Effective healing of large bone defects is a clinical challenge. Extracellular vesicle (EV)-mediated cell-free therapy has great potential in bone defect repair; however, unmodified EVs generally exhibit limited osteogenic potential. Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic cytokines reported to date. Here, we modified the EVs from BMP9-stimulated adipose-derived mesenchymal stem cells (iMAD), designated as B9-EVs. Subcutaneous injections of B9-EVs in immune-competent mice elicited no detectable host immune response. B9-EVs effectively induced in vitro osteogenic markers and promoted subcutaneous bone formation and cranial defect repair in vivo, similar to the direct use of recombinant adenovirus-mediated BMP9 overexpressing (AdR-B9) transduced iMAD cells. The miRNA-seq analysis of B9-EVs identified a distinct set of osteogenesis-related miRNAs. RNA-seq analysis revealed that osteogenesis-associated transcripts regulated in B9-EVs-stimulated MSCs were overlapping with but also distinct from those in AdR-B9-stimulated MSCs. Further bioinformatic analysis established an miRNA-mRNA network and revealed that the functionalized B9-EVs may regulate 10 miRNAs and 11 mRNA transcripts to induce osteogenesis through mechanisms that are unique and distinct from those associated with direct BMP9 stimulation. Collectively, given their cell-free and non-immunogenic nature, the functionalized osteogenic B9-EVs hold great potential for bone tissue engineering by providing effective osteogenic factors through EV-mediated paracrine signaling mechanisms.

An important challenge in the management of thumb carpometacarpal (CMC) joint arthritis is determining the most appropriate surgical approach for any given clinical scenario, once non-operative treatment has been exhausted. The variety of surgical procedures available highlights the fact that there is no general consensus on the optimal surgical treatment of this condition. With the advancement in wrist arthroscopy, the use of arthroscopic-assisted treatment for basilar joint arthritis has become more popular and aims to meet some of the shortcomings of open procedures. We will review arthroscopic interventions, their outcomes and future hurdles in the management of thumb CMC arthritis.

Although distal radius fractures are common injuries, nonunion is extremely rare. Nonunion has been associated with increased metaphyseal comminution, concomitant distal ulna fracture , inadequate immobilization, and patient factors. Nonunion should be suspected in patients with persistent pain, limited range of motion, and worsening wrist deformity after wrist remobilization. Treatment selection depends on presence of infection, status of the radiocarpal and distal radioulnar joints , and type of prior surgical interventions. Multiple surgical techniques exist for managing distal radius nonunions including open reduction and internal fixation of the nonunion site with/without bone graft augmentation versus total wrist arthrodesis .

Although distal radius fractures are common injuries, nonunion is extremely rare. Nonunion has been associated with increased metaphyseal comminution, concomitant distal ulna fracture, inadequate immobilization, and patient factors. Nonunion should be suspected in patients with persistent pain, limited range of motion, and worsening wrist deformity after wrist remobilization. Treatment selection depends on presence of infection, status of the radiocarpal and distal radioulnar joints, and type of prior surgical interventions. Multiple surgical techniques exist for managing distal radius nonunions including open reduction and internal fixation of the nonunion site with/without bone graft augmentation versus total wrist arthrodesis.

Customarily, academic chairs have embodied the triple role of excellence in clinical work,education and research. With the rapid changes in healthcare, it has become clear that surgical expertise and academic achievements do not necessarily translate into leadership greatness. Currently to successfully run an academic department the chairperson must also be an experienced manager, with an understanding of business administration, financial restrictions, productivity goals, and medical ethics. A successful chair needs to be able to balance variable tasks and diverse people, and be proficient in managing uncertainty and change. In this review we summarize the clinical, academic and administrative challenges associated with running an academic department.

Reconstruction of metacarpal hands remains a challenging problem for hand surgeons. In this case report, we present a middle-aged female patient with bilateral Wei Type IIB metacarpal hands secondary to severe burn injuries following a motor vehicle accident. The patient underwent a 2-stage reconstruction with big, second, and third toes transfer in each hand to restore tripod pinch. Long-term follow-up demonstrated excellent functional outcomes, with independence with all activities of daily living and minimal donor site morbidity. This is the first report of a 2-stage 6 toe-to-hand transfer in a patient with bilateral metacarpal hands. Approaching this patient’s reconstruction in only 2 stages allowed for a successful outcome with fewer operations and less surgical morbidity.

OBJECTIVE:To evaluate the union rate and rate of postoperative complications in patients with septic nonunions of the humerus after a two-stage reconstruction using a free vascularized fibula graft.DESIGN:Retrospective case series.SETTING:Academic, tertiary referral center.PATIENTS/PARTICIPANTS:Adult patients with staged reconstruction for infected nonunion of the humerus with at least 2 years follow-up after vascularized fibula graft transfer.INTERVENTION:First, infected nonunion debridement with antibiotic spacer and external fixator placement. After antimicrobial treatment, free vascularized fibula transfer with internal fixation.MAIN OUTCOME MEASUREMENTS:Time to union, pain, affected extremity range of motion, and function.RESULTS:10 patients with septic humerus nonunion treated with staged reconstruction using a free vascularized fibula graft, with a mean follow-up of 32.3 months were included. After the two-stage reconstruction using a free fibula, radiographic union was achieved in 6/10 patients, with a mean time to union of 19.9 weeks. The remaining 4 patients required an additional procedure with graft augmentation and/or implant revision. After the revision procedure, union was noted in 3/4 patients, 21 weeks postoperatively. Mean patient visual analog scale pain scores improved from 5.8 preoperatively to 0.9 at final follow-up ( P = 0.02). Postoperatively, mean elbow flexion was 110 ± 20 degrees and extension 15 ± 7.5 degrees.CONCLUSION:A two-stage reconstruction using a free fibula graft can be used in patients with septic nonunions of the humerus in the setting of multiple failed prior surgeries and compromised local biology. Additional procedures may be needed in some to achieve final union.LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Cutis calcinosis of the hand in the setting of symbrachydactyly is presented in 2 unique patients. Both lesions were treated based on the standard of care protocols with resection of the calcified mass and hand reconstruction, as appropriate. The patients healed uneventfully without recurrence of the calcification at a the 1-year follow-up. The association between symbrachydactyly and calcinosis cutis is discussed along with a hypothesis on the pathophysiologic mechanism that could potentially explain this unusual occurrence and why it might be more common than previously identified.

Background:Upper extremity injuries account for approximately 16.9% of football injuries in the National Collegiate Athletic Association (NCAA). Purpose:To determine the epidemiology, management, and outcomes of hand/wrist injuries in collegiate football athletes so as to identify factors associated with surgical intervention and delayed return to play (RTP). Study Design:Descriptive epidemiology study. Methods:We retrospectively reviewed hand/wrist injuries that occurred within a single NCAA Division I football team from January 1, 2003, to December 31, 2020. Data analyzed included player position, college seniority, injury characteristics, injury management, surgical procedures performed, and timing of RTP. A univariate analysis was performed to identify factors associated with increased risk for surgical intervention and delayed (>21 days) RTP after hand and wrist injury in this cohort. Results:Overall, 124 patients with 168 hand/wrist injuries were identified (9.9 wrist/hand injuries per year). Sprain of the thumb metacarpophalangeal (MCP) joint ulnar collateral ligament (UCL) was the most common diagnosis (19.6%). Surgery was required in 22% of injuries, with injury of the UCL of the thumb MCP joint (8/37) being the most common indication. Injuries occurring during competitive games (odds ratio = 4.29; 95% CI, 1.2-15.9) were associated with an increased risk for surgery. Most (70%) injuries did not lead to time missed from football, whereas the remaining 30% resulted in an average of 33 ± 36 days missed. Conclusion:Over 17 athletic seasons, the annual incidence of hand and wrist injury in these NCAA Division I football players was 9.9 injuries per year, with 22% requiring surgical treatment. Injury to the UCL of the thumb MCP joint was the most common injury and indication for surgery, and 30% of injuries resulted in approximately 1 month lost. Injuries sustained in games were associated with operative management and delayed RTP.

Hansen's disease is a well-described, largely historic infection that is caused by Mycobacterium leprae. Lucio's phenomenon is an aggressive, rare form of untreated lepromatous leprosy characterized by diffuse cutaneous lesions and systemic symptoms. To date, cases of necrotizing soft tissue infection in the setting of leprosy have rarely been reported in the literature. We present the case of a 51-year-old man with no known past medical history who presented for the evaluation of acute-on-chronic left upper extremity ulceration, soft tissue swelling, and pain. The patient was diagnosed with necrotizing soft tissue infection of the left upper extremity and underlying multibacillary lepromatous leprosy with Lucio's phenomenon. He underwent dermatofasciectomy of the affected extremity, followed by staged soft tissue coverage, including dermal allograft placement. Proper antibiotic management was also undertaken. In this article, we describe a case of previously undiagnosed leprosy with Lucio's phenomenon manifesting as necrotizing fasciitis of the upper extremity.

Human adipose-derived mesenchymal stem cells (ASCs) transduced with a lentiviral vector system to express bone morphogenetic protein 2 (LV-BMP-2) have been shown to reliably heal bone defects in animal models. However, the influence of donor characteristics such as age, sex, race, and medical co-morbidities on ASC yield, growth and bone regenerative capacity, while critical to the successful clinical translation of stem cell-based therapies, are not well understood. Human ASCs isolated from the infrapatellar fat pads in 122 ASC donors were evaluated for cell growth characteristics; 44 underwent additional analyses to evaluate in vitro osteogenic potential, with and without LV-BMP-2 transduction. We found that while female donors demonstrated significantly higher cell yield and ASC growth rates, age, race, and the presence of co-morbid conditions were not associated with differences in proliferation. Donor demographics or the presence of comorbidities were not associated with differences in in vitro osteogenic potential or stem cell differentiation, except that transduced ASCs from healthy donors produced more BMP-2 at day 2. Overall, donor age, sex, race, and the presence of co-morbid conditions had a limited influence on cell yield, proliferation, self-renewal capacity, and osteogenic potential for non-transduced and transduced (LV-BMP-2) ASCs. These results suggest that ASCs are a promising resource for both autologous and allogeneic cell-based gene therapy applications.

Regional gene therapy using a lentiviral vector containing the BMP-2 complementary DNA (cDNA) has been shown to heal critical-sized bone defects in rodent models. An appropriate "cellular dose" needs to be defined for eventual translation into human trials. The purpose of this study was to evaluate bone defect healing potential and quality using three different doses of transduced human bone marrow cells (HBMCs). HBMCs were transduced with a lentiviral vector containing either BMP-2 or green fluorescent protein (GFP). All cells were loaded onto compression-resistant matrices and implanted in the bone defect of athymic rats. Treatment groups included femoral defects that were treated with a low-dose (1 x 10(6) cells), standard-dose (5 x 10(6) cells), and high-dose (1.5 x 10(7) cells) HBMCs transduced with lentiviral vector containing BMP-2 cDNA. The three control groups were bone defects treated with HBMCs that were either nontransduced or transduced with vector containing GFP. All animals were sacrificed at 12 weeks. The bone formed in each defect was evaluated with plain radiographs, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. Bone defects treated with higher doses of BMP-2-producing cells were more likely to have healed (6/14 of the low-dose group; 12/14 of the standard-dose group; 14/14 of the high-dose group; chi(2)(2) = 15.501, p < 0.001). None of the bone defects in the control groups had healed. Bone defects treated with high dose and standard dose of BMP-2-producing cells consistently outperformed those treated with a low dose in terms of bone formation, as assessed by microCT and histomorphometry, and biomechanical parameters. However, statistical significance was only seen between defects treated with high dose and low dose. Larger doses of BMP-2-producing cells were associated with a higher likelihood of forming heterotopic ossification. Femurs treated with a standard- and high-dose BMP-2-producing cells demonstrated similar healing and biomechanical properties. Increased doses of BMP-2 delivered through higher cell doses have the potential to heal large bone defects. Adapting regional gene therapy for use in humans will require a balance between promoting bone repair and limiting heterotopic ossification. Impact statement Critical bone loss may result from complex traumatic bone injury (i.e., open fracture or blast injury), revision total joint arthroplasty, and spine pseudoarthrosis. This is a challenging clinical problem to treat and regional gene therapy is an innovative means of addressing it. This study provides information regarding the quantity of cells or "cell dose" of transduced cells needed to treat a critical-sized bone defect in a rat model. This information may be extrapolated for use in humans in future trials.

Introduction: Surgical treatment of humeral shaft nonunions is characterized by variability of fixation methods, graft choices, and rates of union and iatrogenic radial nerve palsy. The aim of the current study is to evaluate the union rate of humeral shaft aseptic nonunions and the rate of postoperative complications following a consistent management protocol. Patients and methods: This is a retrospective review of 41 consecutive adult patients (23 female and 18 male with a mean age of 42 years) with aseptic nonunions of the humeral shaft treated by the senior author in our institution over a 17-year period. Nonunions were located in the middle third of the diaphysis in 33 patients, in the distal third in 6, and in the proximal third in 2 patients. Comorbidities were present in 49% of patients and the most common were smoking in 27% and diabetes mellitus in 17% of patients. Patients were treated at an average of 24 months after their injury. Surgical protocol consisted of careful dissection of the radial nerve, debridement of the nonunion site, stable plate fixation and augmentation of local biology. Results: Thirty-eight patients had mean clinical and radiographic follow-up of 9.4 months. All 38 nonunions healed at a mean time of 3.5 months. There were no persistent nonunions and no failures of fixation. None of the 40 patients with an intact radial nerve preoperatively developed any signs of radial nerve compromise after surgery. Complications consisted of one superficial infection (2%) that resolved with oral antibiotics and one deep infection (2%) that required implant removal and debridement. The mean pain score on the visual analog scale was 0.7. Mean elbow range of motion was 125 degrees with a mean extension deficit of 5 degrees and mean flexion of 130 degrees. Conclusions: Our surgical protocol achieved consistent healing of nonunions of the humeral shaft with a low complication rate and no iatrogenic radial nerve palsy, even in long-standing nonunions in patients with comorbidities. (c) 2021 Elsevier Ltd. All rights reserved.

Adeno-associated viral vectors (AAV) are unique in their ability to transduce a variety of both dividing and nondividing cells, with significantly lower risk of random genomic integration and with no known pathogenicity in humans, but their role in ex vivo regional gene therapy for bone repair has not been definitively established. The goal of this study was to test the ability of AAV vectors carrying the cDNA for BMP-2 to transduce human mesenchymal stem cells (MSCs), produce BMP-2, and induce osteogenesis in vitro as compared with lentiviral gene therapy with a two-step transcriptional amplification system lentiviral vector (LV-TSTA). To this end, we created two AAV vectors (serotypes 2 and 6) expressing the target transgene; eGFP or BMP-2. Transduction of human MSCs isolated from bone marrow (BMSCs) or adipose tissue (ASCs) with AAV2-eGFP and AAV6-eGFP led to low transduction efficiency (BMSCs: 3.57% and 8.82%, respectively, ASCs: 6.17 and 20.2%, respectively) and mean fluorescence intensity as seen with FACS analysis 7 days following transduction, even at MOIs as high as 106. In contrast, strong eGFP expression was detectable in all of the cell types post transduction with LV-TSTA-eGFP. Transduction with BMP-2 producing vectors led to minimal BMP-2 production in AAV-transduced cells 2 and 7 days following transduction. In addition, transduction of ASCs and BMSCs with AAV2-BMP-2 and AAV6-BMP-2 did not enhance their osteogenic potential as seen with an alizarin red assay. In contrast, the LV-TSTA-BMP-2-transduced cells were characterized by an abundant BMP-2 production and induction of the osteogenic phenotype in vitro (p < 0.001 vs. AAV2 and 6). Our results demonstrate that the AAV2 and AAV6 vectors cannot induce a significant transgene expression in human BMSCs and ASCs, even at MOIs as high as 106. The LV-TSTA vector is significantly superior in transducing human MSCs; thus this vector would be preferable when developing an ex vivo regional gene therapy strategy for clinical use in orthopedic surgery applications.

Objectives: Blunt and ballistic injuries are two common injury mechanisms encountered by orthopaedic traumatologists. However the intrinsic nature of these injures may necessitate differences in operative and post-operative care. Given the evolving opioid crisis in the medical community, considerable attention has been given to appropriate management of pain; particularly in orthopaedic patients. We sought to evaluate relative postoperative narcotic use in blunt injuries and ballistic injuries. Design: Retrospective Cohort Study. Setting: Academic Level-1 Trauma Center. Patients: 96 Patients with blunt or ballistic fractures. Intervention: Inpatient narcotic pain management after orthopaedic fracture management. Main outcome measurements: Morphine equivalent units (MEU). Results: Patients with blunt injuries had a higher MEU compared to ballistic injuries in the first 24 hours postoperatively (35.0 vs 29.5 MEU, p = 0.02). There were no differences in opiate consumption 24-48 hours (34.8 vs 28.0 MEU), 48 hours 7 days post op (28.4 vs 30.4 MEU) or the 24 hours before discharge (30.0 vs 28.6 MEU). On multivariate analysis, during the 24-48 hours and 24 hours before discharge time points total EBL was associated with increased opioid usage. During days 3-7 (p < 0.001) and in the final 24 hours prior to discharge (p = 0.012), the number of orthopaedic procedures was a predictor of opioid consumption. Conclusion: Blunt injuries required an increased postoperative narcotic consumption during the first 24 hours of inpatient stay following orthopedic fracture fixation. However, there was no difference at other time points. Immediate post-operative pain regimens may be decreased for patients with ballistic injuries. Level of evidence: III. (c) 2020 Elsevier Ltd. All rights reserved.

The development of an ex vivo regional gene therapy clinical pathway using adipose-derived stem cells (ASCs) may require cryopreservation for cell culture, storage, and transport prior to clinical use. ASCs isolated from five donors were transduced with a lentiviral vector containing BMP-2. Three groups were assessed: transduction without cell freezing (group 1), freezing of cells for 3 weeks followed by transduction (group 2), and cell transduction prior to freezing (group 3). Nontransduced cells were used as a control. The cluster of differentiation (CD) marker profiles, cell number, BMP-2 production, and osteogenic potential were measured. The CD marker profile (CD44, CD73, CD90, and CD105) was unchanged after cryopreservation. Cell number was equivalent among cryopreservation protocols in transduced and nontransduced cells. There was a trend toward decreased BMP-2 production in group 3 compared to groups 1 and 2. Osteogenic potential based on Alizarin red concentration was higher in group 2 compared to group 3, with no difference compared to group 1. Freezing ASCs prior to transduction with a lentiviral vector containing BMP-2 has no detrimental effect on cell number, BMP-2 production, osteogenic potential, or immunophenotype. Transduction prior to freezing, however, may limit the BMP-2 production and potential osteogenic differentiation of the ASCs.

AIMS:To describe and analyze the mid-term functional outcomes of a large series of patients who underwent the Hoffer procedure for brachial plexus birth palsy (BPBP).METHODS:All patients who underwent the Hoffer procedure with minimum two-year follow-up were retrospectively reviewed. Active shoulder range of movement (ROM), aggregate modified Mallet classification scores, Hospital for Sick Children Active Movement Scale (AMS) scores, and/or Toronto Test Scores were used to assess functional outcomes. Subgroup analysis based on age and level of injury was performed. Risk factors for subsequent humeral derotational osteotomy and other complications were also assessed. A total of 107 patients, average age 3.9 years (1.6 to 13) and 59% female, were included in the study with mean 68 months (24 to 194) follow-up.RESULTS:All patients demonstrated statistically significant improvement in all functional outcomes and active shoulder abduction and external rotation ROM (p < 0.001). Patients < 2.5 years of age had higher postoperative AMS, abduction ROM and strength scores, and aggregate postoperative Toronto scores (p ≤ 0.035) compared to patients ≥ 2.5 years old. There were 17 patients (16%) who required a subsequent humeral derotational osteotomy; lower preoperative AMS external rotation scores and external rotation ROM were predictive risk factors (p ≤ 0.016).CONCLUSION:Patients with BPBP who underwent the Hoffer procedure demonstrated significant improvement in postoperative ROM, strength, and functional outcome scores at mid-term follow-up. Patients younger than 2.5 years at the time of surgery generally had better functional outcomes. Limited preoperative external rotation strength and ROM were significantly associated with requirement for subsequent humeral derotational osteotomy. In our chort significant improvements in shoulder function were obtained after the Hoffer procedure for BPBP. Cite this article: Bone Joint J 2020;102-B(2):246-253.

Traditionally, ex vivo gene therapy involves a two-step approach, with culture expansion of cells prior to transduction and implantation. We have tried to simplify this strategy and eliminate the time and cost associated with culture expansion, by introducing "next-day" regional gene therapy using human bone marrow cells. The purpose of this study was to determine whether a lentiviral vector (LV) carrying the cDNA for BMP-2 can transduce freshly isolated human BM cells, leading to abundant BMP production and bone formation in vivo, and evaluate the in vivo osteoinductive potential of "next-day" gene therapy and the standard "two-step" tissue culture expansion approach. To this end, human bone marrow cells (HBMC) from patients undergoing total hip arthroplasty were harvested, transduced with a BMP-2-expressing LV either overnight ("next day" gene therapy; ND) or after culture expansion (cultured "two-step" approach; C) and then implanted into a rat critical-sized femoral defect. The animals were randomly assigned to one of the following groups: I; ND-HBMC transduced with LV-TSTA BMP-2, II; ND-HBMC transduced with LV-TSTA GFP, III; non-transduced ND-HBMC; IV; C-HBMC transduced with LV-TSTA BMP-2, V; C-HBMC transduced with LV-TSTA-GFP, VI; non-transduced C-HBMC. Treatment with either "next-day" or cultured HBMC demonstrated a significant increase in new bone formation compared with all negative control groups as seen in plain radiographs, microCT and histologic/histomorphometric analysis. At 12 weeks post-op, complete defect union on plain X-rays occurred in 7/14 animals in the NDHBMC/BMP-2 group and 12/14 in the C-HBMC/BMP-2 treated rats. The two-step approach was associated with more consistent results, a higher union rate, and superiority with regards to all of the studied bone healing parameters. In this study we demonstrate proof of concept that BMP-2-transduced human bone marrow cells can be used to enhance bone healing in segmental bone defects, and that regional gene therapy using lentiviral transduction has the osteoinductive potential to heal large bone defects in clinical settings.