A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor.

Recombinant bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive growth factor that can promote bone regeneration for challenging skeletal repair and even for ectopic bone formation in spinal fusion procedures. However, serious clinical side effects related to supraphysiological dosing highlight the need for advances in novel biomaterials that can significantly reduce the amount of this biologic. Novel biomaterials could not only reduce clinical side effects but also expand the indications for use of BMP-2, while at the same time lowering the cost of such procedures. To achieve this objective, we have developed a slurry containing a known supramolecular polymer that potentiates BMP-2 signaling and porous collagen microparticles. This slurry exhibits a paste-like consistency that stiffens into an elastic gel upon implantation making it ideal for minimally invasive procedures. We carried out in vivo evaluation of the novel biomaterial in the rabbit posterolateral spine fusion model, and discovered efficacy at unprecedented ultra-low BMP-2 doses (5 µg/implant). This dose reduces the growth factor requirement by more than 100-fold relative to current clinical products. This observation is significant given that spinal fusion involves ectopic bone formation and the rabbit model is known to be predictive of human efficacy. We expect the novel biomaterial can expand BMP-2 indications for difficult cases requiring large volumes of bone formation or involving patients with underlying conditions that compromise bone regeneration.

Orthopaedic Manifestations of Transverse Myelitis in Children.

BACKGROUND: Transverse myelitis (TM) is a rare inflammatory disorder of the spinal cord. It can have a heterogeneous presentation with sensory, motor, and autonomic dysfunction. Neurological sequelae of TM include autonomic dysfunction, motor weakness, and/or spasticity. Studies describing orthopaedic deformities and treatments associated with TM are nonexistent. This purpose of this study was to describe the orthopaedic manifestations of TM in children. METHODS: A multicenter retrospective review was conducted of patients, 0 to 21 years of age, with TM presenting over a 15-year period at 4 academic children's hospitals. Those with confirmed diagnosis of TM and referred to an orthopaedic surgeon were included. Demographics, orthopaedic manifestations, operative/nonoperative treatments, and complications were recorded. Descriptive statistics were used for data reporting. RESULTS: Of 119 patients identified with TM, 37 saw an orthopaedic surgeon. By etiology, 23 were idiopathic (62%), 10 infectious (27%), 3 (8%) inflammatory/autoimmune, and 1 (3%) vascular. The mean age at diagnosis was 6.7 (SD: 5.5) years and at orthopaedic presentation was 8.4 (SD: 5.2) years. Orthopaedic manifestations included scoliosis in 13 (35%), gait abnormalities in 7 (19%), foot deformities in 7 (19%), upper extremity issues in 7 (19%), symptomatic spasticity in 6 (16%), lower extremity muscle contractures in 6 (16%), fractures in 6 (16%), hip displacement in 3 (8%), pain in 2 (5%), and limb length discrepancy in 2 (5%) patients. Seven children (19%) were seen for establishment of care. In all, 14 (38%) underwent operative intervention, mainly for soft-tissue and scoliosis management. Four patients had baclofen pump placement for spasticity management. Postoperative complications occurred in 36% of cases, most commonly because of infection. Neither topographic pattern nor location of lesion had a significant relationship with need for hip or spine surgery. CONCLUSIONS: This report describes the orthopaedic manifestations associated with TM in children, nearly 40% of whom required operative intervention(s). Understanding the breadth of musculoskeletal burden incurred in TM can help develop surveillance programs to identify and treat these deformities in a timely manner. LEVEL OF EVIDENCE: Level IV.

Can Surgeon Demographic Factors Predict Postoperative Complication Rates After Elective Spinal Fusion?

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Determine whether surgeon demographic factors influence postoperative complication rates after elective spine fusion procedures. BACKGROUND: Surgeon demographic factors have been shown to impact decision making in the management of degenerative disease of the lumbar spine. Complication rates are frequently reported outcome measurements used to evaluate surgical treatments, quality-of-care, and determine health care reimbursements. However, there are few studies investigating the association between surgeon demographic factors and complication outcomes after elective spine fusions. METHODS: A database of US spine surgeons with corresponding postoperative complications data after elective spine fusions was compiled utilizing public data provided by the Centers for Medicare and Medicaid Services (2011-2013) and ProPublica Surgeon Scorecard (2009-2013). Demographic data for each surgeon was collected and consisted of: surgical specialty (orthopedic vs. neurosurgery), years in practice, practice setting (private vs. academic), type of medical degree (MD vs. DO), medical school location (United States vs. foreign), sex, and geographic region of practice. General linear mixed models using a Beta distribution with a logit link and pairwise comparison with post hoc Tukey-Kramer were used to assess the relationship between surgeon demographics and complication rates. RESULTS: 2110 US-practicing spine surgeons who performed spine fusions on 125,787 Medicare patients from 2011 to 2013 met inclusion criteria for this study. None of the surgeon demographic factors analyzed were found to significantly affect overall complication rates in lumbar (posterior approach) or cervical spine fusion. CONCLUSIONS: Publicly available complication rates for individual spine surgeons are being utilized by hospital systems and patients to assess aptitude and gauge expectations. The increasing demand for transparency will likely lead to emphasis of these statistics to improve outcomes. We conclude that none of the surgeon demographic factors analyzed in this study are associated with differences in overall complications rates in patients undergoing elective spine fusion as published by the ProPublica Surgeon Scorecard. LEVEL OF EVIDENCE: Level 3.

Factors Associated With Financial Relationships Between Spine Surgeons and Industry: An Analysis of the Open Payments Database.

STUDY DESIGN: A retrospective review of Centers for Medicare and Medicaid Services Database. OBJECTIVE: Utilizing Open Payments data, we aimed to determine the prevalence of industry payments to orthopedic and neurospine surgeons, report the magnitude of those relationships, and help outline the surgeon demographic factors associated with industry relationships. SUMMARY OF BACKGROUND DATA: Previous Open Payments data revealed that orthopedic surgeons receive the highest value of industry payments. No study has investigated the financial relationship between spine surgeons and industry using the most recent release of Open Payments data. METHODS: A database of 5898 spine surgeons in the United States was derived from the Open Payments website. Demographic data were collected, including the type of residency training, years of experience, practice setting, type of medical degree, place of training, gender, and region of practice. Multivariate generalized linear mixed models were utilized to determine the relationship between demographics and industry payments. RESULTS: A total of 5898 spine surgeons met inclusion criteria. About 91.6% of surgeons reported at least one financial relationship with industry. The median total value of payments was $994.07. Surgeons receiving over $1,000,000 from industry during the reporting period represented 6.6% of the database and accounted for 83.5% of the total value exchanged. Orthopedic training (P < 0.001), academic practice setting (P < 0.0001), male gender (P < 0.0001), and West or South region of practice (P < 0.0001) were associated with industry payments. Linear regression analysis revealed a strong inverse relationship between years of experience and number of payments from industry (r = -0.967, P < 0.0001). CONCLUSION: Financial relationships between spine surgeons and industry are highly prevalent. Surgeon demographics have a significant association with industry-surgeon financial relationships. Our reported value of payments did not include ownership or research payments and thus likely underestimates the magnitude of these financial relationships. LEVEL OF EVIDENCE: 3.

Do Demographic Factors of Spine Surgeons Affect the Rate at Which Spinal Fusion Is Performed on Patients?

STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to evaluate associations between spine surgeon demographics and the rate at which elective spine fusion is performed. SUMMARY OF BACKGROUND DATA: Rapidly increasing rates of elective spinal fusion in the United States have given rise to important questions about what factors may drive spine surgeon decision making. METHODS: Publicly available spine surgeon practice pattern data from Centers for Medicare and Medicaid Services were reviewed retrospectively. Fusion rate was defined as the number of fusion procedures performed on Medicare beneficiaries by a surgeon per total number of unique Medicare beneficiaries seen. Inclusion criteria were neurological or orthopedic spine surgeons who performed 11 or more separate spine fusion procedures on Medicare patients between 2011 and 2013 as defined by this database. Demographic information was collected from public record. The increased probability of a surgeon performing spine fusion was assessed using a relative risk (RR) and corresponding 95% confidence interval (CI). RESULTS: A total of 3979 spine surgeons who practice in the United States and performed spine fusion on 171,676 Medicare patients from 2011 to 2013 met the inclusion criteria. The average rate of spine fusion for surgeons in this database was 7.5%. Surgeons with higher fusion rates practiced in an academic versus private setting (RR = 1.44, 95% CI [1.35-1.53]; P < 0.0001), were more likely neurological versus orthopedic surgeons (RR = 1.10, 95% CI [1.05-1.15]; P < 0.0001), and practiced in the West versus Midwest, South, and Northeast region of the United States (RR = 1.20, 95% CI [1.14-1.27]; P < 0.0001). Number of years in practice was significantly associated negatively with fusion rate (P < 0.0001). CONCLUSION: Significant variation in the rate of spine fusion based on practice type, training, region, and experience suggests poor consensus on indications for this procedure. Knowledge of these relationships may help identify underlying reasons for variations in surgical care and improve surgical outcomes. LEVEL OF EVIDENCE: 3.

Sulfated glycopeptide nanostructures for multipotent protein activation.

Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with different polysaccharide-binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal ß-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signalling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model. These highly bioactive nanostructures may enable many therapies in the future involving proteins.

Effects of Conflicts of Interest on Practice Patterns and Complication Rates in Spine Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: We sought to determine whether financial relationships with industry had any impact on operative and/or complication rates of spine surgeons performing fusion surgeries. SUMMARY OF BACKGROUND DATA: Recent actions from Congress and the Institute of Medicine have highlighted the importance of conflicts of interest among physicians. Orthopedic surgeons and neurosurgeons have been identified as receiving the highest amount of industry payments among all specialties. No study has yet investigated the potential effects of disclosed industry payments with quality and choices of patient care. METHODS: A comprehensive database of spine surgeons in the United States with compiled data of industry payments, operative fusion rates, and complication rates was created. Practice pattern data were derived from a publicly available Medicare-based database generated from selected CPT codes from 2011 to 2012. Complication rate data from 2009 to 2013 were extracted from the ProPublica-Surgeon-Scorecard database, which utilizes postoperative inhospital mortality and 30-day-readmission for designated conditions as complications of surgery. Data regarding industry payments from 2013 to 2014 were derived from the Open Payments website. Surgeons performing <10 fusions, those without complication data, and those whose identity could not be verified through public records were excluded. Pearson correlation coefficients and multivariate regression analyses were used to determine the relationship between industry payments, operative fusion rate, and/or complication rate. RESULTS: A total of 2110 surgeons met the inclusion criteria for our database. The average operative fusion rate was 8.8% (SD 4.8%), whereas the average complication rate for lumbar and cervical fusion was 4.1% and 1.9%, respectively. Pearson correlation analysis revealed a statistically significant but negligible relationship between disclosed payments/transactions and both operative fusion and complication rates. CONCLUSION: Our findings do not support a strong correlation between the payments a surgeon receives from industry and their decisions to perform spine fusion or associated complication rates. Large variability in the rate of fusions performed suggests a poor consensus for indications for spine fusion surgery. LEVEL OF EVIDENCE: 3.

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation.

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3'-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.

Intra-Articular Vancomycin Powder Eliminates Methicillin-Resistant S. aureus in a Rat Model of a Contaminated Intra-Articular Implant.

BACKGROUND: Periprosthetic joint infection following hip and knee arthroplasty leads to poor outcomes and exorbitant costs. Topical vancomycin powder has been shown to decrease infection in many procedures such as spine surgery. The role of vancomycin powder in the setting of total joint arthroplasty remains undefined. Our aim was to evaluate the efficacy of intra-articular vancomycin powder in preventing infection in a rat model of a contaminated intra-articular implant. METHODS: Thirty-two female Sprague-Dawley rats underwent knee arthrotomy and implantation of a femoral intramedullary wire with 1 mm of intra-articular communication. The knee joint was also inoculated with 1.5 × 10 colony forming units (CFU)/mL of methicillin-resistant Staphylococcus aureus (MRSA). Four treatment groups were studied: (1) no antibiotics (control), (2) preoperative systemic vancomycin, (3) intra-articular vancomycin powder, and (4) both systemic vancomycin and intra-articular vancomycin powder. The animals were killed on postoperative day 6, and distal femoral bone, joint capsule, and the implanted wire were harvested for bacteriologic analysis. Statistical analyses were performed using Wilcoxon rank sum and Fisher exact tests. RESULTS: There were no postoperative deaths, wound complications, signs of vancomycin-related toxicity, or signs of systemic illness in any of the treatment groups. There were significantly fewer positive cultures in the group that received vancomycin powder in combination with systemic vancomycin compared with the group that received systemic vancomycin alone (bone: 0% versus 75% of 8, p = 0.007; Kirschner wire: 0% versus 63% of 8, p = 0.026; whole animal: 0% versus 88% of 8, p = 0.01). Only animals that received both vancomycin powder and systemic vancomycin showed evidence of complete elimination of bacterial contamination. CONCLUSIONS: In a rat model of a contaminated intra-articular implant, use of intra-articular vancomycin powder in combination with systemic vancomycin completely eliminated MRSA bacterial contamination. Animals treated with systemic vancomycin alone had persistent MRSA contamination. CLINICAL RELEVANCE: This animal study presents data suggesting that the use of intra-articular vancomycin powder for reducing the risk of periprosthetic joint infections should be investigated further in clinical studies.

Return to Play After Lumbar Spine Surgery.

Surgical management of lumbar spine conditions can produce excellent outcomes in athletes. Microdiscectomy for lumbar disc herniation has favorable outcomes; most athletes return to play at preoperative performance levels. Direct pars repair is successful in younger athletes, with high rates of return to play for a variety of fixation techniques. Fusion in athletes with scoliosis is a negative predictor. There are few evidence-based return to play criteria. Athletes should demonstrate full resolution of symptoms and flexibility, endurance, and strength before returning to play. Deciding when to return an athlete to sport depends on particular injury sustained, sport, and individual factors.

The importance of hormesis to public health.

Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models and diverse types of exposure. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. Hormesis appears to be more common than doseresponse curves that are currently used in the risk assessment process. Although a number of mechanisms have been identified that explain many hormetic doseresponse relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.

The importance of hormesis to public health

Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models and diverse types of exposure. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. Hormesis appears to be more common than doseresponse curves that are currently used in the risk assessment process. Although a number of mechanisms have been identified that explain many hormetic doseresponse relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.

A hormese é um tipo específico de dose-resposta não monotônica cuja ocorrência vem sendo documentada largamente por vários modelos biológicos e para diversos tipos de exposição. Os efeitos que ocorrem em múltiplos pontos de uma curva podem ser interpretados como benéficos ou maléficos, dependendo do contexto biológico ou ecológico em que ocorram. Como a hormese parece ser um fenômeno relativamente comum que ainda não foi incorporado em práticas regulatórias, o objetivo deste ensaio é explorar algumas das suas implicações mais óbvias para a saúde pública e avaliação de risco, com ênfase particular nas questões assinaladas atualmente por autores da revista Environmental Health Perspectives. A hormese parece ser mais comum que outras curvas de dose-resposta usadas atualmente no processo de avaliação de riscos. Embora inúmeros mecanismos que explicam relações de dose-resposta desse tipo tenham sido identificados, o melhor entendimento deste fenômeno provavelmente conduzirá a diferentes estratégias de prevenção, de tratamento de doenças e de promoção de uma melhor saúde pública, posto que se relaciona com resultados de saúde tanto específicos quanto mais holísticos. Acreditamos que ignorar a hormese é praticar uma política pobre no campo da saúde pública.

Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

The importance of hormesis to public health.

BACKGROUND: Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models, diverse types of exposure, and a variety of outcomes. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. OBJECTIVE: Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. DISCUSSION: Hormesis appears to be more common than dose-response curves that are currently used in the risk assessment process [e.g., linear no-threshold (LNT)]. Although a number of mechanisms have been identified that explain many hormetic dose-response relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. CONCLUSIONS: We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.

Hormesis: how it could affect the risk assessment process.

If the hormetic dose-response were accepted as the default dose-response model for risk assessment, it could have important implications for environmental exposure standards for noncarcinogens and especially for carcinogens. Most notably it would lead to the recognition that carcinogens act via a threshold process rejecting the concept of linearity at low doses. The hormetic concept also provides agencies with a broader range of toxicologically based exposure options, which permit a consideration for avoiding harm, as well as possibly enhancing benefits for both normal and high-risk segments of the population. By dismissing hormesis, regulatory agencies such as EPA deny the public the opportunity for optimal health and avoidance of disease.

Silicone gel breast implant rupture rates: research issues.

Documenting the rate of rupture of silicone breast implants appears to be deceptively easy. Largely because of the phenomenon of "silent rupture," it isn't. The authors explore the various technical biases (selection, misclassification, and confounding) and methodological problems that have plagued much of the research conducted to date. By means of a series of illustrations, they argue that explantation has limited utility. Noninvasive techniques have to be used to gather the proper type of data on the timing and frequency of these events. Only with the proper incidence data will researchers be able to identify better the different mechanisms underlying implant rupture and the relative importance of each. The authors recommend that better and standardized definitions of implant rupture be developed, that greater recognition be given to the technical biases and a greater effort be made to eliminate them from investigations of implant rupture, and that more research be conducted by multidisciplinary teams. Because of the growing awareness of the complexity of this issue, the authors also recommend that properly constituted advisory teams be used to provide comprehensive oversight of future research projects from beginning to end.