CD47 is Required for Mesenchymal Progenitor Proliferation and Fracture Repair.

CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone volume, bone mineral content, and tissue mineral content as assessed by microcomputed tomography 10 days post-fracture, and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus bone volume and bone mineral content relative to WT. Consistent with our In vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell mass. Finally, WT mice administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of non-ischemic and ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.

CD47 is Required for Mesenchymal Progenitor Proliferation and Fracture Repair.

CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone volume, bone mineral content, and tissue mineral content as assessed by microcomputed tomography 10 days post-fracture, and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus bone volume and bone mineral content relative to WT. Consistent with our in vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell mass. Finally, WT mice administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of non-ischemic and ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.

Biomechanics of fracture healing: how best to optimize your construct in the OR.

Orthopaedic surgeons routinely assess the biomechanical environment of a fracture to create a fixation construct that provides the appropriate amount of stability in efforts to optimize fracture healing. Emerging concepts and technologies including reverse dynamization, "smart plates" that measure construct strain, and FractSim software that models fracture strain represent recent developments in optimizing construct biomechanics to accelerate bone healing and minimize construct failure.

Unipolar Hemiarthroplasty, Bipolar Hemiarthroplasty, or Total Hip Arthroplasty for Hip Fracture in Older Individuals.

BACKGROUND: Practice patterns regarding the use of unipolar hemiarthroplasty, bipolar hemiarthroplasty, and total hip arthroplasty (THA) for femoral neck fractures in older patients vary widely. This is due in part to limited data stipulating the specific circumstances under which each form of arthroplasty provides the most predictable outcome. The purpose of this study was to investigate the patient characteristics for which unipolar hemiarthroplasty, bipolar hemiarthroplasty, or THA might be preferable due to a lower risk of all-cause revision. METHODS: A U.S. health-care system's hip fracture registry was used to identify patients ≥60 years old who underwent unipolar hemiarthroplasty, bipolar hemiarthroplasty, or THA for hip fracture from 2009 through 2021. Unipolar and bipolar hemiarthroplasty were compared with THA within patient subgroups defined by age (60 to 79 versus ≥80 years) and American Society of Anesthesiologists (ASA) classification (I or II versus III); patients with an ASA classification of IV or higher were excluded. Multivariable Cox proportional hazard regression analysis was used to evaluate all-cause revision risk while adjusting for confounders, with mortality considered as a competing risk. RESULTS: There were 14,277 patients in the final sample (median age, 82 years; 70% female; 80% White; 69% with an ASA classification of III; median follow-up, 2.7 years), and the procedures included 7,587 unipolar hemiarthroplasties, 5,479 bipolar hemiarthroplasties, and 1,211 THAs. In the multivariable analysis of all patients, both unipolar (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.48 to 3.12; p < 0.001) and bipolar (HR = 1.92, 95% CI = 1.31 to 2.80; p < 0.001) hemiarthroplasty had higher revision risks than THA. In the age-stratified multivariable analysis of patients aged 60 to 79 years, both unipolar (HR = 2.17, 95% CI = 1.42 to 3.34; p = 0.004) and bipolar (HR = 1.69, 95% CI = 1.08 to 2.65; p = 0.022) hemiarthroplasty also had higher revision risks than THA. In the ASA-stratified multivariable analysis, patients with an ASA classification of I or II had a higher revision risk after either unipolar (HR = 3.52, 95% CI = 1.87 to 6.64; p < 0.001) or bipolar (HR = 2.31, 95% CI = 1.19 to 4.49; p = 0.013) hemiarthroplasty than after THA. No difference in revision risk between either of the hemiarthroplasties and THA was observed among patients with an age of ≥80 years or those with an ASA classification of III. CONCLUSIONS: In this study of hip fractures in older patients, THA was associated with a lower risk of all-cause revision compared with unipolar and bipolar hemiarthroplasty among patients who were 60 to 79 years old and those who had an ASA classification of I or II. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy.

Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the transforming growth factor-ß superfamily member Activin A became very abundant during mouse and human bone fracture healing but was minimally detectable in intact bones. Single-cell RNA-sequencing revealed that the Activin A-encoding gene Inhba was highly expressed in a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character that quickly emerged after fracture and represented the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of neutralizing Activin A antibody inhibited bone healing. In contrast, a single recombinant Activin A implantation at fracture site in young and aged mice boosted: PPC numbers; phosphorylated SMAD2 signaling levels; and bone repair and mechanical properties in endochondral and intramembranous healing models. Activin A directly stimulated myofibroblastic differentiation, chondrogenesis and osteogenesis in periosteal mesenchymal progenitor culture. Our data identify a distinct population of Activin A-expressing PPCs central to fracture healing and establish Activin A as a potential new therapeutic tool.

A Murine Delayed-Healing Model Associates Immune Response with Functional Bone Regeneration after Trauma.

Nonunion and delayed-union fractures pose a significant clinical challenge, often leading to prolonged morbidity and impaired quality of life. Fracture-induced hematoma and acute inflammation are crucial for establishing the healing cascade. However, aberrant inflammatory phenotypes can suppress healing and cause bone resorption. Elucidating these mechanisms is necessary to develop potent immunomodulatory therapies and prevent nonunion. Here, we report a delayed fracture healing model enabling the modulation of interfragmentary strain that mimics the etiology of hypertrophic nonunions to elucidate the role of dysregulated immune response in poor healing outcomes. High interfragmentary strain (>15%) was associated with larger callus volumes but delayed bone healing, increased inflammation, and inferior healing outcomes, while lower strain levels (<5%) corresponded to normal bone healing. In addition, we found distinct differences in the ossification, chondrification, and fibrosis patterns between high and low-strain groups, underscoring the significant impact of strain on the healing process. A comprehensive analysis of the systemic immune response revealed dynamic alterations in immune cell populations and factors, particularly within the early hours and days post-fracture. Several immune factors exhibited significant correlations with various functional healing outcomes, indicating their potential as predictive markers for assessing fracture healing progression. Our results also highlighted the significance of timely resolution of proinflammatory signals and the elevation of pro-regenerative immune cell phenotypes in promoting bone regeneration. Multivariate analysis revealed that CD25+ T-regulatory cells were influential in predicting proper bone healing, followed by CD206+ macrophages, underscoring the pivotal role of immune cell populations in the bone healing process. In conclusion, our study provides valuable insights into the intricate interplay between interfragmentary strain, immune response, and the ultimate outcomes of fracture healing. By shedding light on the underlying mechanisms that drive hypertrophic nonunion pathogenesis, our research lays the foundation for enhanced surgical management of nonunions and offers a promising avenue for developing targeted therapeutic interventions and personalized treatment strategies for individuals suffering from fracture nonunion.

Operative Technique for Sacral Insufficiency Fractures Causing Spinopelvic Dissociation: A Case Report.

CASE: We present a case of a 54-year-old man with atraumatic, U-type sacral insufficiency and L5 compression fractures leading to spinopelvic dissociation, inability to ambulate, and bowel/bladder compromise. The patient underwent L3-4 percutaneous pedicle screw fixation with bilateral iliac bolts and percutaneous iliosacral screw fixation. Postoperatively, the patient had return of bowel/bladder function and independent ambulation at 2.5 years. CONCLUSION: Atraumatic spinopelvic dissociation is an underappreciated pathology in older patients. Here, we describe the result of our preferred treatment strategy, triangular osteosynthesis, to preserve function and independence. Despite optimal, prompt treatment, these injuries pose a difficult rehabilitation process for patients.

Impact of the SARS-CoV-2 outbreak on ACGME-accredited orthopaedic trauma fellowship training.

INTRODUCTION: The SARS-CoV-2 viral outbreak created unprecedented challenges in surgical education. Yet, its impact on reported case volume during orthopaedic trauma fellowship training remains poorly understood. We hypothesized that cases performed during orthopaedic trauma fellowship training would decrease by 8 %-17 % during the 2019-2020 academic year corresponding to the 1-2 month moratorium of non-essential cases during the initial SARS-CoV-2 outbreak in the United States. METHODS: We designed a retrospective cohort study of orthopaedic trauma fellows at Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs (2018-2019 to 2021-2022). Mean case volumes were compared by case category across academic years. RESULTS: There was a -13 % year-over-year decrease in reported case volume during the 2019-2020 academic year (505 ± 126 vs 441 ± 94, P = 0.079, Fig. 1). Case categories with the greatest percentage declines were Treatment of Nonunion / Malunion (-31 %), Fasciotomy (-25 %), External Fixation (-21 %), Forearm / Wrist (-21 %), and Intra-articular Distal Humerus Fracture (-17 %). There was a 7 % year-over-year increase in case volume during the subsequent 2020-2021 academic year with near universal increases in case volume across case categories. CONCLUSION: There was a 13 % decrease in orthopaedic trauma case volume during the 2019-2020 academic year, corresponding to the SARS-CoV-2 outbreak. Certain trauma case categories experienced the greatest negative impact, which subsequently recovered during the next academic year. These results may help inform accrediting bodies and surgical educators on the impact of future viral outbreaks on orthopaedic trauma fellowship training.

The rate of disuse osteopenia in admitted, non-weight-bearing patients.

Disuse osteopenia is a well-recognized consequence of prolonged physical inactivity, but its rate after orthopaedic injuries necessitating non-weight-bearing is not well studied. The purpose of this study was to estimate the rate of disuse osteopenia at the lumbar spine and proximal femur in patients with lower extremity trauma admitted to the hospital. We performed a retrospective chart review of patients with lower extremity trauma with a period of strict non-weight-bearing between completion of two computed tomography (CT) scans. The radiodensity of the proximal femur or lumbar vertebrae was measured from the earliest and latest available CT scans within the non-weight-bearing timeframe. The change in estimated bone mineral density (eBMD) was calculated as a proxy for disuse osteopenia. A total of 189,111 patients were screened, with 17 patients in the proximal femur group and 15 patients in the lumbar spine group meeting inclusion and exclusion criteria. The average rate of change in eBMD of the proximal femur was a decrease of 7.54 HU/day, 95% confidence interval (CI) [3.65, 11.43]. The average rate of change in eBMD of the lumbar spine was an increase of 1.45 HU/day, 95% CI [-3.15, 6.06]. In admitted, non-weight-bearing orthopaedic trauma patients, our novel study suggests that the proximal femur experiences disuse osteopenia during periods of non-weight-bearing, although this finding was not observed at the lumbar spine. The clinical significance of this data underscores the important consideration of disuse osteopenia by all physicians when caring for patients that may require non-weight-bearing restrictions.

How do surgeons decide when to treat proximal humerus fractures with operative versus nonoperative management?

PURPOSE: The objective of this study was to determine the underlying factors that drive the decision for surgeons to pursue operative versus nonoperative management for proximal humerus fractures (PHF) and if fellowship training had an impact on these decisions. METHODS: An electronic survey was distributed to members of the Orthopaedic Trauma Association and the American Shoulder and Elbow Surgeons Society to assess differences in patient selection for operative versus nonoperative management of PHF. Descriptive statistics were reported for all respondents. RESULTS: A total of 250 fellowship trained Orthopaedic Surgeons responded to the online survey. A greater proportion of trauma surgeons preferred nonoperative management for displaced PHF fractures in patients over the age of 70. Operative management was preferred for older patients with fracture dislocations (98%), limited humeral head bone subchondral bone (78%), and intraarticular head split (79%). Similar proportions of trauma surgeons and shoulder surgeons cited that acquiring a CT was crucial to distinguish between operative and nonoperative management. CONCLUSION: We found that surgeons base their decisions on when to operate primarily on patient's comorbidities, age, and the amount of fracture displacement when treating younger patients. Further, we found a greater proportion of trauma surgeons elected to proceed with nonoperative management in patients older than the age of 70 years old as compared to shoulder surgeons.

A new classification for quadrilateral plate fracture of acetabulum.

BACKGROUND: Recently, quadrilateral plate (QLP) fractures of acetabulum have attracted increasing attention. However, evidence for the appropriate classification of QLP fractures is still lacking, making it difficult to understand and manage these fractures. This study aimed to introduce a new classification for QLP fractures and evaluate its reproducibility. METHODS: A series of 1101 consecutive patients with acetabular fractures from 8 level-I trauma centers were enrolled in this study. All patients underwent preoperative radiograph and computed tomography imaging. QLP fractures were identified and classified using the new and Judet-Letournel classification system. The inter- and intra-observer reliabilities (kappa coefficients, κ) of these two systems were investigated by 4 observers. Furthermore, surgical approaches and fixation methods for each fracture type are described. RESULTS: In total, 243 (243/1101, 22%) patients with QLP fractures were identified and included in this analysis. The mean κ value of the intra-observer reliability was 0.84 (range, 0.763-0.919) for the new classification, indicating excellent agreement, and the inter-observer reliability was 0.762 (range, 0.625-0.876), indicating substantial agreement. The values were 0.649 (range, 0.523-0.708) and 0.584 (0.497-0.646), respectively, according to the Judet-Letournel classification. Six cases (6/243, 2.5%) could not be classified using the Judet-Letournel classification. The selection of surgical approaches and fixation methods depends on the fracture type; however, an anterior intra-pelvic approach and buttressing fixation using the plate or screw are preferred for QLP fractures. CONCLUSION: This study presents a new classification for QLP fractures, showing higher intra- and inter-observer reliabilities than those obtained using the Judet-Letournel classification. This allowed us to obtain an in-depth and comprehensive understanding of QLP fractures. Additionally, the new classification might guide further studies on surgical strategies for QLP fractures. LEVEL OF EVIDENCE: Level II.

Fracture healing-orthobiologics: from basic science to clinical application.

Orthopaedics as a field and a profession is fundamentally concerned with the treatment of musculoskeletal disease, in all of its many forms. Our collective understanding of the cellular mechanisms underlying musculoskeletal pathology resulting from injury continues to evolve, opening novel opportunities to develop orthobiologic treatments to improve care. It is a long path to move from an understanding of cellular pathology to development of successful clinical treatment, and this article proposes to discuss some of the challenges to achieving translational therapies in orthopaedics. The article will focus on challenges that clinicians will likely face in seeking to bring promising treatments forward to clinical practice and strategies for improving success in translational efforts.

Full Reversal of Anticoagulants Before Cephalomedullary Fixation of Geriatric Hip Fractures May Not Be Necessary.

OBJECTIVES: To examine the relationship between anticoagulant and antiplatelet drugs and surgical blood loss for geriatric patients undergoing cephalomedullary nail fixation of extracapsular proximal femur fractures. DESIGN: Multicenter, retrospective, cohort study using bivariate and multivariable regression analyses. SETTING: Two Level-1 trauma centers. PATIENTS: One thousand four hundred forty-two geriatric (ages 60-105 years) patients undergoing isolated primary intramedullary fixation of nonpathologic extracapsular hip fractures from 2009 to 2018 including 657 taking an antiplatelet drug alone (including aspirin), 99 taking warfarin alone, 37 taking a direct oral anticoagulant (DOAC) alone, 59 taking an antiplatelet drug and an anticoagulant, and 590 taking neither. INTERVENTION: Cephalomedullary nail fixation. MAIN OUTCOME MEASUREMENTS: Blood transfusion and calculated blood loss. RESULTS: More patients taking antiplatelet drugs required a transfusion than controls (43% vs. 33%, P < 0.001), whereas patients taking warfarin or DOACs did not (35% or 32% vs. 33%). Median calculated blood loss was increased in patients taking antiplatelet drugs (1275 mL vs. 1059 mL, P < 0.001) but not in patients taking warfarin or DOACs (913 mL or 859 mL vs. 1059 mL). Antiplatelet drugs were independently associated with an odds ratio of transfusion of 1.45 [95% confidence interval (CI), 1.1-1.9] in contrast with 0.76 (95% CI, 0.5-1.2) for warfarin and 0.67 (95% CI, 0.3-1.4) for DOACs. CONCLUSIONS: Geriatric patients taking warfarin (incompletely reversed) or DOACs lose less blood during cephalomedullary nail fixation of hip fractures than those taking aspirin. Delaying surgery to mitigate anticoagulant-related surgical blood loss may be unwarranted. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Evaluation and treatment of postoperative periprosthetic humeral fragility fractures.

Postoperative periprosthetic humeral shaft fractures represent a growing and difficult complication to treat given the aging patient population and associated bone loss. Determining the best treatment option is multifactorial, including patient characteristics, fracture pattern, remaining bone stock, and implant stability. Possible treatment options include nonoperative management with bracing or surgical intervention. Nonoperative treatment has been shown to have higher nonunion rates, thus should only be selected for a specific patient population with minimally displaced fractures or those that are unfit for surgery. Surgical management is recommended with prosthetic loosening, fracture nonunion, or failure of nonoperative treatment. Surgical options include open reduction and internal fixation, revision arthroplasty, or hybrid fixation. Careful evaluation, decision making, and planning is required in the treatment of these fractures.

Early identification of life-threatening soft-tissue infection using dynamic fluorescence imaging: first-in-kind clinical study of first-pass kinetics.

Necrotizing soft-tissue infections (NSTIs) are aggressive and deadly. Immediate surgical debridement is standard-of-care, but patients often present with non-specific symptoms, thereby delaying treatment. Because NSTIs cause microvascular thrombosis, we hypothesized that perfusion imaging using indocyanine green (ICG) would show diminished fluorescence signal in NSTI-affected tissues, particularly compared to non-necrotizing, superficial infections. Through a first-in-kind clinical study, we performed first-pass ICG fluorescence perfusion imaging of patients with suspected NSTIs. Early results support our hypothesis that ICG signal voids occur in NSTI-affected tissues and that dynamic contrast-enhanced fluorescence parameters reveal tissue kinetics that may be related to disease progression and extent.

Median survival following geriatric hip fracture among 17,868 males from the Veterans Health Administration.

Background: The expected value of treatments for geriatric femoral neck fracture is influenced by the predicted duration of survival after injury. Specifically, total hip arthroplasty is more suited for patients likely to live long enough to reap its longer-term benefits. For predicting short- and medium-term survival, there are many tools available, but for longer-term survival prognosis the current literature is insufficient. Our hypothesis is that patient age at the time of injury correlates with median life expectancy and survival rates, and these values can anchor a prediction regarding a given patient's life expectancy. We therefore sought to determine median and fractional survival rates at 30 days, and 1, 2, 5 and 10 years after surgery for a large cohort of elderly patients with hip fracture as a function of age. Methods: 17,868 male patients, 65-89 years of age, treated surgically for hip fracture within the Veterans Affairs system were assessed. From this set, 10,000 patients were randomly selected, and their ages at surgery and death (if any) were recorded at least 10 years post-operatively. Median and fractional survival rates were recorded at 1 month and 1, 2, 5, and 10 years. The mathematical relationship between age and median survival was determined. All findings from the 10,000-patient cohort were compared to corresponding values of the remaining 7,868 patients, to assess the predictive power of the initial observations. Results: The median survival rate for the entire cohort was 2.2 years, with 90.4% of the group surviving at 30 days. The percentage of the cohort surviving at 1, 2, 5 and 10 years after treatment was 64.5%, 52.3%, 27.1% and 8.9% respectively. Median survival was approximately (13 - (0.13 × age-at-time-of-surgery) years for patients of all ages. Conclusions: Median survival after geriatric hip fracture can be accurately predicted by the patient's age at the time of injury. Median survival and fractional survival at key milestones can help estimate life-expectancy and thereby help guide treatment.