Evidence based review of literature on detriments to healing of diabetic foot ulcers.

BACKGROUND: Diabetes mellitus places a substantial burden on society worldwide. Diabetic foot ulcers are a challenging problem for clinicians. Seven generally accepted detriments to healing of diabetic foot ulcers were identified: infection, glycaemic control, vascular supply, smoking, nutrition, deformity and offloading. The aim of this paper is to present a comprehensive evidence based review of the literature available on detriments to healing of diabetic foot ulcers. METHOD: A research question was generated for each of the detriments to healing and a comprehensive review of the literature was performed using the Pubmed database in July 2014. All articles were assessed for relevancy and a level of evidence was assigned. An analysis of the total body of literature was used to assign a grade of recommendation to each detriment. RESULTS: Grade A recommendation was assigned to offloading as there was good evidence supporting this intervention. Grade B recommendation was assigned to deformity as there was fair evidence consistent with the hypothesis. Infection and vascular supply had poor quality evidence supporting the research question and grade C recommendation was assigned. Grade I recommendation was assigned to glycaemic control, smoking and nutrition as there was insufficient and conflicting evidence available. CONCLUSION: Our literature review revealed good evidence for some factors and insufficient literature on others. Further studies are needed to provide quality evidence regarding detriments to healing of diabetic ulcers.

The effect of locally delivered recombinant human bone morphogenetic protein-2 with hydroxyapatite/tri-calcium phosphate on the biomechanical properties of bone in diabetes-related osteoporosis.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is particularly effective in improving osteogenesis in patients with diminished bone healing capabilities, such as individuals with type 1 diabetes mellitus (T1DM) who have impaired bone healing capabilities and increased risk of developing osteoporosis. This study measured the effects of rhBMP-2 treatment on osteogenesis by observing the dose-dependent effect of localized delivery of rhBMP-2 on biomechanical parameters of bone using a hydroxyapatite/tri-calcium phosphate (HA/TCP) carrier in a T1DM-related osteoporosis animal model. MATERIALS AND METHODS: Two different doses of rhBMP-2 (LD low dose, HD high dose) with a HA/TCP carrier were injected into the femoral intramedullary canal of rats with T1DM-related osteoporosis. Two more diabetic rat groups were injected with saline alone and with HA/TCP carrier alone. Radiographs and micro-computed tomography were utilized for qualitative assessment of bone mineral density (BMD). Biomechanical testing occurred at 4- and 8-week time points; parameters tested included torque to failure, torsional rigidity, shear stress, and shear modulus. RESULTS: At the 4-week time point, the LD and HD groups both exhibited significantly higher BMD than controls; at the 8-week time point, the HD group exhibited significantly higher BMD than controls. Biomechanical testing revealed dose-dependent, higher trends in all parameters tested at the 4- and 8-week time points, with minimal significant differences. CONCLUSIONS: Groups treated with rhBMP-2 demonstrated improved bone mineral density at both 4 and 8 weeks compared to control saline groups, in addition to strong trends towards improvement of intrinsic and extrinsic biomechanical properties when compared to control groups. Data revealed trends toward dose-dependent increases in peak torque, torsional rigidity, shear stress, and shear modulus 4 weeks after rhBMP-2 treatment. LEVEL OF EVIDENCE: Not applicable.

Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats.

We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca(2+) transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca(2+) absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca(2+) transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca(2+) transport rate as well as in expression of intestinal and renal Ca(2+) transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca(2+) transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca(2+) transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca(2+) and vitamin D deficiency.

Dietary fructose inhibits lactation-induced adaptations in rat 1,25-(OH)2D3 synthesis and calcium transport.

We recently showed that excessive fructose consumption, already associated with numerous metabolic abnormalities, reduces rates of intestinal Ca(2+) transport. Using a rat lactation model with increased Ca(2+) requirements, we tested the hypothesis that mechanisms underlying these inhibitory effects of fructose involve reductions in renal synthesis of 1,25-(OH)(2)D(3). Pregnant and virgin (control) rats were fed isocaloric fructose or, as controls, glucose, and starch diets from d 2 of gestation to the end of lactation. Compared to virgins, lactating dams fed glucose or starch had higher rates of intestinal transcellular Ca(2+) transport, elevated intestinal and renal expression of Ca(2+) channels, Ca(2+)-binding proteins, and CaATPases, as well as increased levels of 25-(OH)D(3) and 1,25-(OH)(2)D(3). Fructose consumption prevented almost all of these lactation-induced increases, and reduced vitamin D receptor binding to promoter regions of Ca(2+) channels and binding proteins. Changes in 1,25-(OH)(2)D(3) level were tightly correlated with alterations in expression of 1α-hydroxylase but not with levels of parathyroid hormone and of 24-hydroxylase. Bone mineral density, content, and mechanical strength each decreased with lactation, but then fructose exacerbated these effects. When Ca(2+) requirements increase during lactation or similar physiologically challenging conditions, excessive fructose consumption may perturb Ca(2+) homeostasis because of fructose-induced reductions in synthesis of 1,25-(OH)(2)D(3).

Incidence and risk factors for surgical site infection (SSI) after primary hip hemiarthroplasty: an analysis of the ACS-NSQIP hip fracture procedure targeted database.

INTRODUCTION: Primary hip hemiarthroplasty (HHA) is frequently utilized to treat geriatric hip fractures, which are associated with significantly higher morbidity and mortality. While not particularly common, surgical site infection (SSI) is a major complication that frequently requires revision surgery in a frail population. The objective of this study was to determine the incidence of and risk factors for SSI after HHA in hip fracture patients. MATERIALS AND METHODS: This retrospective cohort study was performed using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Geriatric patients (65+) who underwent HHA for non-pathologic, traumatic hip fractures between 2016-2017 were included. Demographic variables, comorbidities, operative variables, and complications were compared between "SSI" and "non-SSI" groups. Multivariate regression identified independent risk factors for postoperative SSI. Significance was set at P = 0.05. RESULTS: A total of 6169 patients were included. The overall incidence of SSI was 1.3%. SSI was significantly associated with body mass index (BMI), preoperative functional status, congestive heart failure, chronic corticosteroid use, intraoperative time, sepsis, wound dehiscence, readmission within 30-days, and reoperation. On multivariate analysis, chronic steroid use (OR: 2.30, 95% CI: 1.13-4.70), BMI ≥ 35 kg/m2 (OR: 3.59, 95% CI: 1.57-8.18), and intraoperative time ≥120 mins (OR: 2.15, 95% CI: 1.08-4.27) were found to be independent risk factors. CONCLUSIONS: Postoperative SSI is a serious complication that is responsible for prolonged hospital stays, increased mortality, and greater healthcare costs. Here, we identified multiple risk factors for SSI after primary HHA in the US elderly population.

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.

Prospective, randomized, multi-center feasibility trial of rhPDGF-BB versus autologous bone graft in a foot and ankle fusion model.

BACKGROUND: The increased morbidity and surgical time associated with harvesting autologous bone graft (ABG) have encouraged surgeons to develop synthetic orthobiologic alternatives. The recombinant form of platelet-derived growth factor (rhPDGF-BB), an angiogenic, mitogenic, and chemotactic cytokine, has been shown to significantly enhance bone formation in human periodontal osseous defects when combined with a tricalcium phosphate carrier (ß-TCP). The purpose of this prospective, controlled, randomized, multi-center feasibility clinical trial was to compare the safety and efficacy of this biosynthetic bone graft substitute (Augment™ Bone Graft) to ABG during ankle and hindfoot fusion. MATERIALS AND METHODS: Twenty adult subjects requiring ankle or hindfoot fusion from three U.S. centers were enrolled and randomized in a 2:1 ratio to receive Augment™ or ABG, respectively. Surgical approach and fixation techniques were standardized, and minimum followup was 9 months. The primary endpoint was radiographic osseous union, evaluated by a blinded independent radiologist. Secondary endpoints included assessment of clinical success, union rate by serial computed tomography (CT) examination, time to full weightbearing, AOFAS Ankle-Hindfoot Score (AOFAS), Foot Function Index (FFI), Short Form-12 (SF-12), and Visual Analog pain assessment Scale (Pain VAS). RESULTS: At 36 weeks, 77% (10/13) of the Augment™ and 50% (3/6) of the ABG patients were fused based on radiographic criteria. There were two nonunions in the Augment™ group (9%, 2/14). Healing rates based on 12 week CT scanning (50% osseous bridging) were 69% (9/13) in the Augment™ and 60% (3/5) in the ABG groups, respectively. All functional outcome measures (FFI, AOFAS, SF-12), as well as the VAS pain scores, improved in both groups over time. Surgical procedure times lasted an average 26 minutes longer for the ABG as compared to the Augment™ populations. There were no device related serious adverse events in this study. CONCLUSION: Based on the available data, the rate of radiographic union, time to full weightbearing, and outcomes scores between the Augment™ and ABG subjects appear comparable. Augment™ may represent a safe and efficacious treatment alternative to ABG during foot and ankle arthrodesis.

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.

Complications of ankle fracture in patients with diabetes.

Ankle fractures in patients with diabetes mellitus have long been recognized as a challenge to practicing clinicians. Complications of impaired wound healing, infection, malunion, delayed union, nonunion, and Charcot arthropathy are prevalent in this patient population. Controversy exists as to whether diabetic ankle fractures are best treated noninvasively or by open reduction and internal fixation. Patients with diabetes are at significant risk for soft-tissue complications. In addition, diabetic ankle fractures heal, but significant delays in bone healing exist. Also, Charcot ankle arthropathy occurs more commonly in patients who were initially undiagnosed and had a delay in immobilization and in patients treated nonsurgically for displaced ankle fractures. Several techniques have been described to minimize complications associated with diabetic ankle fractures (eg, rigid external fixation, use of Kirschner wires or Steinmann pins to increase rigidity). Regardless of the specifics of treatment, adherence to the basic principles of preoperative planning, meticulous soft-tissue management, and attention to stable, rigid fixation with prolonged, protected immobilization are paramount in minimizing problems and yielding good functional outcomes.

In vivo kinematics of the salto total ankle prosthesis.

BACKGROUND: Recent technological advancements in total ankle arthroplasty (TAA) have included the introduction of the mobile bearing concept. This bearing has several advantages, but researchers have questioned whether or not increased mobility sacrifices joint stability or durability of the implant. The present study evaluated the kinematics of this type of prosthesis implanted in patients. MATERIALS AND METHODS: Fluoroscopy and 3D-to-2D registration techniques were used to determine the in vivo kinematics for 20 TAA subjects performing two activities: gait and step-up. The motion of the prostheses was described in terms of clinical rotations and as rotation about the helical (screw) axis. Then, the anterior-posterior translation and axial rotation of the mobile bearing insert were determined. RESULTS: Among the clinical rotations, the dorsi-/plantarflexion was the most dominant, revealing the greatest pattern change and the largest magnitude. During gait, the orientation of the prosthetic components changed smoothly from plantarflexion to dorsiflexion. The average range of this motion was 9.2 degrees. For step-up activity, the range was 8.0 degrees. However, between 33% and 66% of stance phase, the talar component's orientation changed from dorsiflexion to plantarflexion. The average absolute range of anterior-posterior translation of the mobile bearing insert was 1.5 mm and 2.3 mm for gait and step-up, respectively. CONCLUSION: These measured translations were relatively small and may suggest that the rotational portion of the motion was more dominant than translational and provided sufficient mobility.

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.

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.].

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.