experience.

For more than a decade, the radiographic and histologic appearance of a refined calcium sulfate has been studied in various experimental animal models in our laboratory and in clinical applications. This report summarizes our institution’s experience with calcium sulfate as a synthetic bone graft1, a graft expander (the synergistic combination of calcium sulfate with demineralized bone matrix)2-4, and a method for local delivery of antibiotics5-8. Historically, orthopaedic usage of calcium sulfate was popularized by Peltier. Clinically, we have used calcium sulfate to treat numerous osseous lesions and conditions occurring in the axial and appendicular skeleton, including a variety of benign lesions of bone, osseous defects following implant removal, corrective osteotomy sites, spinal fusion sites, graft sites, fracture defects, and osteomyelitic lesions. Both our research studies and clinical experience have shown consistent osteoconduction, excellent biocompatibility, and complete resorption of calcium sulfate, which was replaced by newly formed bone that ultimately remodeled to be comparable with autogenous bone. The scientific basis for the use of calcium sulfate, the typical radiographic and histologic progression of the implanted material, and the indications and expectations for clinical use are illustrated. Contributions from orthopaedic surgeons from several subspecialties demonstrate the use of calcium sulfate in various applications and anatomic sites. ### Research Synthetic bone-graft materials are of clinical interest because of the morbidity, potential for disease transmission, and procurement issues associated with autografts and allografts. The purpose of this study was to evaluate healing after the use of calcium sulfate as a synthetic bone graft compared with spontaneous healing with no graft material and healing after use of autogenous bone graft in a large medullary defect model1. ### Methods Graft materials: The grafts consisted of either circular 4.7 3-mm tablets of calcium sulfate dihydrate (CaSO4) or autogenous cancellous …

Remodeling and ingrowth of bone at two years in a canine cementless total hip-arthroplasty model.

Remodeling and ingrowth of bone in association with the use of uncemented femoral components were examined at two years in a canine total hip-arthroplasty model. Twenty-two dogs received a unilateral uncemented femoral stem that was made of Ti6A14V and was covered with one of three types of titanium porous coating: fiber-metal, beads, or plasma flame-spray. The amount and distribution of ingrowth of bone differed somewhat among the groups at two years, but the patterns of remodeling of bone in the medullary canal and cortex were similar. In general, about 15 to 18 per cent of the cortical bone was lost adjacent to the levels of the stem that were covered with the porous coating. Most of the loss of cortical bone was due to subperiosteal resorption proximally and endosteal resorption at the middle and distal levels of the stem. Increased cortical porosity accounted for only a small fraction of the loss of cortical bone. The amount of medullary bone increased proximally and distally, so that the loss of total bone mass was significantly only at the mid-part of the stem. The amount of loss of cortical bone was similar to that observed in a previous six-month study, suggesting that a steady state was achieved in the present model.

Increased bone formation using calcium sulfate-calcium phosphate composite graft.

Calcium phosphates (CaPO4) and faster-resorbing calcium sulfate (CaSO4) are successfully employed as synthetic bone grafts for treatment of contained defects. We used a canine critical-sized bone defect model to study an injectable CaSO4/CaPO4 composite graft that incorporated a matrix of CaSO4 and dicalcium phosphate dihydrate into which β-tricalcium phosphate granules were distributed. The area fraction, ultimate compressive stress, and elastic modulus of restored bone and the relative rates of material resorption were compared between the CaSO4/CaPO4 composite graft and pure CaSO4 pellets and to normal canine bone. The area fraction of bone in stained sections and the ultimate compressive stress of the regenerated bone were greater using the CaSO4/CaPO4 composite graft compared to pure CaSO4 pellets after 13 and 26 weeks and were greater than normal bone. The elastic modulus of restored bone in defects treated with CaSO4/CaPO4 composite graft was greater than in defects treated with CaSO4 pellets after 26 weeks, but similar to specimens of normal bone. A small amount of CaSO4/CaPO4 composite graft and no CaSO4 pellets remained after 13 or 26 weeks. This novel CaSO4/CaPO4 composite holds promise for clinical applications where a strong, injectable, slower-resorbing, and biocompatible bone graft substitute would be advantageous.

Locally delivered rhTGF-β2 enhances bone ingrowth and bone regeneration at local and remote sites of skeletal injury

The purposes of the present study were to determine if recombinant human transforming growth factor‐beta‐2 (rhTGF‐β2) enhances bone ingrowth into porous‐coated implants and bone regeneration in gaps between the implant and surrounding host bone. The implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs in the presence of a 3‐mm gap. In three treatment groups of animals, the test implant was treated with hydroxyapatite/tricalcium phosphate (HA/TCP) and rhTGF‐β2 in buffer at a dose per implant of 1.2 μg (n = 6), 12 μg (n = 7), or 120 μg (n = 7) and placed in the left humerus. In these same animals, an internal control implant treated only with HA/TCP and buffer was placed in the right humerus. In a non‐TGF‐β treated external control group of animals (n = 7), one implant was treated with HA/TCP while the contralateral implant was not treated with the ceramic. In vitro analyses showed that approximately 15% of the applied dose was released within 120 h with most of the release occurring in the first 24 h. The TGF‐μ treated implants had significantly more bone ingrowth than the controls with the greatest effect in the 12 μg/implant group (a 2.2‐fold increase over the paired internal control (P = 0.004) and a 4‐fold increase over the external control (P < 0.001)). The TGF‐β treated implants had significantly more bone formation in the gap than the controls with the greatest effect in the 12 and 120 μg groups (1.8‐fold increases over the paired internal controls (P = 0.003 and P = 0.012, respectively) and 2.8‐fold increases over the external controls (P < 0.001 and P = 0.001, respectively)). Compared to the external controls, the internal control implants tended to have more bone ingrowth (1.9‐fold increase, P = 0.066) and had significantly more bone formation in the gap (1.7‐fold increase, P = 0.008). Thus, application of rhTGF‐β2 to a porous‐coated implant‐stimulated local bone ingrowth and gap healing in a weakly dose‐dependent manner and stimulated bone regeneration in the 3‐mm gap surrounding the contralateral control implant, a site remote from the local treatment with the growth factor.

The use of acellular dermal matrix as a scaffold for periosteum replacement.

Three preclinical models were used to evaluate GraftJacket Acellular Periosteum Replacement Scaffold (Wright Medical Technology, Inc, Arlington, Tenn). The studies assessed the ability of the acellular dermal matrix to repopulate with cells, revascularize, provide a protected environment for bone defect restoration, and minimize fibrous tissue infiltration. An athymic nude rat muscle implantation study demonstrated a steady increase in cellular repopulation through days 2-21. The formation of blood vessels occurred between days 7-14 in this study. Results from a porcine femoral drill hole study indicated that the scaffold material was intact and adherent to surrounding bone and allowed cellular repopulation and vascular infiltration at a 5-week time period. A preliminary porcine segmental bone defect model at a 6-week time period demonstrated the ability of the scaffold material to protect the bone defect site as revealed by new bone formation within the margins of the defect and adjacent to the scaffold. The segmental model also indicated minimal to no soft tissue invasion into the defect site. The combined studies provided preliminary evidence that the dermal membrane material may be used as a scaffold for periosteum regeneration by allowing for cellular repopulation, revascularization, and bone defect restoration.