Improved osteogenesis in rat femur segmental defects treated with human allograft and zinc adjuvants.

Bone allograft is widely used to treat large bone defects or complex fractures. However, processing methods can significantly compromise allograft osteogenic activity. Adjuvants that can restore the osteogenic activity of processed allograft should improve clinical outcomes. In this study, zinc was tested as an adjuvant to increase the osteogenic activity of human allograft in a Rag2 null rat femoral defect model. Femoral defects were treated with human demineralized bone matrix (DBM) mixed with carboxy methyl cellulose containing ZnCl2 (0, 75, 150, 300 µg) or Zn stearate (347 µg). Rat femur defects treated with DBM-ZnCl2 (75 µg) and DBM-Zn stearate (347 µg) showed increased calcified tissue in the defect site compared to DBM alone. Radiograph scoring and µCT (microcomputed tomography) analysis showed an increased amount of bone formation at the defects treated with DBM-Zn stearate. Use of zinc as an adjuvant was also tested using human cancellous bone chips. The bone chips were soaked in ZnCl2 solutions before being added to defect sites. Zn adsorbed onto the chips in a time- and concentration-dependent manner. Rat femur defects treated with Zn-bound bone chips had more new bone in the defects based on µCT and histomorphometric analyses. The results indicate that zinc supplementation of human bone allograft improves allograft osteogenic activity in the rat femur defect model.

Effects of local vanadium delivery on diabetic fracture healing.

This study evaluated the effect of local vanadyl acetylacetonate (VAC), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, and radiographic scoring were performed, as well as histomorphometry, including percent bone, percent cartilage, and osteoclast numbers. Fractures treated with local 1.5 mg/kg VAC possessed significantly increased mechanical properties compared to controls at 6 weeks post-fracture, including increased torque to failure (15%; p = 0.046), shear modulus (89%; p = 0.043), and shear stress (81%; p = 0.009). The radiographic scoring analysis showed increased cortical bridging at 4 weeks and 6 weeks (119%; p = 0.036 and 209%; p = 0.002) in 1.5 mg/kg VAC treated groups. Histomorphometry of the fracture callus at days 10 and 14 showed increased percent cartilage (121%; p = 0.009 and 45%; p = 0.035) and percent mineralized tissue (66%; p = 0.035 and 58%; p = 0.006) with local VAC treated groups compared to control. Additionally, fewer osteoclasts were observed in the local VAC treated animals as compared to controls at day 14 (0.45% ± 0.29% vs. 0.83% ± 0.36% of callus area; p = 0.032). The results suggest local administration of VAC acts to modulate osteoclast activity and increase percentage of early callus cartilage, ultimately enhancing mechanical properties comparably to non-diabetic animals treated with local VAC. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2174-2180, 2017.

The Importance of Sufficient Graft Material in Achieving Foot or Ankle Fusion.

BACKGROUND: Nonunion, an important complication following foot and ankle arthrodesis, causes substantial morbidity and disability. In patients undergoing hindfoot and ankle arthrodesis, autogenous bone graft (autograft) or a suitable alternative is often used to promote osseous fusion across the joint. This study assessed the importance of adequate graft material in the fusion space to achieve joint fusion during ankle and hindfoot arthrodesis. METHODS: This study used data from a previously published clinical trial of grafting material (recombinant human platelet-derived growth factor-BB with beta-tricalcium phosphate [rhPDGF-BB/ß-TCP] or autograft) for healing in hindfoot and ankle arthrodesis to correlate the amount of graft fill at 9 weeks with ultimate healing. Patients who received supplemental graft material for ankle or hindfoot arthrodesis for end-stage ankle or hindfoot arthritis were stratified according to nonunion risk factors and surgical fusion site. Patients underwent arthrodesis using standard rigid internal fixation. Graft fill was defined as "adequate" if the material occupied ≥50% of the cross-sectional area of the fusion space on a computed tomography (CT) scan made at 9 weeks. Fusion was defined as osseous bridging of ≥50% of each articulation on a CT scan made at 24 weeks. Three hundred and seventy-nine patients with 573 joints (383 managed with rhPDGF-BB/ß-TCP and 190 managed with autograft) that underwent arthrodesis had complete follow-up with 9-week and 24-week CT scans available. RESULTS: Overall, 472 (82%) of 573 joints had adequate graft fill; of those, 383 (81%) were successfully fused at 24 weeks compared with 21 (21%) of 101 joints without adequate graft fill (p < 0.0001). Absolute fusion rate differences (joints with adequate fill minus those without adequate fill) were consistent across joints (61% to 63%) and for graft materials. The overall odds ratio (OR) of successful fusion in joints with adequate graft fill compared with those without adequate graft fill was 16.4 (95% confidence interval, 9.6 to 27.9). CONCLUSIONS: This study demonstrates an association between the amount of graft material and successful hindfoot and ankle arthrodesis. Graft material filling of ≥50% of the fusion space at 9 weeks, regardless of type or origin, was associated with significantly higher fusion rates at 24 weeks. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Zinc has insulin-mimetic properties which enhance spinal fusion in a rat model.

BACKGROUND CONTEXT: Previous studies have found that insulin or insulin-like growth factor treatment can stimulate fracture healing in diabetic and normal animal models, and increase fusion rates in a rat spinal fusion model. Insulin-mimetic agents, such as zinc, have demonstrated antidiabetic effects in animal and human studies, and these agents that mimic the effects of insulin could produce the same beneficial effects on bone regeneration and spinal fusion. PURPOSE: The purpose of this study was to analyze the effects of locally applied zinc on spinal fusion in a rat model. STUDY DESIGN/SETTING: Institutional Animal Care and Use Committee-approved animal study using Sprague-Dawley rats was used as the study design. METHODS: Thirty Sprague-Dawley rats (450-500 g) underwent L4-L5 posterolateral lumbar fusion (PLF). After decortication and application of approximately 0.3 g of autograft per side, one of three pellets were added to each site: high-dose zinc calcium sulfate (ZnCaSO4), low-dose ZnCaSO4 (half of the high dose), or a control palmitic acid pellet (no Zn dose). Systemic blood glucose levels were measured 24 hours postoperatively. Rats were sacrificed after 8weeks and the PLFs analyzed qualitatively by manual palpation and radiograph review, and quantitatively by micro-computed tomography (CT) analysis of bone volume and trabecular thickness. Statistical analyses with p-values set at .05 were accomplished with analysis of variance, followed by posthoc tests for quantitative data, or Mann-Whitney rank tests for qualitative assessments. RESULTS: Compared with controls, the low-dose zinc group demonstrated a significantly higher manual palpation grade (p=.011), radiographic score (p=.045), and bone formation on micro-CT (172.9 mm(3) vs. 126.7 mm(3) for controls) (p<.01). The high-dose zinc also demonstrated a significantly higher radiographic score (p=.017) and bone formation on micro-CT (172.7 mm(3) vs. 126.7 mm(3)) (p<.01) versus controls, and was trending toward higher manual palpation scores (p=.058). CONCLUSIONS: This study demonstrates the potential benefit of a locally applied insulin-mimetic agent, such as zinc, in a rat lumbar fusion model. Previous studies have demonstrated the benefits of local insulin application in the same model, and it appears that zinc has similar effects.

Local insulin therapy affects fracture healing in a rat model.

A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.

Bone and wound healing in the diabetic patient.

Impaired soft tissue regeneration and delayed osseous healing are known complications associated with diabetes mellitus with regard to orthopedic surgery, making the management and treatment of diabetic patients undergoing foot and ankle surgery more complex and difficult. At the moment several options are available to address the known issues that complicate the clinical outcomes in these high-risk patients. Using a multifaceted approach, with close attention to intraoperative and perioperative considerations including modification of surgical technique to supplement fixation, local application of orthobiologics, tight glycemic control, administration of supplementary oxygen, and biophysical stimulation via low-intensity pulsed ultrasound and electrical bone stimulation, the impediments associated with diabetic healing can potentially be overcome, to yield improved clinical results for diabetic patients after acute or elective foot and ankle surgery.

Recombinant human platelet-derived growth factor BB (rhPDGF-BB) and beta-tricalcium phosphate/collagen matrix enhance fracture healing in a diabetic rat model.

Diabetes mellitus is a common systemic disease that has been associated with poor fracture healing outcomes. The mechanism through which diabetes impairs bone regeneration is unknown. One possible mechanism may be related to either decreased or uncoordinated release of local growth factors at the fracture site. Indeed, previous studies have found reduced platelet-derived growth factor (PDGF) levels in the fracture callus of diabetic rats, suggesting that local application of PDGF may overcome the negative effects of diabetes and promote fracture healing. To test this hypothesis, low (22 microg) and high (75 ug) doses of recombinant human PDGF-BB (rhPDGF-BB) were applied directly to femur fracture sites in BB Wistar diabetic rats that were then compared to untreated or vehicle-treated animals. rhPDGF-BB treatment significantly increased early callus cell proliferation compared to that in control specimens. Low dose rhPDGF-BB treatment significantly increased callus peak torque values (p < 0.05) at 8 weeks after fracture as compared to controls. High dose rhPDGF-BB treatment increased callus bone area at 12 weeks postfracture. These data indicate that rhPDGF-BB treatment ameliorates the effects of diabetes on fracture healing by promoting early cellular proliferation that ultimately leads to more bone formation. Local application of rhPDGF-BB may be a new therapeutic approach to treat diabetes-impaired fracture healing.

Stimulation of ankle cartilage: other emerging technologies (cellular, electricomagnetic, etc.).

Advances in understanding age-related changes in articular cartilage, joint homeostasis, the natural healing process after cartilage injury, and improved standards for evaluation of a joint surface made the ultimate goal of cartilage repair a possibility. New strategies for enhancement of articular cartilages' limited healing potential and biologic regeneration include advances in tissue engineering and the use of electromagnetic fields. This article reviews developments in basic science and clinical research made with these emerging technologies concerning treatment of articular cartilage defects and treatment of osteoarthritis of the ankle.

Bioadjuvants for complex ankle and hindfoot reconstruction.

Many reconstructive options exist for symptomatic hindfoot and ankle problems. Hindfoot and tibiotalar fusions are reliable procedures with consistent results. Unfortunately, many potential complications have been cited throughout the literature. Although the most important aspect in any fusion surgery is meticulous technique, advances in technology, including PRP, bone stimulators, and BMPs seem to be useful additions in the quest to achieve solid fusions with decreased complications.