Laura P. Patron

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.

Comparison of methods for determining the presence and extent of anterior lumbar interbody fusion.

Study Design. Titanium alloy interbody fusion devices with autogenous bone were placed in the L5–L6 disc space of 31 adult pig-tailed monkeys through an anterolateral (retroperitoneal) approach. Anteroposterior and lateral radiographs, CT imaging, and histologic analysis of the specimens were performed. Objectives. This study compared the accuracy of plain film radiographs and CT imaging for determining bony fusion of a titanium interbody device implanted in a non-human primate model. The accuracy of the assessments was determined by comparison to histologic analysis. Summary of Background Data. Interbody fusion assessment is often difficult to compare in clinical studies because of differences in definition of fusion criteria. In addition, the accuracy of plain film radiographs and CT imaging assessments of fusion are debated because of device material radiopacity and introduction of artifacts. Methods. A uniform grading system evaluating both the presence and extent of bony fusion was applied to all evaluation techniques. Matched-pair nonparametric t tests were used to determine differences in scoring. Results. The radiographic and histologic presence of fusion grades was equivalent in only 13 of 29 cases (45%), while the CT imaging was equivalent to histologic assessment in 24 of 29 cases (83%). However, the extent of bony fusion in CT imaging and histologic assessment was equivalent in only 4 of 29 cases (14%). Grading of CT images significantly overestimated the extent of fusion. Conclusions. This study demonstrated CT imaging techniques to be superior to plain film radiographs in determining the presence of bony fusion. However, CT imaging did not accurately determine the extent of bony fusion present as confirmed by histologic analysis.

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.

Low-intensity pulsed ultrasound improves spinal fusion

BACKGROUND CONTEXT Increasing the incidence of solid bony fusion is a primary goal in spine surgery. Daily low-intensity pulsed ultrasound therapy has been shown to improve and accelerate the bone healing process. PURPOSE The purpose of this study was to evaluate the efficacy of daily low-intensity pulsed ultrasound therapy to improve the rate and quality of spinal fusion. STUDY DESIGN Canine fusion model prospective study. PATIENT SAMPLE Fourteen adult male dogs were used. OUTCOME MEASURES Radiographic grading of plain films, computed tomography (CT) and magnetic resonance imaging (MRI), gross palpation, torsional stiffness and histologic grading were used to determine the presence or absence of fusion. METHODS Posterior noninstrumented bilateral fusions were evaluated at the L2-L3 and L5-L6 levels. Treatment with low-intensity pulsed ultrasound for 20 minutes per day over the fusion site (stimulated) was compared with fusion sites that received no stimulation (nontreated controls) at 6 and 12 weeks after surgery. Plain film radiographs, CT and MRI, mechanical torsion testing and histologic examination were performed. RESULTS At 6 weeks, ultrasound treated sites were more frequently fused compared with nontreated controls, although the difference in fusion rate was not statistically significant. At 12 weeks after surgery complete radiographic and histologic fusion occurred in 100% of ultrasound-treated sites. In the nontreated control sites 78% had achieved complete radiographic fusion and 44% had complete histologic fusion. Compared with control sites, the histological and mechanical fusion rate was significantly greater in ultrasound-treated sites (P<.05) at 12 weeks. A statistically significant increase in mechanical stiffness in ultrasound-treated sites was also found at 12 weeks after surgery. CONCLUSIONS Low-intensity pulsed ultrasound therapy may be a useful means to ensure successful spine fusion.

Patellar tracking during simulated quadriceps contraction.

The current study compared patella tracking during simulated concentric and eccentric quadriceps contractions in 12 knees from cadavers using a three-dimensional electromagnetic tracking system. The patella shifted (translated) and tilted medially during approximately the initial 22° tibiofemoral flexion. The patella then shifted and tilted laterally for the remaining arc of tibiofemoral flexion (90°). At 90° tibiofemoral flexion, the patella had an orientation of lateral patella shift and lateral patella tilt. Patella shift was significantly more lateral between 40° and 70° tibiofemoral flexion during concentric quadriceps action than during eccentric contraction. Patella tilt was significantly more lateral between 45° and 55° tibiofemoral flexion during concentric quadriceps contraction than during eccentric action. No other significant differences were seen between the quadriceps contraction conditions. The current study supports the hypothesis that patellar instability is most likely a result of various anatomic and physiologic factors causing a failure of the extensor mechanism to deliver the patella into the femoral sulcus and that a patellar dislocation rarely would occur in a normal knee.

The Effect of Low-Intensity Pulsed Ultrasound on Autologous Osteochondral Plugs in a Canine Model:

Background Low-intensity pulsed ultrasound promotes the enchondral portion of fracture healing, which has a direct stimulatory effect on cartilage formation and maturation. Hypothesis Daily ultrasound treatment positively affects the repair and incorporation of modified autologous osteochondral plugs in a canine model. Study Design Controlled laboratory study. Methods In 18 dogs, 2 autologous plugs separated from host cartilage by a 1.5-mm gap were created on the medial femoral condyle in both knees of each dog. One knee was treated daily with a clinically available ultrasound bone stimulator. Animals were sacrificed after 6 and 12 weeks of therapy and the articular surfaces evaluated grossly and histologically. Results Ultrasound-treated sites had significantly improved gross appearance at 6 weeks and histologic appearance at 6 and 12 weeks. The interface repair tissue of ultrasound-treated sites had a more normal translucent appearance than control sites. Ultrasound treatment improved the cell morphologic characteristics of the interface repair tissue and increased subchondral bone regeneration. Bonding of the interface repair tissue between plug and adjacent cartilage was significantly improved compared with control sites. Conclusion Low-intensity pulsed ultrasound improved interface cartilage repair of autologous osteochondral plugs compared with controls in a canine model. Clinical Relevance Improvements in the quality and rate of repair of autologous osteochondral plugs may reduce postoperative recovery time and improve functional outcome.

Comparison of methods for determining presence and extent of anterior lumbar interbody fusion

Abstract Purpose of study: The purpose of this study was to compare radiographic, computed tomography (CT) imaging and histologic results for presence and extent of bony fusion of a titanium anterior lumbar interbody fusion device placed in a nonhuman primate model. Methods used: Anterior lumbar interbody fusions were performed at the L5–L6 level in 33 adult pigtail macaque monkeys using a titanium device and autogenous iliac crest bone graft. The presence of fusion (bridging trabeculations) and percent of anterior-posterior (AP) diameter healed (extent of fusion) were determined using serial AP and lateral radiographs, CT images and quantitive histology using identical evaluation methods. Matched pair nonparametric t tests were used to determine differences in results for the three techniques used. of findings: Plain film radiographs tended to overestimate the presence of bony fusion compared with both CT imaging and histology. In only 39% of cases radiographic grades were equivalent to CT and histology grades, whereas in 55% of the remaining cases the radiographic grades were greater. The difference was not, however, statistically significant. Although presence of fusion grades were equivalent in 82% of CT and histology evaluations, in only 15% of cases was the extent of fusion grade equivalent for the two techniques. CT imaging overestimated the percent AP diameter healed compared with actual histologic measurement in 73% of comparisons. This difference was statistically significant (p Relationship between findings and existing knowledge: The accuracy of plain film radiographs for determining anterior lumbar fusion is often debated with wide ranges in bony fusion reported. CT imaging is believed to be a more definitive technique. However, only through histologic evaluation can the actual presence and extent of fusion be determined and the various techniques validated. Overall significance of findings: Plain film radiographs tended to overestimate the presence of anterior interbody fusion. Although CT imaging accurately predicted the presence of fusion, it significantly overestimated the extent of bony fusion present. The lack of extensive fusion in patients with anterior interbody fusions may affect long-term stability and contribute to clinical failure. Disclosures: No disclosures. Conflict of interest: Stephen Cook, consultant; Laura Patron, grant research support; Kirk Bailey, other support; Paul Glazer, consultant, EBI.