A Mechanistic and Preclinical Assessment of BioRestore Bioactive Glass as a Synthetic Bone Graft Extender and Substitute for Osteoinduction and Spine Fusion.

STUDY DESIGN: Preclinical animal study. OBJECTIVE: Evaluate the osteoinductivity and bone regenerative capacity of BioRestore bioactive glass. SUMMARY OF BACKGROUND DATA: BioRestore is a Food and Drug Administration (FDA)-approved bone void filler that has not yet been evaluated as a bone graft extender or substitute for spine fusion. METHODS: In vitro and in vivo methods were used to compare BioRestore with other biomaterials for the capacity to promote osteodifferentiation and spinal fusion. The materials evaluated (1) absorbable collagen sponge (ACS), (2) allograft, (3) BioRestore, (4) Human Demineralized Bone Matrix (DBM), and (5) MasterGraft. For in vitro studies, rat bone marrow-derived stem cells (BMSC) were cultured on the materials in either standard or osteogenic media (SM, OM), followed by quantification of osteogenic marker genes (Runx2, Osx, Alpl, Bglap, Spp1) and alkaline phosphatase (ALP) activity. Sixty female Fischer rats underwent L4-5 posterolateral fusion (PLF) with placement of 1 of 5 implants: (1) ICBG from syngeneic rats; (2) ICBG+BioRestore; (3) BioRestore alone; (4) ICBG+Allograft; or (5) ICBG+MasterGraft. Spines were harvested 8 weeks postoperatively and evaluated for bone formation and fusion via radiography, blinded manual palpation, microCT, and histology. RESULTS: After culture for 1 week, BioRestore promoted similar expression levels of Runx2 and Osx to cells grown on DBM. At the 2-week timepoint, the relative ALP activity for BioRestore-OM was significantly higher (P<0.001) than that of ACS-OM and DBM-OM (P<0.01) and statistically equivalent to cells grown on allograft-OM. In vivo, radiographic and microCT evaluation showed some degree of bridging bone formation in all groups tested, with the exception of BioRestore alone, which did not produce successful fusions. CONCLUSIONS: This study demonstrates the capacity of BioRestore to promote osteoinductivity in vitro. In vivo, BioRestore performed similarly to commercially available bone graft extender materials but was incapable of producing fusion as a bone graft substitute. LEVEL OF EVIDENCE: Level V.

Knowledge of radiation exposure associated with common trauma imaging modalities among orthopaedic surgeons, emergency medicine physicians, and general surgeons in the United States.

BACKGROUND: Few contemporary studies have assessed physicians' knowledge of radiation exposure associated with common imaging studies, especially in trauma care. The purpose of this study was to assess the knowledge of physicians involved in caring for trauma patients regarding the effective radiation doses of musculoskeletal (MSK) imaging studies routinely utilized in the trauma setting. METHODS: An electronic survey was distributed to United States orthopaedic surgery, general surgery, and emergency medicine (EM) residency programs. Participants were asked to estimate the radiation dose for common imaging modalities of the pelvis, lumbar spine, and lower extremity, in terms of chest X-ray (CXR) equivalents. Physician estimates were compared to the true effective radiation doses. Additionally, participants were asked to report the frequency of discussing radiation risk with patients. RESULTS: A total of 218 physicians completed the survey; 102 (46.8%) were EM physicians, 88 (40.4%) were orthopaedic surgeons, and 28 (12.8%) were general surgeons. Physicians underestimated the effective radiation doses of nearly all imaging modalities, most notably for pelvic computed tomaography (CT) (median 50 CXR estimation vs. 162 CXR actual) and lumbar CT (median 50 CXR estimation vs. 638 CXR actual). There was no difference between physician specialties regarding estimation accuracy (P=0.133). Physicians who regularly discussed radiation risks with patients more accurately estimated radiation exposure (P=0.007). CONCLUSION: The knowledge among orthopaedic and general surgeons and EM physicians regarding the radiation exposure associated with common MSK trauma imaging is lacking. Further investigation with larger scale studies is warranted, and additional education in this area may improve care.

Epidemiology of C2 fractures in the United States: A National Electronic Injury Surveillance System database study.

Introduction: C2 fractures are one of the most common traumatic injuries of the cervical spine, with high rates of morbidity and mortality. Current literature on the incidence of C2 fractures is limited to populations outside of the United States (US), prior to 2014, or specific age cohorts. The purpose of this study is to report the incidence rate (IR) of C2 fractures and associated patient demographics in the US between 2002 and 2021 using the National Electronic Injury Surveillance System (NEISS) database. Methods: This study analyzed the NEISS database to identify cases of C2 fractures presenting to US Emergency Departments (EDs) from 2002 to 2021. Annual and overall numbers of fractures, IR, and patient demographics were analyzed. IR is expressed as the number of fractures per 100,000 person-years at risk (PYR). Patients were split into three different age groups for comparison (children and young adults, 0-64 years; older adults, 65-79 years; elderly individuals, 80 + years). Results: A national estimate of n = 72,764 patients (95% confidence interval [CI] = 54,371-91,156) presented to US EDs with a C2 fracture (IR was 1.17/PYR; 95% CI = 0.87-1.46), and elderly individuals had the highest IR overall (IR = 15.9; P < 0.05). The IR of C2 fractures between 2002 and 2021, reported as average annual percent change (AAPC), increased significantly, regardless of age or sex (AAPC = 10.9; 95% CI = 6.3-15.6; P < 0.0001). Conclusion: C2 fractures occur at higher rates than previous years, with especially high IR in elderly individuals. Emphasis of public health efforts toward osteoporosis and coordination difficulties in elderly individuals would likely significantly reduce the overall IR of these injuries.

Trends and epidemiology of knee extensor mechanism injuries presenting to United States emergency departments from 2001 to 2020.

OBJECTIVES: Injuries to the native extensor mechanism (EM) of the knee are potentially disabling and often require surgical treatment. Large-scale, updated epidemiological data on these injuries is lacking. The objective of the current study was to examine recent trends in EM injuries presenting to United States (US) Emergency Departments (EDs) over the last 20 years using a nationally representative sample. METHODS: This study retrospectively analyzed the National Electronic Injury Surveillance System (NEISS) database to identify cases of EM injuries (defined as either a quadriceps tendon rupture, a patella fracture, or a patellar tendon rupture) presenting to EDs in the US from 2001 to 2020. RESULTS: During the study period, an estimated 214,817 EM injuries occurred in an at-risk population of 6,183,899,410 person-years for an overall incidence rate of 3.47 per 100,000 person-years. Patella fractures (PFs) were the most common injury type, representing 77.5% of all EM injuries (overall incidence rate: 2.69), followed by patellar tendon ruptures (PTRs; 13.5%; incidence: 0.48) and quadriceps tendon ruptures (QTRs; 9%; incidence: 0.31). Demographic characteristics and mechanisms of injury differed between injury types. Annual incidence rates increased significantly during the study period for all EM injury types, with PTRs demonstrating the largest relative increase (average annual percent increase: PF, 2.8%; PTR, 7.2%; QTR, 5.3%). Accounting for population growth yielded an increasing incidence of all EM injuries combined from 3.65 in 2001 to 4.9 in 2020. The largest relative increases in incidence rates were observed in older age groups. CONCLUSION: Extensor mechanism injuries of the knee are increasing in the US, which likely reflects an aging and more active population. These types of injuries are associated with substantial functional impairment and recent increases in incidence rates highlight the need for injury prevention and management strategies.

Accuracy of self-reported opioid use in orthopaedic trauma patients.

PURPOSE: Opioids have long been a mainstay of treatment for pain in patients with orthopaedic injuries, but little is known about the accuracy of self-reported narcotic usage in orthopaedic trauma. The purpose of this study is to evaluate the accuracy of self-reported opioid usage in orthopaedic trauma patients. METHODS: A retrospective review of all new patients presenting to the orthopaedic trauma clinic of a level 1 trauma centre with a chief complaint of recent orthopaedic-related injury over a 2-year time frame was conducted. Participants were administered a survey inquiring about narcotic usage within the prior 3 months. Responses were cross-referenced against a query of a statewide prescription drug monitoring program system. RESULTS: The study comprised 241 participants; 206 (85.5%) were accurate reporters, while 35 (14.5%) were inaccurate reporters. Significantly increased accuracy was associated with hospital admission prior to clinic visit (ß = - 1.33; χ2 = 10.68, P < 0.01; OR: 0.07, 95% CI 0.01-0.62). Decreased accuracy was associated with higher pre-visit total morphine equivalent dose (MED) (ß = 0.002; χ2 = 11.30, P < 0.01), with accurate reporters having significantly lower pre-index visit MED levels compared to underreporters (89.2 ± 208.7 mg vs. 249.6 ± 509.3 mg; P = 0.04). An Emergency Department (ED) visit prior to the index visit significantly predicted underreporting (ß = 0.424; χ2 = 4.28, P = 0.04; OR: 2.34, 95% CI 1.01-5.38). CONCLUSION: This study suggests that most new patients presenting to an orthopaedic trauma clinic with acute injury will accurately report their narcotic usage within the preceding 3 months. Prior hospital admissions increased the likelihood of accurate reporting while higher MEDs or an ED visit prior to the initial visit increased the likelihood of underreporting.

Epidemiology of patellar dislocations in the United States from 2001 to 2020: results of a national emergency department database.

OBJECTIVES: Recent studies have shown an increasing incidence of patellar dislocations among children and adolescents. Updated, population-based studies of all patellar dislocations in the United States (US), however, are lacking. This study investigated recent trends in injury rates and demographics among patients sustaining patellar dislocations in the US from 2001 to 2020. METHODS: This descriptive epidemiologic study retrospectively analyzed the National Electronic Injury Surveillance System (NEISS) database to identify cases of acute patellar dislocations presenting to US Emergency Departments (EDs) from 2001 to 2020. Annual, overall, and age-adjusted incidence rates (IRs, expressed per 100,000 at-risk person-years) and additional patient/injury characteristics were analyzed. Average annual percent change (AAPC) estimates are presented to indicate the magnitude/direction of trends in annual injury rates. RESULTS: An estimated total of 159,529 patellar dislocations occurred over the study period for an overall IR of 2.58 (95% CI = 2.04-3.12). Accounting for population growth, the overall annual incidence increased significantly from 2.61 in 2001 to 3.0 in 2020 (AAPC = 2.8, p < 0.0001). When considering sex and age, statistically significant increases in annual IRs were observed among males aged 10-19 years (AAPC = 3.8, p < 0.0001), females aged 10-19 years (AAPC = 5.3, p < 0.0001), and females aged 20-29 years (AAPC = 3.5, p = 0.0152), while no significant changes were observed in any other age groups. Two-thirds of patellar dislocations involved sports-related injury mechanisms. The annual incidence of both sports-related and non-sports-related injuries increased significantly over the study period (sports-related: AAPC = 2.6, p = 0.0001; non-sports-related: AAPC = 3.4, p = 0.0001). Athletic patellar dislocations occurred most commonly in basketball and dance. CONCLUSION: The number of patients sustaining patellar dislocations is increasing in the US. Similar increasing trends were observed in both males and females aged 10-19 years, whereas injury rates increased in the third decade only among females. A large percentage of injuries occur during athletic activity, but both sports- and non-sports-related patellar dislocations are on the rise.

Funding has no effect on clinical outcomes of total joint arthroplasty emerging technologies: a systematic review of bibliometrics and conflicts of interest.

BACKGROUND: The use of new total joint arthroplasty technologies, including patient-specific implants/instrumentation (PSI), computer-assisted (CA), and robotic-assisted (RA) techniques, is increasing. There is an ongoing debate regarding the value provided and potential concerns about conflicts of interest (COI). METHODS: PRISMA guidelines were followed. PubMed, MEDLINE, and Web of Science databases were searched for total hip and knee arthroplasties, unicompartmental knee arthroplasties (UKA), PSI, CA, and RA. Bibliometric data, financial COI, clinical/functional scores, and patient-reported outcomes were assessed. RESULTS: Eighty-seven studies were evaluated, with 35 (40.2%) including at least one author reporting COI, and 13 (14.9%) disclosing industry funding. COI and industry funding had no significant effects on outcomes (P = 0.682, P = 0.447), and there were no significant effects of conflicts or funding on level of evidence (P = 0.508, P = 0.826). Studies in which author(s) disclosed COI had significantly higher relative citation ratio (RCR) and impact factor (IF) than those without (P < 0.001, P = 0.032). Subanalysis demonstrated RA and PSI studies were more likely to report COI or industry funding (P = 0.045). RA (OR = 6.31, 95% CI: 1.61-24.68) and UKA (OR = 9.14, 95% CI: 1.43-58.53) had higher odds of reporting favorable outcomes than PSI. CONCLUSIONS: Author COIs (about 40%) may be lower than previously reported in orthopedic technologies/techniques reviews. Studies utilizing RA and PSI were more likely to report COI, while RA and UKA studies were more likely to report favorable outcomes than PSI. No statistically significant association between the presence of COIs and/or industry funding and the frequency of favorable outcomes or study level of evidence was found. LEVEL OF EVIDENCE: Level V Systematic Review.

Effects of veterans' mental health service-connections on patient-reported outcomes following total joint arthroplasty.

Background: Studies report poor outcomes of elective orthopaedic surgeries among civilian patients receiving Workers' Compensation (WC). However, little is known about surgical outcomes in veterans receiving similar benefits through the Veterans Affairs (VA) service-connected (SC) disability compensation program. Methods: Veterans undergoing primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) at a VA Medical Center between 07/2019-12/2021 were analyzed by SC status. Outcomes were evaluated using Hip disability and Osteoarthritis Outcome Score for Joint Replacement (HOOS-JR) and Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores collected preoperatively and at 2- and 12-months postoperatively. Repeated measures mixed models were used to test for the effect of SC on HOOS-JR/KOOS-JR scores, controlling for baseline age, sex, and Charlson Comorbidity Index (CCI). SC and baseline joint function (stratified into quartiles using baseline HOOS-JR/KOOS-JR scores) were analyzed for effects on achieving substantial clinical benefit (SCB) at 12-month follow-up. Results: The analysis included 67 hips and 142 knees. SC and non-SC (NSC) veterans had similar baseline HOOS-JR/KOOS-JR and CCI. HOOS-JR remained similar between groups through 12 months (79.9 ± 19.2 vs. 82.7 ± 18.8) as did KOOS-JR (70.4 ± 15.6 vs. 74.6 ± 15.3). The designation of any SC and mental health SC reached significance for KOOS-JR (P = 0.034 and P = 0.032, respectively). For HOOS-JR and KOOS-JR, baseline function score quartile significantly influenced final score (P < 0.001), with patients in the lowest quartiles (i.e., worst baseline function) exhibiting significantly greater improvements than patients in higher quartiles. Conclusions: Mental health SC and high preoperative functional status are variables that may have unfavorable influences on self-reported outcomes of TKA in veteran patients. SC status does not appear to influence the outcomes of THA or the likelihood of achieving SCB after either THA or TKA. Regardless of SC status, most veterans can expect significant clinical improvements after total joint arthroplasty.

Epidemiology of ballistic fractures in the United States: A 20-year analysis of the Firearm Injury Surveillance Study.

INTRODUCTION: Ballistic (i.e., gunshot-induced) fractures present unique treatment challenges and can be associated with high rates of complications and considerable morbidity. Large-scale epidemiologic data on these types of fractures are scarce. There is concern that gun-related violence may be on the rise, potentially increasing the burden of ballistic orthopaedic trauma, but there are few contemporary studies on the topic. The aim of this study, therefore, was to investigate the incidence and demographics of patients with ballistic fractures in the United States (US) over the last 20 years. MATERIALS AND METHODS: This descriptive epidemiology study retrospectively analyzed the Firearm Injury Surveillance Study to identify cases of ballistic fractures in the US from 2000 to 2019. Overall and annual numbers of fractures and fracture incidence rates (IRs), patient demographics, incident characteristics, and temporal trends were analyzed. Patients of all ages were included. Ballistic fractures were grouped by anatomic location for comparisons (non-spine axial, spine, upper extremity, lower extremity). RESULTS: An estimated N = 240,555 patients (n = 8,322 unweighted cases) sustained ballistic fractures over the 20-year study period for an overall IR of 39.2 per 1,000,000 person-years at-risk (PYR). Overall, lower extremity fractures accounted for the largest percentage of cases (45.9%; IR=18.8 PYR), followed by upper extremity fractures (32.8%; IR=13.4 PYR), non-spine axial fractures (16.1%; IR=6.6 PYR), and spine fractures (5.2%; IR=2.1 PYR). Diaphyseal femur fractures were the most common ballistic fractures overall. Nearly three-fourths (71.2%) of all cases occurred in males in the second through fourth decades. The most common injury intent was assault (71.8%) and a majority of patients (71.2%) required hospital admission. Accounting for population growth yielded a significantly increasing incidence of all ballistic fractures over the study period from 15.7 PYR in 2000 to 96.8 PYR in 2019 (average annual percent change=10.3, p < 0.00001). CONCLUSION: These data suggest that the nationwide burden of ballistic fractures in the US has increased significantly in the last two decades. Ballistic fractures are associated with significant morbidity and societal cost, and increasing injury rates highlight the need for future research aimed at better understanding the ideal treatment of these types of fractures and their outcomes.

A review of current practices in periprosthetic joint infection debridement and revision arthroplasty.

BACKGROUND: Periprosthetic joint infection remains a significant challenge for arthroplasty surgeons globally. Over the last few decades, there has been much advancement in terms of treatment and diagnosis, however, the fight rages on. As management of periprosthetic joint infections continues to evolve, it is critical to reflect back on current debridement practices to establish common ground as well as identify areas for future research and improvement. BODY: In order to understand the debridement techniques of periprosthetic joint infections, one must also understand how to diagnose a periprosthetic joint infection. Multiple definitions have been elucidated over the years with no single consensus established but rather sets of criteria. Once a diagnosis has been established the decision of debridement method becomes whether to proceed with single vs two-stage revision based on the probability of infection as well as individual patient factors. After much study, two-stage revision has emerged as the gold standard in the management of periprosthetic infections but single-stage remains prominent with further and further research. CONCLUSION: Despite decades of data, there is no single treatment algorithm for periprosthetic joint infections and subsequent debridement technique. Our review touches on the goals of debridement while providing a perspective as to diagnosis and the particulars of how intraoperative factors such as intraarticular irrigation can play pivotal roles in infection eradication. By providing a perspective on current debridement practices, we hope to encourage future study and debate on how to address periprosthetic joint infections best.

Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model.

STUDY DESIGN: This was a preclinical study. OBJECTIVE: Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. SUMMARY OF BACKGROUND DATA: Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. MATERIALS AND METHODS: Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 µg of bone morphogenetic protein-2 (10 µg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 µm level. RESULTS: Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males ( P <0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P <0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm 3 , respectively, P <0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P <0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm -1 , respectively, P <0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. CONCLUSIONS: This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.

Reduction in Operating Room Airborne Particle Burden and Time-Dependent Contamination of Sterile Instrument Trays With the Use of a Novel Air Filtration System.

Introduction Postoperative infections represent a substantial burden to patients and healthcare systems. To improve patient care and reduce healthcare expenditures, interventions to reduce surgical infections must be employed. The crystalline C-band ultraviolet (UV-C) air filtration technology (Aerobiotix Inc., Miamisburg, OH, USA) has been designed to reduce airborne bioburden through high-quality filtration and germicidal irradiation. The purpose of this study was to assess the ability of a novel UV-C air filtration device to reduce airborne particle counts and contamination of surgical instrument trays in an operating room (OR) setting. Materials and methods Thirty sterile instrument trays were opened in a positive-air-flow OR. The trays were randomly assigned to one of two groups (UV-C or control, n=15 per group). In the UV-C group, the UV-C filtration device was used and in the control, it was not. All trays were opened with the use of a sterile technique and left exposed in the OR for four hours. Air was sampled by a particle counter to measure the numbers of 5µm and 10µm particles. Culture specimens were obtained from the trays to assess for bacterial contamination. Outcome data were collected at 30-minute intervals for the duration of the four-hour study period. Results Use of the UV-C device resulted in statistically significant reductions in the numbers of 5µm (average of 64.9% reduction when compared with the control, p<0.001) and 10µm (average of 65.7% reduction when compared with the control, p<0.001)-sized particles detectable in the OR. There was no significant difference in the overall rates of contamination (33.3% in the control group vs. 26.7% in the UV-C group, p=1.0) or the time to contamination (mean survival of 114 minutes in the control group vs. 105 minutes in the UV-C group, p=0.72) of surgical instrument trays with the use of the UV-C device. Conclusions The results demonstrate that the UV-C filtration device can successfully reduce airborne bioburden in standard ORs, suggesting that it may have the potential to reduce the risk for wound and hardware infections. Further clinical trials are necessary to better determine the effect of this air filtration system on postoperative infection rates.

Screw Thread Configuration Has No Effect on Outcomes of In Situ Fixation for Stable Slipped Capital Femoral Epiphysis.

BACKGROUND: No consensus exists regarding the optimal surgical management of slipped capital femoral epiphysis (SCFE). Treatment goals include avoiding slip progression and sequelae such as avascular necrosis (AVN). Factors associated with surgical implants merit further research. This study investigates the effect of screw thread configuration and the number of screws on surgical outcomes. METHODS: A total of 152 patients undergoing cannulated, stainless steel, in situ screw fixation of SCFE between January 2005 and April 2018 were included. Procedure laterality, screw number and thread configuration (partially threaded/fully threaded), bilateral diagnosis, Loder classification, final follow-up, patient demographics, and endocrinopathy history were analyzed. Primary outcomes were return to the operating room (ROR), AVN, hardware failure/removal, and femoroacetabular impingement (FAI). RESULTS: Most patients received a single (86.2%), partially threaded (81.6%) screw; most were unilateral (67.8%) and stable (79.6%). Mean follow-up was 2.0±2.7 years, with a 15.8% rate of ROR, 5.3% exhibiting AVN, 6.6% exhibiting FAI, and 9.2% experiencing hardware failure/removal. Number of screws was the sole predictor of ROR [odds ratio (OR)=3.35, 95% confidence interval (CI): 1.18-9.49]. Unstable SCFE increased the odds of AVN (OR=38.44; 95% CI: 4.35-339.50) as did older age (OR=1.43, 95% CI: 1.01-2.03). Female sex increased risk for FAI (OR=4.87, 95% CI: 1.20-19.70), and bilateral SCFE elevated risk for hardware failure/removal versus unilateral SCFE (OR=4.41, 95% CI: 1.39-14.00). Screw thread configuration had no significant effect on any outcome (for each, P ≥0.159). CONCLUSIONS: Rates of ROR, AVN, FAI, and hardware failure/removal did not differ between patients treated with partially threaded or fully threaded screws. The use of 2 screws was associated with an increased likelihood of ROR. These findings suggest that screw thread configuration has no impact on complication rates, whereas screw number may be an important consideration in SCFE fixation. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Osteoinductivity and biomechanical assessment of a 3D printed demineralized bone matrix-ceramic composite in a rat spine fusion model.

We recently developed a recombinant growth factor-free bone regenerative scaffold composed of stoichiometric hydroxyapatite (HA) ceramic particles and human demineralized bone matrix (DBM) particles (HA-DBM). Here, we performed the first pre-clinical comparative evaluation of HA-DBM relative to the industry standard and established positive control, recombinant human bone morphogenetic protein-2 (rhBMP-2), using a rat posterolateral spinal fusion model (PLF). Female Sprague-Dawley rats underwent bilateral L4-L5 PLF with implantation of the HA-DBM scaffold or rhBMP-2. Fusion was evaluated using radiography and blinded manual palpation, while biomechanical testing quantified the segmental flexion-extension range-of-motion (ROM) and stiffness of the fused segments at 8-weeks postoperatively. For mechanistic studies, pro-osteogenic gene and protein expression at 2-days and 1-, 2-, and 8-weeks postoperatively was assessed with another cohort. Unilateral fusion rates did not differ between the HA-DBM (93%) and rhBMP-2 (100%) groups; however, fusion scores were higher with rhBMP-2 (p = 0.008). Both treatments resulted in significantly reduced segmental ROM (p < 0.001) and greater stiffness (p = 0.009) when compared with non-operated controls; however, the degree of stabilization was significantly higher with rhBMP-2 treatment relative to the HA-DBM scaffold. In the mechanistic studies, PLGA and HA scaffolds were used as negative controls. Both rhBMP-2 and HA-DBM treatments resulted in significant elevations of several osteogenesis-associated genes, including Runx2, Osx, and Alp. The rhBMP-2 treatment led to significantly greater early, mid, and late osteogenic markers, which may be the mechanism in which early clinical complications are seen. The HA-DBM scaffold also induced osteogenic gene expression, but primarily at the 2-week postoperative timepoint. Overall, our findings show promise for this 3D-printed composite as a recombinant growth factor-free bone graft substitute for spinal fusion. STATEMENT OF SIGNIFICANCE: Despite current developments in bone graft technology, there remains a significant void in adequate materials for bone regeneration in clinical applications. Two of the most efficacious bone graft options are the gold-standard iliac crest bone graft and recombinant human-derived bone morphogenetic protein-2 (rhBMP-2), available commercially as Infuse™. Although efficacious, autologous graft is associated with donor-site morbidity, and Infuse™ has known side effects related to its substantial host inflammatory response, possibly associated with a immediate, robust osteoinductive response. Hence, there is a need for a bone graft substitute that provides adequate osteogenesis without associated adverse events. This study represents a significant step in the design of off-the-shelf growth factor-free devices for spine fusion.

Nanostructured Biomaterials for Bone Regeneration.

This review article addresses the various aspects of nano-biomaterials used in or being pursued for the purpose of promoting bone regeneration. In the last decade, significant growth in the fields of polymer sciences, nanotechnology, and biotechnology has resulted in the development of new nano-biomaterials. These are extensively explored as drug delivery carriers and as implantable devices. At the interface of nanomaterials and biological systems, the organic and synthetic worlds have merged over the past two decades, forming a new scientific field incorporating nano-material design for biological applications. For this field to evolve, there is a need to understand the dynamic forces and molecular components that shape these interactions and influence function, while also considering safety. While there is still much to learn about the bio-physicochemical interactions at the interface, we are at a point where pockets of accumulated knowledge can provide a conceptual framework to guide further exploration and inform future product development. This review is intended as a resource for academics, scientists, and physicians working in the field of orthopedics and bone repair.

5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing.

The idea that serotonergic synaptic transmission plays an essential role in the control of mood and the pharmacotherapy of anxiety and depression is one of the cornerstones of modern biological psychiatry. As a result, there is intense interest in understanding the mechanisms controlling the activity of serotonin-synthesizing (serotonergic) neurons. One of the oldest and most durable ideas emerging from this work is that serotonergic neurons are capable of autonomously regulating their own basal firing rate. Serotonergic neurons express on their surface 5-HT1A receptors (autoreceptors) that, when activated, induce the opening of potassium channels that hyperpolarize and thereby inhibit cell firing. Activity-dependent release of serotonin within serotonergic nuclei is thought to activate these autoreceptors, thus completing an autoinhibitory feedback loop. This concept, which was originally proposed in the 1970s, has proven to be enormously fruitful and has guided the interpretation of a broad range of clinical and preclinical work. Yet, remarkably, electrophysiological studies seeking to directly demonstrate this phenomenon, especially in in vitro brain slices, have produced mixed results. Here, we critically review this work with a focus on electrophysiological studies, which directly assess neuronal activity. We also highlight recent work suggesting that 5-HT1A receptor-mediated autoinhibition may play other roles in the control of firing besides acting as a feedback regulator for the pacemaker-like firing rate of serotonergic neurons.