Effect of Vancomycin Applied to the Surgical Site on Fracture Healing in a Diabetic Rat Model.

BACKGROUND: Prophylactic vancomycin treatment decreases the prevalence of surgical site and deep infections by >70% in diabetic patients undergoing reconstructive foot and ankle surgery. Thus, determining whether clinically relevant local vancomycin doses affect diabetic fracture healing is of medical interest. We hypothesized that application of vancomycin powder to the fracture site during surgery would not affect healing outcomes, but continuous exposure of vancomycin would inhibit differentiation of osteoblast precursor cells and their osteogenic activity in vitro. METHODS: The vancomycin dose used to treat the diabetic rats was a modest increase to routine surgical site vancomycin application of 1 to 2 g for a 70-kg adult (21 mg/kg). After femur fracture in BB-Wistar type 1 diabetic rats, powdered vancomycin (25 mg/kg) was administered to the fracture site. Bone marrow and periosteal cells isolated from diabetic bones were cultured and treated with increasing levels of vancomycin (0, 5, 50, 500, or 5000 µg/mL). RESULTS: Radiographic scoring, micro-computed tomography (µCT) analysis, and torsion mechanical testing failed to identify any statistical difference between the vancomycin-treated and the untreated fractured femurs 6 weeks postfracture. Low to moderate levels of vancomycin treatment (5 and 50 µg/mL) did not impair cell viability, osteoblast differentiation, or calcium deposition in either the periosteum or bone marrow-derived cell cultures. In contrast, high doses of vancomycin (5000 µg/mL) did impair viability, differentiation, and calcium deposition. CLINICAL RELEVANCE: In this diabetic rodent fracture model, vancomycin powder application at clinically relevant doses did not affect fracture healing or osteogenesis.

Local zinc treatment enhances fracture callus properties in diabetic rats.

The effects of locally applied zinc chloride (ZnCl2 ) on early and late-stage parameters of fracture healing were evaluated in a diabetic rat model. Type 1 Diabetes has been shown to negatively impact mechanical parameters of bone as well as biologic markers associated with bone healing. Zinc treatments have been shown to reverse those outcomes in tests of nondiabetic and diabetic animals. This study is the first to assess the efficacy of a noncarrier mediated ZnCl2 on bony healing in diabetic animals. This is a promising basic science approach which may lead to benefits for diabetic patients in the future. Treatment and healing were assessed through quantification of callus zinc, radiographic scoring, microcomputed tomography (µCT), histomorphometry, and mechanical testing. Local ZnCl2 treatment increased callus zinc levels at 1 and 3 days after fracture (p ≤ 0.025). Femur fractures treated with ZnCl2 showed increased mechanical properties after 4 and 6 weeks of healing. Histomorphometry of the ZnCl2 -treated fractures found increased callus cartilage area at Day 7 (p = 0.033) and increased callus bone area at Day 10 (p = 0.038). In contrast, callus cartilage area was decreased (p < 0.01) after 14 days in the ZnCl2 -treated rats. µCT analysis showed increased bone volume in the fracture callus of ZnCl2 -treated rats at 6 weeks (p = 0.0012) with an associated increase in the proportion of µCT voxel axial projections (Z-rays) spanning the fracture site. The results suggest that local ZnCl2 administration improves callus chondrogenesis leading to greater callus bone formation and improved fracture healing in diabetic rats.

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.

Local insulin application has a dose-dependent effect on lumbar fusion in a rabbit model.

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.

Low Intensity Pulsed Ultrasound Therapy (LIPUS): A review of evidence and potential applications in diabetics.

Low Intensity Pulsed Ultrasound Therapy (LIPUS) is a non-invasive treatment and aims to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing. In 2018, the National Institute for Health and Clinical Excellence (NICE) recommended that the evidence for LIPUS to promote healing of delayed-union and non-union fractures raised no major safety concerns, but the current evidence on efficacy is inadequate in quality. Little is known about the potential benefits of LIPUS for fracture healing in diabetic patients. In this article, we review the current evidence of LIPUS therapy both in animal and human studies and its possible application on fractures in diabetics.

Zinc as a Therapeutic Agent in Bone Regeneration.

Zinc is an essential mineral that is required for normal skeletal growth and bone homeostasis. Furthermore, zinc appears to be able to promote bone regeneration. However, the cellular and molecular pathways through which zinc promotes bone growth, homeostasis, and regeneration are poorly understood. Zinc can positively affect chondrocyte and osteoblast functions, while inhibiting osteoclast activity, consistent with a beneficial role for zinc in bone homeostasis and regeneration. Based on the effects of zinc on skeletal cell populations and the role of zinc in skeletal growth, therapeutic approaches using zinc to improve bone regeneration are being developed. This review focuses on the role of zinc in bone growth, homeostasis, and regeneration while providing an overview of the existing studies that use zinc as a bone regeneration therapeutic.

Medical Malpractice in Orthopedic Surgery: A Westlaw-Based Demographic Analysis.

A recent study that evaluated the risk of facing a malpractice claim by physician specialty found that orthopedic surgeons were at a significantly greater risk of being sued than other medical specialists. To date, no studies have characterized trends in orthopedic surgery malpractice claims. The Westlaw legal database was used to locate state and federal jury verdicts and settlements related to medical malpractice and orthopedic surgery from 2010 to 2016. Eighty-one cases were analyzed. The mean age of the affected patients and/or plaintiffs was 53.4 years. Spine surgery (21 cases; 25.9%), knee surgery (17 cases; 21.0%), and hip surgery (11 cases; 13.6%) were litigated most often. Procedural error (71 cases; 87.7%) and negligence (58 cases; 71.6%) were the 2 most commonly cited reasons for litigation. The jury found in favor of the defendant in most (50 cases; 61.7%) of the cases. The mean plaintiff (17 cases; 21.0%) verdict payout was $3,015,872, and the mean settlement (13 cases; 16.0%) value was $1,570,833. Unnecessary surgery (odds ratio [OR], 12.29; 95% confidence interval [CI], 1.91-108.46; P=.040) and surgery resulting in death (OR, 26.26; 95% CI, 2.55-497.42; P=.040) were significant predictors of a verdict in favor of the plaintiff. Patient death (OR, 0.05; 95% CI, 0.01-0.38; P=.021) and male patient sex (OR, 0.26; 95% CI, 0.09-0.71; P=.033) were significant negative predictors of a verdict in favor of the defendant. The jury found in favor of the defendant orthopedic surgeon in most cases. Procedural error and/or negligence were cited most commonly by the plaintiffs as the bases for the claims. Verdicts in favor of the plaintiffs resulted in payouts nearly double those of settlements. [Orthopedics. 2018; 41(5):e615-e620.].

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.

Local Zinc Chloride Release From a Calcium Sulfate Carrier Enhances Fracture Healing.

BACKGROUND: This study examined the efficacy of calcium sulfate (CaSO4) as a carrier for intramedullary delivery of zinc chloride (ZnCl2) to treat fracture healing in a BB Wistar rat model. A non-carrier-mediated injection of 3.0 mg/kg of ZnCl2 has previously been shown to enhance fracture healing. METHODS: A heterogeneous mixture of ZnCl2 and CaSO4 was administered into the intramedullary femoral canal and a mid-diaphyseal femur fracture was created unilaterally. Early and late parameters of fracture healing were assessed using biomechanical testing, radiographic scoring, quantitative histomorphometry (for percentage of new cartilage and bone within the fracture callus), and long-term histologic evaluation. RESULTS: Fractures treated with 1.0 mg/kg of ZnCl2/CaSO4 demonstrated a significantly higher maximum torque to failure compared with both CaSO4 (P = 0.048) and saline (P = 0.005) controls at 4 weeks postfracture (396.4 versus 251.3 versus 178.7 N mm, respectively). Statistically significant increases in torsional rigidity, effective shear modulus, and effective shear stress were also found, as well as a 3.5 times increase in radiographic score (based on bone union). Histologic examination of the fracture callus indicated enhanced chondrogenesis at day 14 postfracture, with increased percent cartilage for the ZnCl2/CaSO4 group compared with saline (P = 0.0004) and CaSO4 (P = 0.0453) controls. Long-term radiographic and histologic evaluation revealed no abnormal bone formation or infection up to 12 weeks postoperatively. CONCLUSIONS: The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site.

The Role of Orthobiologics in Fracture Healing and Arthrodesis.

Nonunion after tibial shaft fracture and hindfoot arthrodesis remains a major problem. Known risk factors include advanced age, immunosuppression, smoking, and diabetes. Several factors must be considered in the fracture healing process. This review evaluates the efficacy of orthobiologics in improving union rates after fracture or arthrodesis. Use of compounds have shown increased cellular proliferation experimentally. Percutaneous autologous bone marrow has shown increased cellular proliferation. Matrix supplementation has shown significant improvements in bone healing. Several studies have highlighted the importance of adequate graft fill over graft type. Patients at increased risk for nonunion would benefit most from these adjuvant therapies.

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.

Orthobiologics in Foot and Ankle Surgery.

Exploration into the molecular aspects of the healing process has led to the development of autologous and recombinant biologic agents. These products, collectively known as orthobiologics, have the potential to optimize favorable outcomes with respect to bone and soft-tissue restoration and to maximize the natural healing response. These orthobiologics include platelet-derived growth factor, bone morphogenetic proteins, and platelet-rich plasma. Although the usefulness of these growth factors is well described in various fields of surgery, few data exist to support or oppose the specific application of growth factors in foot and ankle surgery.