Samantha L. Salkeld

Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates.

The effect of recombinant human osteogenic protein-1 on the healing of segmental bone defects was studied in twenty-eight African green monkeys (Cercopithecus aethiops). A 2.0-centimeter osteoperiosteal defect was created in the middle of the ulnar shaft in fourteen animals and in the diaphysis of the tibia in the other fourteen. The ulnar defect was filled with an implant consisting of 1000 micrograms of recombinant human osteogenic protein-1 in 400 milligrams of bovine bone-collagen carrier in six animals, with collagen carrier alone in two animals, and with autogenous cancellous bone graft from the contralateral tibia and femur in six animals. The tibial defect was filled with 250, 500 (two tibiae), 1000, or 2000 micrograms of recombinant human osteogenic protein-1 in 400 milligrams of collagen carrier in five animals, with collagen carrier alone in one animal, and with autogenous cancellous bone graft in six animals; in the two remaining animals (controls), the tibial defect was left unfilled. The tibial defects were stabilized with an intramedullary Steinmann pin. All animals were killed at twenty weeks postoperatively. Healing of the defects was evaluated with biweekly radiographs, with histological examination, and with mechanical testing. Radiographically, all of the defects that had been treated with recombinant human osteogenic protein-1 exhibited new-bone formation, but they differed in the degree of healing and remodeling. Five of the six ulnae treated with recombinant human osteogenic protein-1 and four of the five tibiae treated with this substance exhibited complete healing at six to eight weeks, with bridging of the defect by new bone first observed at four weeks. The two unhealed defects both exhibited new-bone formation but incomplete union, which precluded mechanical testing. No defect that had been filled with collagen carrier or that had been left unfilled exhibited any signs of healing or major new-bone formation. None of the six ulnae that had been filled with autogenous bone graft exhibited complete healing, compared with five of the six tibiae that had been so treated. Histological evaluation of the defects treated with recombinant human osteogenic protein-1 revealed the formation of new cortices with areas of woven and lamellar bone and normal-appearing marrow elements at twenty weeks postoperatively. The tibial defects that had been treated with autogenous bone graft had a similar appearance. All control ulnar and tibial defects and all ulnar defects that had been treated with autogenous bone graft had fibrous union with little new-bone formation.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone.

Background: Large amounts of bone graft are frequently used to elicit the healing of bone defects resulting from reconstructive procedures. Autograft and allograft bone are often used, but each has its limitations. Bone morphogenetic proteins (BMPs) improve the healing of segmental bone defects treated with autograft or allograft. The objective of the present study was to determine the effect of implantation of a recombinant osteogenic protein-1 (OP-1) in combination with bone graft on the healing of a critical-sized (2.5-cm) segmental defect in canine ulnae. Methods: Either autograft bone, allograft bone, osteogenic protein-1 (OP-1) mixed with type-1 bovine collagen, or various combinations of OP-1 and collagen (OP-1 device) mixed with allograft or autograft were implanted in the segmental bone defects. The combinations included 67% bone graft with 33% OP-1 device and 33% bone graft with 67% OP-1 device. The healing of the defects was assessed with radiographic, biomechanical, and histological studies. The animals were killed at twelve weeks postoperatively. Results: The use of the OP-1 device alone or any combination of autograft or allograft bone and the OP-1 device demonstrated improved healing on radiographic, mechanical, and histological studies compared with that demonstrated after use of autograft or allograft bone alone. The highest radiographic and histological grades and the greatest mechanical strength were achieved with the use of 33% allograft and 67% OP-1 device, although no significant differences were observed among the different groups containing the OP-1 device. At twelve weeks postoperatively, the defects treated with any amount of the OP-1 device obtained greater mechanical strength than that obtained by autograft bone alone. Conclusions: Major bone defects may be treated with allograft bone combined with the OP-1 device, instead of autograft alone, to avoid complications associated with the use of autograft. The combination of allograft bone and the OP-1 device resulted in optimum healing of the defect, according to the radiographic, mechanical, and histological parameters measured in this study. Clinical Relevance: The combination of freeze-dried allograft bone with the OP-1 device is an attractive graft material for the treatment of large bone defects. Although similar results were observed when autogenous bone graft was used in combination with the OP-1 device, the results of the present study suggest that allograft, because of its relatively unlimited supply, can be substituted without reduced efficacy. In addition, avoiding the need to harvest autogenous bone eliminates the additional operative time and risk associated with a second surgical procedure.

Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs.

Background: Articular cartilage injury has a poor prognosis for repair. Mesenchymal cells, when exposed to osteogenic proteins and other cytokines, can differentiate into cells that behave phenotypically as chondrocytes. In this study, we examined the ability of recombinant human osteogenic protein-1 (rhOP-1 or rhBMP-7) to elicit the repair of osteochondral defects in dogs.Methods: Bilateral osteochondral defects that were 5 mm in diameter by 6 mm deep were surgically created in the medial femoral condyles of sixty-five adult dogs. rhOP-1-treated (100 mg of a 3.5-mg rhOP-1/g bovine bone-derived Type-I collagen device) and control defects (untreated or treated with 100 mg bovine bone-derived collagen implants) were evaluated grossly and histologically at six, twelve, sixteen, twenty-six, and fifty-two weeks postoperatively. The influence of protected initial weight-bearing and surgical placement of periosteal flaps was also evaluated.Results: Gross and histologic grading of the defect repair indicated improvement in the rhOP-1-treated defects compared with that in the controls. Grossly, the repair tissue in the rhOP-1-treated defects was continuous with the adjacent intact cartilage and appeared translucent. By comparison, the repair tissue in the control defects was discontinuous and opaque or inhomogeneous in nature. Histologically, maturing cartilage similar in appearance to the intact articular cartilage was present in the rhOP-1-treated defects. Cartilage at the defect interface was minimally degraded. The control defects were filled primarily with fibrous tissue and fibrocartilage. Significant differences based upon treatment type were observed at twelve weeks, sixteen weeks, and for all time-periods combined (p = 0.0385, p = 0.0070, and p = 0.0026, respectively).Conclusion: rhOP-1 (rhBMP-7) induced hyaline cartilage-like repair of full-thickness osteochondral defects in a dog model. Differences in cartilage repair were maintained at fifty-two weeks postoperatively with no significant degradation of the rhOP-1-induced repair tissue.Clinical Relevance: The dog osteochondral defect model is a challenging one that reflects the difficulties of eliciting articular cartilage repair that are seen in the clinical setting. The results of this study indicate that rhOP-1 may improve the repair of articular cartilage, and they demonstrate the importance of further investigation to characterize the effects of growth factors on the cartilage repair process.

Improved cartilage repair after treatment with low-intensity pulsed ultrasound.

Low-intensity pulsed ultrasound accelerates bone healing via upregulation of cartilage formation and maturation phases of endchondral bone formation. The current authors evaluated the effect of ultrasound therapy on the repair of full-thickness osteochondral defects. Bilateral, 3.2 mm diameter by 5.0 mm deep osteochondral defects were created in the patellar groove of 106 adult male New Zealand rabbits. The defects were treated with daily low-intensity pulsed ultrasound therapy on the right knee. The left knee was not treated. In Part I, the effect of ultrasound therapy was evaluated at 4, 8, 12, 24, and 52 weeks after surgery. In Part II, the effect of the length of treatment (5, 10, or 40 minutes of daily ultrasound therapy) compared with standard 20 minute therapy was evaluated. The repair cartilage was evaluated and graded on a standard scale for the gross and histologic appearance. Ultrasound treatment significantly improved the morphologic features and histologic characteristics of the repair cartilage compared with nontreated controls. Earlier, better repair with less degenerative changes at later times was observed in defects treated with ultrasound. Doubling the treatment time to 40 minutes daily significantly increased the histologic quality of the repair cartilage. In the current animal model, daily low-intensity pulsed ultrasound had a significant positive effect on the healing of osteochondral defects.

Biomechanical evaluation and preliminary clinical experience with an expansive pedicle screw design

The advantages of pedicle screw fixation depend on their ability to retain bony purchase until the fusion mass is stable. Osteoporotic bone and removal and replacement of pedicle screws in revision procedures substantially reduce screw mechanical fixation strength and can lead to clinical failure. The objective of this study was to determine if an expansive pedicle screw design could be used to improve biomechanical fixation in bone of compromised quality. Axial mechanical pullout testing was performed on paired expansive and conventional pedicle screws placed in fresh, unembalmed cadaveric vertebrae. Bone mineral density measurements (made using a dual-energy X-ray absorption meter) were used to characterize bone quality. A preliminary clinical and radiographic evaluation of 14 patients was also performed at a minimum 2-year follow-up. The mean axial pullout force in bone of all qualities was increased 30% when the expansive pedicle screw design was used. This included an appropriate 50% increase in pullout force in bone of poor quality (low bone mineral density). The preliminary clinical and radiographic results were supportive of the biomechanical design rationale and mechanical testing. The results were similar to those expected for spinal instrumentation using pedicle screws, even though compromised bone was present in two thirds of the cases in which the expansive screw was used.

Lumbosacral fixation using expandable pedicle screws. an alternative in reoperation and osteoporosis.

BACKGROUND CONTEXT Pedicle screw fixation in osteoporotic bone and in revision of previous pedicle screw fixation cases presents a significant challenge to spine surgeons. Biomechanical tests have shown that a pedicle screw that expands within the vertebrae body can substantially improve fixation in the presence of compromised bone. PURPOSE To review the clinical and radiographic results with the use of expandable pedicle screws. STUDY DESIGN One hundred forty-five patients received one or more expandable pedicle screws from the Omega21 spinal fixation system (EBI, L.P., Parsippany, NJ) to obtain thorocolumbar or lumbosacral stabilization. PATIENT SAMPLE The indications for use of the expandable screws were osteoporosis (21 cases), reoperation of previous pedicle instrumentation (27 cases), intraoperative screw relocation (17 cases), construct reinforcement (23 cases), and sacral anchoring to avoid the necessity of anterior penetration of the sacral cortex (57 cases). OUTCOME MEASURES The presence of radiographic fusion and complications arising from the instrumentation were reviewed at a mean follow-up period of 35 months (range, 24-72 months). METHODS A retrospective clinical and radiographic review was performed. Fusion was evaluated based on anterior-posterior and lateral radiographs as well as dynamic radiographs in flexion and extension. RESULTS Radiographic evidence of fusion was obtained in 125 of the 145 cases (86%). Eighty-six percent of patients with osteoporosis and 89% of reoperations fused. There were no instances of screw loosening or pullout of the expandable screws. Screw breakage occurred in four patients (2.8%), including three patients where fusion was not obtained. In six patients the expandable screws were removed without difficulty after fusion because of local discomfort. CONCLUSION The results of this study have shown that expandable pedicle screws can be efficacious in cases in which pedicle screw fixation is difficult and adds a valuable tool to the growing armamentarium of spinal instrumentation.

A biomechanical comparison of intramedullary nailing systems for the humerus

Summary: This study evaluated the rotational and bending stability of three interlocking nail systems in paired cadaveric humeri. The Russell-Taylor Humeral Interlocking Nail, the Seidel Humeral Locking Nail, and the True-Flex Humeral Nail were mechanically tested in torsion and four-point bending. The Russell-Taylor and the Seidel interlocking nails are reamed systems that rely on proximal interlocking screws and distal screws or phalanges respectively for rotational stability. However, axillary nerve damage may result during proximal screw placement, and these systems exhibit low resistance to rotation. The True-Flex intramedullary nail is an unreamed system that relies on crosssectional geometry to achieve rotational stability. By not relying on interlocking screws for stability, nerve damage associated with the screw placement may be eliminated. However, the results indicate the cross-sectional geometry of the True-Flex nail is not able to provide the same degree of static locking as the Russell-Taylor or Seidel interlocking nails. Humeri implanted with the Russell-Taylor and Seidel nails also had a significantly greater torsional stiffness than the True-Flex nail. As expected, humeri implanted with the Russell- Taylor and Seidel nails also had a significantly greater bending stiffness than the True-Flex nail in both anterior-posterior and medial-lateral bending.

Use of an osteoinductive biomaterial (rhOP-1) in healing large segmental bone defects.

OBJECTIVE To assess the radiographic, histologic, and mechanical characteristics of new bone formation in large segmental bone defects treated with a new osteoconductive material, recombinant human osteogenic protein-1 (rhOP-1). DESIGN In vivo animal study. INTERVENTION Sixteen dogs (thirty-two limbs) with an ulna segmental defect (2.5 centimeters) were randomized to three treatment groups: rhOP-1, collagen alone, and no implant. MAIN OUTCOME MEASUREMENTS Radiographic evidence of defect healing, mechanical testing (torsional strength) as compared with thirty-one control intact dog ulnas, and histologic analysis. RESULTS At twelve weeks, complete radiographic healing was observed in twenty-five of twenty-eight defects (89 percent) treated with rhOP-1. The mechanical strength of the rhOP-1-treated defects at twelve weeks was 65 percent of that of intact ulnas. Histologic analysis revealed that defects treated with rhOP-1 were bridged with lamellar and woven bone that was in continuity with the host bone. CONCLUSIONS The results indicate that osteoinductive materials, which have the ability to quickly fill and heal large defects, may have advantages over osteoconductive materials, which are typically used to fill smaller non-load-bearing bone voids.

Strut allograft healing to the femur with recombinant human osteogenic protein-1

Allograft struts are used to reinforce the deficient proximal femur in hip arthroplasty or for fixation of a periprosthetic fracture. Although the use of strut grafts wired or cabled to the proximal femur generally has been successful, the time for healing is slow. The purpose of the current study was to determine whether cortical strut graft healing to the femur could be enhanced by the addition of recombinant human osteogenic protein-1. Fourteen adult dogs underwent bilateral onlay allograft strut procedures to the midfemur using stainless steel cables. In each animal one femur received 500 mg of osteogenic protein-1 device (2.5 mg recombinant human osteogenic protein-1/g Type I collagen) interposed between the graft and host bone. The results showed that the healing of cortical strut grafts to the femur was enhanced dramatically by the addition of the osteogenic protein-1 device. The sites treated with osteogenic protein-1 had significantly greater radiographic, histologic, and microradiographic scores at all times. Rapid formation of new bone and graft incorporation was observed in sites treated with the osteogenic protein-1 device. Strut healing with the osteogenic protein-1 device at 4 weeks postoperative was superior to the healing in control sites at 8 weeks. Improving and accelerating the course of cortical strut graft healing should provide a substantial clinical benefit in lowering the risk of graft nonunion and fracture and shorten the time of protected weightbearing and functional disability.

Healing Course of Primate Ulna Segmental Defects Treated With Osteogenic Protein-1

Twelve African green monkeys were implanted with recombinant human osteogenic protein-1 (rhOP-1) placed on a bovine bone-derived Type I collagen carrier to characterize healing in an ulna segmental bone defect model at 1, 3, 12, and 20 weeks postoperative. Defect healing was evaluated by plain film radiography, computed tomography (CT), magnetic resonance imaging (MRI), bone mineral density (BMD), and histologic analysis. Radiographically, new bone formation was observed as early as 3 weeks postoperative. By 6 weeks, new bone was visible in five of six defects. Increased quantity and mineralization of the new bone were apparent by 12 weeks. Reformation of the medullary cavity with appearance of marrow elements was demonstrated by CT and MRI at 20 weeks. BMD studies revealed a significant increase in the presence of bone with time. Histology at 1 week demonstrated that the implant material was well contained in the defect, and a proliferation of cells occurred at the defect borders. At 3 weeks cell proliferation continued and cell phenotype differentiation was recognized. By 12 weeks substantially less residual carrier was found in the defects, and calcifying tissues with plump chondrocytes, osteoblasts, and immature woven bone were observed. Areas of lamellar and woven bone were identified at 12 weeks, with advanced remodeling and revascularization observed at 20 weeks. The use of osteoinductive implants may provide an alternative to autologous and allogeneic bone tissue in the therapeutic approach to bone defects and promotion of fusion by eliminating the donor site morbidity associated with autogenous bone and the decreased efficacy and potential for disease transmission associated with allogeneic bone.