Pain Relief and Safety Outcomes with Cervical 10 kHz Spinal Cord Stimulation: Systematic Literature Review and Meta-analysis.

BACKGROUND: Chronic pain in head, neck, shoulders and upper limbs is debilitating, and patients usually rely on pain medications or surgery to manage their symptoms. However, given the current opioid epidemic, non-pharmacological interventions that reduce pain, such as spinal cord stimulation (SCS), are needed. The purpose of this study was to review the evidence on paresthesia-free 10 kHz SCS therapy for neck and upper extremity pain. METHODS: Systematic literature search was performed for studies reporting outcomes for cervical 10 kHz SCS using date limits from May 2008 to November 2020. The study results were analyzed and described qualitatively. Additionally, when feasible, meta-analyses of the outcome data, with 95% confidence intervals (CIs), were conducted using both the fixed-effects (FE) and random-effects (RE) models. RESULTS: A total of 15 studies were eligible for inclusion. The proportion of patients who achieved ≥ 50% pain reduction was 83% (95% CI 77-89%) in both the FE and RE models. The proportion of patients who reduced/eliminated their opioid consumption was 39% (95% CI 31-46%) in the FE model and 39% (95% CI 31-48%) in the RE model. Pain or discomfort with the implant, lead migration, and infections were potential risks following cervical SCS. Explant rate was 0.1 (95% CI 0.0-0.2) events per 100 person-months, and no patients in the included studies experienced a neurological complication or paresthesia. CONCLUSION: Findings suggest 10 kHz SCS is a promising, safe, minimally invasive alternative for managing chronic upper limb and neck pain.

Bidirectional Expandable Technology for Transforaminal or Posterior Lumbar Interbody Fusion: A Retrospective Analysis of Safety and Performance.

BACKGROUND: Expandable devices for transforaminal or posterior lumbar interbody fusion (TLIF and PLIF, respectively) may enable greater restoration of disc height, foraminal height, and stability within the interbody space than static spacers. Medial-lateral expansion may also increase stability and resistance to subsidence. This study evaluates the clinical and radiographic outcomes from early experience with a bidirectional expandable device. METHODS: This was a retrospective analysis of a continuous series of patients across 3 sites who had previously undergone TLIF or PLIF surgery with a bidirectional expandable interbody fusion device (FlareHawk, Integrity Implants, Inc) at 1 or 2 contiguous levels between L2 and S1. Outcomes included the Oswestry Disability Index (ODI), a visual analog scale (VAS) for back pain or leg pain, radiographic fusion by 1 year of follow-up, subsidence, device migration, and adverse events (AE). RESULTS: There were 58 eligible patients with radiographs for 1-year fusion assessments and 45 patients with ODI, VAS back pain, or VAS leg pain data at baseline and a mean follow-up of 4.5 months. The ODI, VAS back pain, and VAS leg pain scores improved significantly from baseline to final follow-up, with mean improvements of 14.6 ± 19.1, 3.4 ± 2.6, and 3.9 ± 3.4 points (P < .001 for each), respectively. In addition, 58% of patients achieved clinically significant improvements in ODI, 76% in VAS back pain, and 71% in VAS leg pain. By 1 year, 96.6% of patients and 97.4% of levels were considered fused. There were zero cases of device subsidence and 1 case of device migration (1.7%). There were zero device-related AEs, 1 intraoperative dural tear, and 3 subsequent surgical interventions. CONCLUSIONS: The fusion rate, improvements in patient-reported outcomes, and the AEs observed are consistent with those of other devices. The bidirectional expansion mechanism may provide other important clinical value, but further studies will be required to elucidate the unique advantages. LEVEL OF EVIDENCE: 4.

Cement augmentation of calcar screws may provide the greatest reduction in predicted screw cut-out risk for proximal humerus plating based on validated parametric computational modelling: Augmenting proximal humerus fracture plating.

AIMS: Fixation of osteoporotic proximal humerus fractures remains challenging even with state-of-the-art locking plates. Despite the demonstrated biomechanical benefit of screw tip augmentation with bone cement, the clinical findings have remained unclear, potentially as the optimal augmentation combinations are unknown. The aim of this study was to systematically evaluate the biomechanical benefits of the augmentation options in a humeral locking plate using finite element analysis (FEA). METHODS: A total of 64 cement augmentation configurations were analyzed using six screws of a locking plate to virtually fix unstable three-part fractures in 24 low-density proximal humerus models under three physiological loading cases (4,608 simulations). The biomechanical benefit of augmentation was evaluated through an established FEA methodology using the average peri-screw bone strain as a validated predictor of cyclic cut-out failure. RESULTS: The biomechanical benefit was already significant with a single cemented screw and increased with the number of augmented screws, but the configuration was highly influential. The best two-screw (mean 23%, SD 3% reduction) and the worst four-screw (mean 22%, SD 5%) combinations performed similarly. The largest benefits were achieved with augmenting screws purchasing into the calcar and having posteriorly located tips. Local bone mineral density was not directly related to the improvement. CONCLUSION: The number and configuration of cemented screws strongly determined how augmentation can alleviate the predicted risk of cut-out failure. Screws purchasing in the calcar and posterior humeral head regions may be prioritized. Although requiring clinical corroborations, these findings may explain the controversial results of previous clinical studies not controlling the choices of screw augmentation.

Lumbar Discectomy and Reoperation Among Workers' Compensation Cases in Florida and New York: Are Treatment Trends Similar to Other Payer Types?

OBJECTIVE: The aim of this study was to better understand current treatment trends and revision rates for lumbar disc herniation (LDH) in the workers' compensation (WC) population compared with other payer types. METHODS: This was a retrospective analysis of outpatient claims data from Florida and New York during 2014 to 2016. RESULTS: WC patients were less likely to undergo discectomy in Florida (15% vs 19%; P < 0.001) and New York (10% vs 15%; P < 0.001). The odds of WC patients undergoing revision discectomy were 1.5 times greater than patients covered by private payers or all other non-WC payers (P = 0.002). CONCLUSIONS: WC patients undergo discectomy significantly less often than non-WC counterparts, which may be related to a higher risk of reoperation. New evidence-based treatments, such as annular repair, may be critical to advancing care in this unique population.

Superiority Claims for Spinal Devices: A Systematic Review of Randomized Controlled Trials.

STUDY DESIGN: Systematic review. OBJECTIVES: Superiority claims for medical devices are commonly derived from noninferiority trials, but interpretation of such claims can be challenging. This study aimed to (a) establish the prevalence of noninferiority and superiority designs among spinal device trials, (b) assess the frequency of post hoc superiority claims from noninferiority studies, and (c) critically evaluate the risk of bias in claims that could translate to misleading conclusions. METHODS: Study bias was assessed using the Cochrane Risk of Bias Tool. The risk of bias for the superiority claim was established based on post hoc hypothesis specification, analysis of the intention-to-treat population, post hoc modification of a priori primary outcomes, and sensitivity analyses. RESULTS: Forty-one studies were identified from 1895 records. Nineteen (46%) were noninferiority trials. Fifteen more (37%) were noninferiority trials with a secondary superiority hypothesis specified a priori. Seven (17%) were superiority trials. Of the 34 noninferiority trials, 14 (41%) made superiority claims. A medium or high risk of bias was related to the superiority claim in 9 of those trials (64%), which was due to the analyzed population, lacking sensitivity analyses, claims not being robust during sensitivity analyses, post hoc hypotheses, or modified endpoints. Only 4 of the 14 (29%) noninferiority studies provided low bias in the superiority claim, compared with 3 of the 5 (60%) superiority trials. CONCLUSIONS: Health care decision makers should carefully evaluate the risk of bias in each superiority claim and weigh their conclusions appropriately.

Closing the Treatment Gap for Lumbar Disc Herniation Patients with Large Annular Defects: A Systematic Review of Techniques and Outcomes in this High-risk Population.

Lumbar disc herniation (LDH) is one of the most common spinal pathologies and can be associated with debilitating pain and neurological dysfunction. Discectomy is the primary surgical intervention for LDH and is typically successful. Yet, some patients experience recurrent LDH (RLDH) after discectomy, which is associated with worse clinical outcomes and greater socioeconomic burden. Large defects in the annulus fibrosis are a significant risk factor for RLDH and present a critical treatment challenge. It is essential to identify reliable and cost-effective treatments for this at-risk population. A systematic review of the PubMed and Embase databases was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies describing the treatment of LDH patients with large annular defects. The incidence of large annular defects, measurement technique, RLDH rate, and reoperation rate were compiled and stratified by surgical technique. The risk of bias was scored for each study and for the identification of RLDH and reoperation. Study heterogeneity and pooled estimates were calculated from the included articles. Fifteen unique studies describing 2,768 subjects were included. The pooled incidence of patients with a large annular defect was 44%. The pooled incidence of RLDH and reoperation following conventional limited discectomy in this population was 10.6% and 6.0%, respectively. A more aggressive technique, subtotal discectomy, tended to have lower rates of RLDH (5.8%) and reoperation (3.8%). However, patients treated with subtotal discectomy reported greater back and leg pain associated with disc degeneration. The quality of evidence was low for subtotal discectomy as an alternative to limited discectomy. Each report had a high risk of bias and treatments were never randomized. A recent randomized controlled trial with 550 subjects examined an annular closure device (ACD) and observed significant reductions in RLDH and reoperation rates (>50% reduction). Based on the available evidence, current discectomy techniques are inadequate for patients with large annular defects, leaving a treatment gap for this high-risk population. Currently, the strongest evidence indicates that augmenting limited discectomy with an ACD can reduce RLDH and revision rates in patients with large annular defects, with a low risk of device complications.

Adjustable Rigid Interspinous Process Fixation: A Biomechanical Study of Segmental Lordosis and Interbody Loading in the Lumbar Spine.

Background Rigid interspinous process fixation (ISPF) may serve as a minimally disruptive adjunct to lumbar interbody fusion. Previous biomechanical assessments of ISPF have demonstrated particularly advantageous outcomes in stabilizing the sagittal plane. However, ISPF has not been well characterized in regard to its impact on interbody load, which has implications for the risk of cage migration or subsidence, and sagittal alignment. The purpose of this study was to biomechanically assess in vitro the interbody load (IBL), focal lordosis (FL), and spinous process loading generated by in situ compression/distraction with a novel ISPF device capable of incremental in situ shortening/extension. Bilateral pedicle screw fixation (BPSF) was used as a control. Methods Two fresh frozen human lumbar spines were thawed and musculature was removed, leaving ligaments intact. Seven functional spinal units were iteratively tested, which involved a standard lateral discectomy, placement of a modified lateral cage possessing two load cells, and posterior fixation. BPSF and ISPF were performed at each level, with order of fixation was randomized. BPSF was first performed with maximum compressive exertion followed by 75% exertion to represent clinical application. The ISPF device was implanted at a neutral height and incrementally shortened/extended in situ in 1-mm increments. IBL and FL were measured under each condition. Loads on the spinous processes were estimated through bench-top mechanical calibration. Results No significant differences in IBL were observed, but the ISPF device produced a significantly greater change in FL compared to the clinically relevant BPSF compression. IBL, as a function of ISPF device height, expressed linear behavior during compression and exponential behavior during distraction. Conclusions The novel ISPF device produced clinically effective IBL and FL, performing well in comparison to BPSF. Additionally, incremental ISPF device manipulation demonstrated predictable and clinically safe trends regarding loading of the interbody space and spinous processes.

Logistical and Economic Advantages of Sterile-Packed, Single-Use Instruments for Total Knee Arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) is well established as a clinically successful and cost-effective procedure. The transition of the US healthcare system from a fee-for-service model to a value-based care model requires careful examination of patient care to ensure both quality and efficiency. Sterile-packed, single-use instruments have been introduced as a tool to help streamline the operating room (OR) logistics while reducing sterilization requirements. The aim of this study was to examine the potential logistic and economic benefits of single-use instruments compared to traditional, reusable instruments for TKA. METHODS: Four variables related to TKA costs and logistics were modeled in this study: OR turnover time tray sterilization, tray management time, and 90-day infection rates. Model input data for traditional instruments and single-use instruments were based on peer-reviewed literature. A total of 200 sites and 500 cases per site were simulated using the Monte-Carlo-Technique. RESULTS: The median total cost savings with single-use instruments was $994 per case. The largest driver for cost savings was tray sterilization. Sites with higher staff wages and sterilization costs had a larger probability of realizing greater cost savings with adoption of single-use instruments. In cases using single-use instruments, up to 51% of operating days could have accommodated an additional procedure due to the time savings in OR turnover. CONCLUSION: This cost modeling study observed significant potential for logistical and economic improvements in TKA with single-use vs reusable instruments. Although few studies have been conducted to measure the impact of single-use instruments in practice, the results of these simulations motivate further investigation.

Post-lumbar discectomy reoperations that are associated with poor clinical and socioeconomic outcomes can be reduced through use of a novel annular closure device: results from a 2-year randomized controlled trial.

INTRODUCTION: Lumbar discectomy patients with large annular defects are at a high risk for reherniation and reoperation, which could be mitigated through the use of an annular closure device (ACD). To identify the most effective treatment pathways for this high-risk population, it is critical to understand the clinical outcomes and socioeconomic costs among reoperated patients as well as the utility of ACD for minimizing reoperation risk. METHODS: This was a post hoc analysis of a prospective, multicenter, randomized controlled trial (RCT) designed to investigate the safety and efficacy of an ACD. All 550 patients (both ACD treated and control) from the RCT with follow-up data through 2 years were included in this analysis (69 reoperated and 481 non-reoperated). Reoperations were defined as any revision surgery of the index level, regardless of indication. Equivalent U.S. Medicare expenditures for reoperations were estimated through cost multipliers derived from the commercially available PearlDiver database. RESULTS: A significantly greater number of control patients (45/278; 16%) compared to ACD patients (24/272; 9%) underwent a revision surgery at the index level within 2 years of followup (p=0.01). At 2 years of follow-up, the reoperated patients had significantly worse Oswestry Disability Index scores and visual analog scale for leg and back pain scores compared to their non-reoperated counterparts (p<0.0001). The total estimated direct medical costs for reoperation were US $952,348 ($13,802 per reoperated patient), with control patients accounting for the majority of this cost burden ($565,188; 59%). CONCLUSION: Post-discectomy reoperation is associated with significantly increased patient morbidity, missed work, and direct treatment costs in a population at high risk for reherniation. Annular closure helped minimize this clinical and socioeconomic burden by reducing the incidence of reoperation by nearly 50% (16% control vs 9% ACD).

Validated computational framework for efficient systematic evaluation of osteoporotic fracture fixation in the proximal humerus.

The high rate of fixation failure in osteoporotic proximal humerus fractures indicate the need for improved solutions. Computer simulations may help to overcome the limitations of the gold standard biomechanical testing in evaluating the performance of new implants and enhance the effectivity and outcome of the design process. This study presents a framework for automated computational analysis that facilitates efficient and systematic evaluation of proximal humerus fracture plating under a variety of conditions including bone quality, fracture pattern, implant configuration and loading regime. The underlying finite element methodology was previously validated. The capabilities of the software tool are demonstrated by virtually reproducing a previously published biomechanical study on the effect of screw augmentation and showing that the models capture the essence of the experimental results. Due to the modular design of the framework, the currently available set of angle-stable plate implants can be readily expanded to include other fixations such as intramedullary nails. Besides the capability to compare already existing solutions, the tool can provide rapid feedback on novel ideas. Therefore, it is expected to efficiently complement and partially replace expensive experimental tests and aid development and optimization of implant designs for improved fixation of osteoporotic proximal humerus fractures.

Fatigue failure of plated osteoporotic proximal humerus fractures is predicted by the strain around the proximal screws.

The high rate of required reoperation indicates that treatment of fragility fractures at the proximal humerus still remains a major challenge in trauma surgery. Improved fixation approaches are needed. Several limitations of the conventional implant development process involving experimental testing could be overcome by using computer models that would allow systematic and efficient analyses. However, such models require experimental validation. This study investigated if linear elastic continuum finite element (FE) models can predict experimental fatigue failure in locking plate fixation of osteoporotic proximal humerus fractures. Three-part fractures were created in twenty fresh-frozen proximal humeri of elderly donors, stabilized with angular stable plate osteosythesis and tested to failure in a previously developed experimental setup using a cyclic loading protocol with increasing peak load. Case-specific, linear elastic FE models of the instrumented samples were created from CT images and loaded virtually by mimicking the experimental conditions. Average principal strains were evaluated in cylindrical regions around the proximal screws. Parametric sensitivity analysis was performed to investigate the effects of specific model parameters on the results. The number of cycles to failure was 10500 ± 3300 (mean ± SD, range: 3100 - 16400) and showed a strong logarithmic correlation with the average compressive principal strain around the screws (R2 = 0.90). These results suggest that the latter parameter may be used as a surrogate estimate for construct stability under cyclic loading. The computationally cheap linear elastic continuum FE analysis could be used as an efficient screening tool for optimization and development of implants. Further work is required to investigate if the findings of this study apply to other loading modes and bone-implant constructs.

New approaches for cement-based prophylactic augmentation of the osteoporotic proximal femur provide enhanced reinforcement as predicted by non-linear finite element simulations.

BACKGROUND: High incidence and increased mortality related to secondary, contralateral proximal femoral fractures may justify invasive prophylactic augmentation that reinforces the osteoporotic proximal femur to reduce fracture risk. Bone cement-based approaches (femoroplasty) may deliver the required strengthening effect; however, the significant variation in the results of previous studies calls for a systematic analysis and optimization of this method. Our hypothesis was that efficient generalized augmentation strategies can be identified via computational optimization. METHODS: This study investigated, by means of finite element analysis, the effect of cement location and volume on the biomechanical properties of fifteen proximal femora in sideways fall. Novel cement cloud locations were developed using the principles of bone remodeling and compared to the "single central" location that was previously reported to be optimal. FINDINGS: The new augmentation strategies provided significantly greater biomechanical benefits compared to the "single central" cement location. Augmenting with approximately 12ml of cement in the newly identified location achieved increases of 11% in stiffness, 64% in yield force, 156% in yield energy and 59% in maximum force, on average, compared to the non-augmented state. The weaker bones experienced a greater biomechanical benefit from augmentation than stronger bones. The effect of cement volume on the biomechanical properties was approximately linear. Results of the "single central" model showed good agreement with previous experimental studies. INTERPRETATION: These findings indicate enhanced potential of cement-based prophylactic augmentation using the newly developed cementing strategy. Future studies should determine the required level of strengthening and confirm these numerical results experimentally.

3D Printing of Calcium Phosphate Ceramics for Bone Tissue Engineering and Drug Delivery.

Additive manufacturing, also known as 3D printing, has emerged over the past 3 decades as a disruptive technology for rapid prototyping and manufacturing. Vat polymerization, powder bed fusion, material extrusion, and binder jetting are distinct technologies of additive manufacturing, which have been used in a wide variety of fields, including biomedical research and tissue engineering. The ability to print biocompatible, patient-specific geometries with controlled macro- and micro-pores, and to incorporate cells, drugs and proteins has made 3D-printing ideal for orthopaedic applications, such as bone grafting. Herein, we performed a systematic review examining the fabrication of calcium phosphate (CaP) ceramics by 3D printing, their biocompatibility in vitro, and their bone regenerative potential in vivo, as well as their use in localized delivery of bioactive molecules or cells. Understanding the advantages and limitations of the different 3D printing approaches, CaP materials, and bioactive additives through critical evaluation of in vitro and in vivo evidence of efficacy is essential for developing new classes of bone graft substitutes that can perform as well as autografts and allografts or even surpass the performance of these clinical standards.

Biomechanical comparison of plate and screw fixation in anterior pelvic ring fractures with low bone mineral density.

INTRODUCTION: Osteosynthesis of anterior pubic ramus fractures can be challenging, especially in poor bone quality. The aim of the present study was to compare plate and retrograde endomedullary screw fixation of the superior pubic ramus with low bone mineral density (BMD). MATERIALS AND METHODS: Twelve human cadaveric hemi-pelvises were analyzed in a matched pair study design. BMD of the specimens was 35±30mgHA/cm(3), as measured in the fifth lumbar vertebra. A simulated two-fragment superior pubic ramus fracture model was fixed with either a 7.3-mm cannulated retrograde screw (Group 1) or a 10-hole 3.5-mm reconstruction plate (Group 2). Cyclic progressively increasing axial loading was applied through the acetabulum. Relative interfragmentary movements were captured using an optical motion tracking system. RESULTS: Initial axial construct stiffness was 424±116.1N/mm in Group 1 and 464±69.7N/mm in Group 2, with no significant difference (p=0.345). Displacement and gap angle at the fracture site during cyclic loading were significantly higher in Group 1 compared to Group 2. Cycles to failure, based on clinically relevant criteria, were significantly lower in Group 1 (3469±1837) compared to Group 2 (10,226±3295) (p=0.028). Failure mode in Group 1 was characterized by screw cutting through the cancellous bone. In Group 2 the specimens exclusively failed by plate bending. CONCLUSIONS: From biomechanical point of view, pubic ramus stabilization with plate osteosynthesis is superior compared to a single retrograde screw fixation in osteoporotic bone. However, the extensive surgical approach needed for plating must be considered.

Implicit modeling of screw threads for efficient finite element analysis of complex bone-implant systems.

Finite element analysis is commonly used to assist in the development and evaluation of orthopedic devices. The physics of these models are simplified through approximations that enable more efficient simulations, without compromising the accuracy of the relative comparisons between implant designs or configurations. This study developed and evaluated a technique to approximate the behavior of a finely threaded screw using a smooth cylinder with the threads implicitly represented through interfacial contact conditions. This pseudo-threaded model was calibrated by comparing to simulations that explicitly modeled the thread geometry with frictional contact. A parametric analysis was performed with a single screw-in-bone system, five loading directions, and three Young׳s moduli that span the range of cancellous bone (200, 600, and 1,000MPa). Considering that screw cut-out from cancellous bone is a critical clinical issue in the osteoporotic proximal humerus, the pseudo-threaded model was compared with a bonded interface to examine three different screw configurations in a 3-part proximal humerus fracture across 10 patients. In the single screw-in-bone system, the pseudo-threaded model predicted the screw displacement of the explicitly threaded model with 1-5% difference and estimated the strain distributions and magnitudes more accurately than a bonded interface. Yet, the relative comparisons of implant stability across the three different screw configurations in the proximal humerus were not affected by the modeling choice for the bone-screw interface. Therefore, the bonded interface could serve as a more efficient methodology for making relative comparisons between implants that utilize the same thread profile.

NOTCH signaling in skeletal progenitors is critical for fracture repair.

Fracture nonunions develop in 10%-20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity.

Biomaterials approaches to treating implant-associated osteomyelitis.

Orthopaedic devices are the most common surgical devices associated with implant-related infections and Staphylococcus aureus (S. aureus) is the most common causative pathogen in chronic bone infections (osteomyelitis). Treatment of these chronic bone infections often involves combinations of antibiotics given systemically and locally to the affected site via a biomaterial spacer. The gold standard biomaterial for local antibiotic delivery against osteomyelitis, poly(methyl methacrylate) (PMMA) bone cement, bears many limitations. Such shortcomings include limited antibiotic release, incompatibility with many antimicrobial agents, and the need for follow-up surgeries to remove the non-biodegradable cement before surgical reconstruction of the lost bone. Therefore, extensive research pursuits are targeting alternative, biodegradable materials to replace PMMA in osteomyelitis applications. Herein, we provide an overview of the primary clinical treatment strategies and emerging biodegradable materials that may be employed for management of implant-related osteomyelitis. We performed a systematic review of experimental biomaterials systems that have been evaluated for treating established S. aureus osteomyelitis in an animal model. Many experimental biomaterials were not decisively more efficacious for infection management than PMMA when delivering the same antibiotic. However, alternative biomaterials have reduced the number of follow-up surgeries, enhanced the antimicrobial efficacy by delivering agents that are incompatible with PMMA, and regenerated bone in an infected defect. Understanding the advantages, limitations, and potential for clinical translation of each biomaterial, along with the conditions under which it was evaluated (e.g. animal model), is critical for surgeons and researchers to navigate the plethora of options for local antibiotic delivery.

Effects of Combined Exposure to Lead and High-Fat Diet on Bone Quality in Juvenile Male Mice.

BACKGROUND: Lead (Pb) exposure and obesity are co-occurring risk factors for decreased bone mass in the young, particularly in low socioeconomic communities. OBJECTIVES: The goal of this study was to determine whether the comorbidities of Pb exposure and high-fat diet-induced obesity amplify skeletal deficits independently associated with each of these risk factors, and to explore associated mechanisms of the observed deficiencies. METHODS: Five-week-old male C57BL/6J mice were placed on low-fat (10% kcal, LFD) or high-fat (60% kcal, HFD) diets for 12 weeks. Mice were exposed to lifetime Pb (50 ppm) through drinking water. RESULTS: HFD was associated with increased body mass and glucose intolerance. Both HFD and Pb increased fasting glucose and serum leptin levels. Pb and HFD each reduced trabecular bone quality and together had a further detrimental effect on these bone parameters. Mechanical bone properties of strength were depressed in Pb-exposed bones, but HFD had no significant effect. Both Pb and HFD altered progenitor cell differentiation, promoting osteoclastogenesis and increasing adipogenesis while suppressing osteoblastogenesis. In support of this lineage shift being mediated through altered Wnt signaling, Pb and non-esterified fatty acids in MC3T3 cells increased in vitro PPAR-γ activity and inhibited ß-catenin activity. Combining Pb and non-esterified fatty acids enhanced these effects. CONCLUSIONS: Pb and HFD produced selective deficits in bone accrual that were associated with alterations in progenitor cell activity that may involve reduced Wnt signaling. This study emphasizes the need to assess toxicants together with other risk factors relevant to human health and disease.

Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation.

Approximately 10% of skeletal fractures result in healing complications and non-union, while most fractures repair with appropriate stabilization and without pharmacologic intervention. It is the latter injuries that cannot be underestimated as the expenses associated with their treatment and subsequent lost productivity are predicted to increase to over $74 billion by 2015. During fracture repair, local mesenchymal stem/progenitor cells (MSCs) differentiate to form new cartilage and bone, reminiscent of events during skeletal development. We previously demonstrated that permanent loss of gamma-secretase activity and Notch signaling accelerates bone and cartilage formation from MSC progenitors during skeletal development, leading to pathologic acquisition of bone and depletion of bone marrow derived MSCs. Here, we investigated whether transient and systemic gamma-secretase and Notch inhibition is capable of accelerating and enhancing fracture repair by promoting controlled MSC differentiation near the fracture site. Our radiographic, microCT, histological, cell and molecular analyses reveal that single and intermittent gamma-secretase inhibitor (GSI) treatments significantly enhance cartilage and bone callus formation via the promotion of MSC differentiation, resulting in only a moderate reduction of local MSCs. Biomechanical testing further demonstrates that GSI treated fractures exhibit superior strength earlier in the healing process, with single dose GSI treated fractures exhibiting bone strength approaching that of un-fractured tibiae. These data further establish that transient inhibition of gamma-secretase activity and Notch signaling temporarily increases osteoclastogenesis and accelerates bone remodeling, which coupled with the effects on MSCs likely explains the accelerated and enhanced fracture repair. Therefore, we propose that the Notch pathway serves as an important therapeutic target during skeletal fracture repair.

A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery.

Mice are the small animal model of choice in biomedical research due to the low cost and availability of genetically engineered lines. However, the devices utilized in current mouse models of implant-associated bone infection have been limited to intramedullary or trans-cortical pins, which are not amenable to treatments involving extensive debridement of a full-thickness bone loss and placement of a segmental antibiotic spacer. To overcome these limitations, we developed a clinically faithful model that utilizes a locking fracture fixation plate to enable debridement of an infected segmental bone defect (full-thickness osteotomy) during a revision surgery, and investigated the therapeutic effects of placing an antibiotic-laden spacer in the segmental bone defect. To first determine the ideal time point for revision following infection, a 0.7 mm osteotomy in the femoral mid-shaft was stabilized with a radiolucent PEEK fixation plate. The defect was inoculated with bioluminescent Staphylococcus aureus, and the infection was monitored over 14 days by bioluminescent imaging (BLI). Osteolysis and reactive bone formation were assessed by X-ray and micro-computed tomography (micro-CT). The active bacterial infection peaked by 5 days post-inoculation, however the stability of the implant fixation became compromised by 10-14 days post-inoculation due to osteolysis around the screws. Thus, day 7 was defined as the ideal time point to perform the revision surgery. During the revision surgery, the infected tissue was debrided and the osteotomy was widened to 3mm to place a poly-methyl methacrylate spacer, with or without vancomycin. Half of the groups also received systemic vancomycin for the remaining 21 days of the study. The viable bacteria remaining at the end of the study were measured using colony forming unit assays. Volumetric bone changes (osteolysis and reactive bone formation) were directly measured using micro-CT image analysis. Mice that were treated with local or systemic vancomycin did not display gross pathology at the end of the study. While localized vancomycin delivery alone tended to decrease the bacterial burden and osteolysis, these effects were only significant when combined with systemic antibiotic therapy. This novel mouse model replicates key features of implant-associated osteomyelitis that make treatment extremely difficult, such as biofilm formation and osteolysis, and imitates the clinical practice of placing an antibiotic-laden spacer after infected tissue debridement. In addition, the model demonstrates the limitations of current PMMA spacers and could be an invaluable tool for evaluating alternative antimicrobial treatments for implant-associated bone infection.