Controlling axonal regeneration with acellular nerve allograft limits neuroma formation in peripheral nerve transection: An experimental study in a swine model.

BACKGROUND: Symptomatic neuromata are a common indication for revision surgery following amputation. Previously described treatments, including traction neurectomy, nerve transposition, targeted muscle re-innervation, and nerve capping, have provided inconsistent results or are technically challenging. Prior research using acellular nerve allografts (ANA) has shown controlled termination of axonal regrowth in long grafts. The purpose of this study was to determine the ability of a long ANA to prevent neuroma formation following transection of a peripheral nerve in a swine model. MATERIALS AND METHODS: Twenty-two adult female Yucatan miniature swine (Sus scrofa; 4-6 months, 15-25 kg) were assigned to control (ulnar nerve transection only, n = 10), treatment (ulnar transection and coaptation of 50 mm ANA, n = 10), or donor (n = 2) groups. Nerves harvested from donor group animals were treated to create the ANA. After 20 weeks, the transected nerves including any neuroma or graft were harvested. Both qualitative (nerve architecture, axonal sprouting) and quantitative histologic analyses (myelinated axon number, cross sectional area of nerve tissue) were performed. RESULTS: Qualitative histologic analysis of control specimens revealed robust axon growth into dense scar tissue. In contrast, the treatment group revealed dwindling axons in the terminal tissue, consistent with attenuated neuroma formation. Quantitative analysis revealed a significantly decreased number of myelinated axons in the treatment group (1232 ± 540) compared to the control group (44,380 ± 7204) (p < .0001). Cross sectional area of nerve tissue was significantly smaller in treatment group (2.83 ± 1.53 mm2 ) compared to the control group (9.14 ± 1.19 mm2 ) (p = .0012). CONCLUSIONS: Aberrant axonal growth is controlled to termination with coaptation of a 50 mm ANA in a swine model of nerve injury. These early results suggest further investigation of this technique to prevent and/or treat neuroma formation.

The Use of Distal Ulnar Hounsfield Units to Predict Future Fragility Fracture Risk.

PURPOSE: Distal ulnar Hounsfield unit (HU) measurements obtained from computed tomography (CT) scans of the wrist can be used to accurately screen for low bone mineral density. It is unknown whether HU measurements can also predict the risk of future fragility fractures. Therefore, the purpose of this study was to determine if the HU values of the distal ulna correlate to fragility fracture risk. METHODS: An electronic database of radiographs at a single institution was searched for all wrist CT scans, obtained for any reason, between January 1, 2002, and December 31, 2008, to allow a minimum of 5-year follow-up. Manual measurement of HU on sequential coronal CT slices of the distal ulnar head was taken, and mean values were recorded. Previously determined cutoff values for the diagnosis of low bone mineral density were implemented to stratify patients as at risk or not at risk for future fragility fracture. Medical records were then manually reviewed for the occurrence of any future fragility fracture (hip, spine, proximal humerus, or rib). RESULTS: There were 161 CTs in 157 patients and 34 fragility fractures in 21 patients, with a prevalence of 13.4%. The mean HU in the fragility fracture group was significantly lower (134.2 vs 197.1 HU). The percentage of low HU patients with fragility fractures was significantly higher (22.7% vs 3.8%). The odds ratio for fragility fracture in the low HU group was 7.4 (95% confidence interval, 2.1-26.2). Using previously determined cutoff values, the sensitivity and specificity of distal ulna HU values for identifying patients who would sustain at least 1 future fragility fracture were 85.7% and 55.2%, respectively. CONCLUSIONS: Patients with low distal ulnar HU were significantly more likely to sustain a subsequent fragility fracture. A determination of distal ulnar HUs represents a quick, simple tool to identify patients potentially at risk for fragility fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

BMP Ligand Trap ALK3-Fc Attenuates Osteogenesis and Heterotopic Ossification in Blast-Related Lower Extremity Trauma.

Traumatic heterotopic ossification (tHO) commonly develops in wounded service members who sustain high-energy and blast-related traumatic amputations. Currently, no safe and effective preventive measures have been identified for this patient population. Bone morphogenetic protein (BMP) signaling blockade has previously been shown to reduce ectopic bone formation in genetic models of HO. In this study, we demonstrate the efficacy of small-molecule inhibition with LDN193189 (ALK2/ALK3 inhibition), LDN212854 (ALK2-biased inhibition), and BMP ligand trap ALK3-Fc at inhibiting early and late osteogenic differentiation of tissue-resident mesenchymal progenitor cells (MPCs) harvested from mice subjected to burn/tenotomy, a well-characterized trauma-induced model of HO. Using an established rat tHO model of blast-related extremity trauma and methicillin-resistant Staphylococcus aureus infection, a significant decrease in ectopic bone volume was observed by micro-computed tomography imaging following treatment with LDN193189, LDN212854, and ALK3-Fc. The efficacy of LDN193189 and LDN212854 in this model was associated with weight loss (17%-19%) within the first two postoperative weeks, and in the case of LDN193189, delayed wound healing and metastatic infection was observed, while ALK3-Fc was well tolerated. At day 14 following injury, RNA-Seq and quantitative reverse transcriptase-polymerase chain reaction analysis revealed that ALK3-Fc enhanced the expression of skeletal muscle structural genes and myogenic transcriptional factors while inhibiting the expression of inflammatory genes. Tissue-resident MPCs harvested from rats treated with ALK3-Fc exhibited reduced osteogenic differentiation, proliferation, and self-renewal capacity and diminished expression of genes associated with endochondral ossification and SMAD-dependent signaling pathways. Together, these results confirm the contribution of BMP signaling in osteogenic differentiation and ectopic bone formation and that a selective ligand-trap approach such as ALK3-Fc may be an effective and tolerable prophylactic strategy for tHO.

Intrasite Antibiotic Powder for the Prevention of Surgical Site Infection in Extremity Surgery: A Systematic Review.

INTRODUCTION: Although the role of intrasite antibiotic powder in preventing surgical site infections (SSIs) has been extensively explored in spinal surgery, it remains underevaluated in the other orthopaedic subspecialties. This systematic review examines the utilization of intrawound antibiotic powder as a prophylactic measure against SSIs in orthopaedic procedures. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, electronic searches were conducted on Ovid MEDLINE, and PubMed. Only English language, nonspine clinical studies published before May 2018 were included. RESULTS: The initial search identified 179 individual citations, and 11 studies met the eligibility criteria. All included studies were level III retrospective studies. Represented subspecialties included total joint arthroplasty, upper extremity, foot and ankle, and trauma. Eight studies demonstrated a statistically significant decrease in SSIs with the use of intrasite antibiotic powder. DISCUSSION: There are no current guidelines for the use of intrasite antibiotic powder for the prevention of SSIs in orthopaedic procedures. Despite the lack of high-quality evidence available in the literature, published smaller studies do suggest a significant protective effect. However, recommendations with regard to this technique after common orthopaedic procedures cannot yet be made.

Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma.

Heterotopic ossification (HO) is defined as ectopic bone formation around joints and in soft tissues following trauma, particularly blast-related extremity injuries, thermal injuries, central nerve injuries, or orthopaedic surgeries, leading to increased pain and diminished quality of life. Current treatment options include pharmacotherapy with non-steroidal anti-inflammatory drugs, radiotherapy, and surgical excision, but these treatments have limited efficacy and have associated complication profiles. In contrast, small molecule inhibitors have been shown to have higher specificity and less systemic cytotoxicity. Previous studies have shown that bone morphogenetic protein (BMP) signaling and downstream non-canonical (SMAD-independent) BMP signaling mediated induction of TGF-ß activated kinase-1 (TAK1) contributes to HO. In the current study, small molecule inhibition of TAK1, NG-25, was evaluated for its efficacy in limiting ectopic bone formation following a rat blast-associated lower limb trauma and a murine burn tenotomy injury model. A significant decrease in total HO volume in the rat blast injury model was observed by microCT imaging with no systemic complications following NG-25 therapy. Furthermore, tissue-resident mesenchymal progenitor cells (MPCs) harvested from rats treated with NG-25 demonstrated decreased proliferation, limited osteogenic differentiation capacity, and reduced gene expression of Tac1, Col10a1, Ibsp, Smad3, and Sox2 (P < 0.05). Single cell RNA-sequencing of murine cells harvested from the injury site in a burn tenotomy injury model showed increased expression of these genes in MPCs during stages of chondrogenic differentiation. Additional in vitro cell cultures of murine tissue-resident MPCs and osteochondrogenic progenitors (OCPs) treated with NG-25 demonstrated reduced chondrogenic differentiation by 10.2-fold (P < 0.001) and 133.3-fold (P < 0.001), respectively, as well as associated reduction in chondrogenic gene expression. Induction of HO in Tak1 knockout mice demonstrated a 7.1-fold (P < 0.001) and 2.7-fold reduction (P < 0.001) in chondrogenic differentiation of murine MPCs and OCPs, respectively, with reduced chondrogenic gene expression. Together, our in vivo models and in vitro cell culture studies demonstrate the importance of TAK1 signaling in chondrogenic differentiation and HO formation and suggest that small molecule inhibition of TAK1 is a promising therapy to limit the formation and progression of HO.

Combat and Noncombat Musculoskeletal Injuries in the US Military.

Musculoskeletal Injuries (MSKI) are exceedingly common in the US Military, resulting in compromised military medical readiness and a substantial burden on both health care and financial resources. Severe combat-related MSKI sustained during nearly 2 decades of conflict in Iraq and Afghanistan have resulted in frequently devastating injuries that challenge acute care capabilities, require extensive rehabilitation, and often result in long-term disability. Non-combat-related MSKI, while often less severe, are far more common than combat-related MSKI and overall cause a substantially greater number of lost duty days and nondeployable Service Members. Given the strain placed on health care and financial resources by MSKI, further efforts must be directed towards prevention, treatment, and rehabilitative strategies in order to mitigate the burden of MSKI in the US Military.

Measurement of Distal Ulnar Hounsfield Units Accurately Predicts Bone Mineral Density of the Forearm.

BACKGROUND: Hounsfield unit (HU) measurement obtained from computed tomography (CT) scans of the wrist is a potential new screening method for low bone mineral density (BMD). We hypothesized that HU measurements of the ulnar head obtained from CT scans would correlate with BMD assessed with dual x-ray absorptiometry (DXA) scans of the forearm. METHODS: Patients with both upper-extremity CT and DXA scans performed at a single institution were included in the study. Hounsfield units were manually measured in the distal part of the ulna by 1 author blinded to the DXA results. Average values were then compared with forearm BMD values as determined with a DXA scan. RESULTS: Seventy-seven CT scans of 74 patients were included. Average HU values were significantly lower in the osteoporotic and osteopenic groups in comparison with the normal BMD group. The upper limit of the 95% confidence interval for osteopenic patients was 145.9 HU. The average forearm T-score for patients with an HU value at or below the cutoff of 146 was significantly lower than the average T-score for those with an HU value of >146 HU (p < 0.0001). Sensitivity and negative predictive value for low BMD using this cutoff value were calculated to be 91% and 89%, respectively. CONCLUSIONS: Distal ulnar HU measurements accurately reflect the BMD of the forearm as diagnosed with a DXA scan. Our results suggest that distal ulnar HU measurements of ≤146 HU are strongly associated with low BMD and that values above this cutoff accurately rule out low forearm BMD with a high degree of sensitivity and negative predictive value. Utilizing this technique may improve the capture of at-risk patients and streamline the screening process for osteoporosis. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Revision Anterior Cruciate Ligament Reconstruction in Military Personnel.

This study aims to report the clinical and functional outcomes of revision anterior cruciate ligament (ACL) reconstruction in a young, active duty military population. Patients undergoing revision ACL reconstruction were enrolled in an institutional clinical database and followed prospectively. The primary outcomes were patients' scores on a timed run, as compared with recorded scores before reinjury. Secondary outcomes included scores on the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the International Knee Documentation Committee subjective (IKDC subjective), the Short Form - 36 health survey (SF-36) version 2, the Single Assessment Numeric Evaluation (SANE), and the Tegner activity scale. A total of 13 patients were identified who met the inclusion criteria and had complete follow-up. The mean age at revision ACL reconstruction was 20.5 years (range, 19-22 years), and mean follow-up was 40.2 months (range, 13-66 months). All patients underwent a single stage revision ACL reconstruction with ipsilateral bone-patellar tendon-bone autograft, ipsilateral hamstring autograft, or bone-tendon-bone allograft. Mean physical readiness test (PRT) score at final follow-up was not statistically different than documented preinjury PRT score (77.9 vs. 85.5, p > 0.05), nor was the mean run time (7:12 vs. 6:43/mile, p > 0.05). Significant improvements exceeding published minimal clinically important differences were seen in SANE score, SF-36 physical component summary score, KOOS sports and recreation, KOOS quality of life, WOMAC pain score, and WOMAC function score. Patients undergoing revision ACL reconstruction at our facility show good recovery of baseline physical performance as measured by the semiannual PRT and timed run test, and significant improvements in patient-reported outcome scores. Level of Evidence Level IV, case series.

Hybrid Tibia Fixation of Soft Tissue Grafts in Anterior Cruciate Ligament Reconstruction: A Systematic Review.

BACKGROUND: Optimal fixation of soft tissue grafts in anterior cruciate ligament (ACL) reconstruction remains a controversial topic, and tibial-sided fixation is frequently cited as the "weak point" of the femur-graft-tibia construct. Some studies have recommended the use of hybrid fixation (combining intratunnel aperture fixation and extracortical suspensory fixation) on the tibial side to increase the strength of the reconstructed ACL and decrease the risk of graft slippage and subsequent failure. However, no consensus has emerged on the necessity or suitability of this technique, relative to single modes of fixation. PURPOSE: This study sought answers to the following questions: (1) Does hybrid fixation result in stronger, stiffer initial fixation of soft tissue grafts? (2) Does hybrid fixation reduce side-to-side laxity differences in clinical practice? (3) Does hybrid fixation increase complication rates when compared with a single mode of tibial fixation? STUDY DESIGN: Systematic review. METHODS: A systematic keyword search of PubMed, EMBASE, the Cochrane Library of Systematic Reviews, and the PROSPERO International Prospective Register of Systematic Reviews was performed. Candidate articles were included if they compared biomechanical or clinical characteristics of tibial-sided hybrid fixation (defined as a combination of aperture and suspensory fixation methods) with single-mode fixation of soft tissue grafts in ACL reconstruction. RESULTS: A total of 21 studies (15 biomechanical, 6 clinical) met criteria for inclusion. Most biomechanical studies reported significantly increased strength and stiffness with hybrid fixation versus single modes of fixation. Among clinical studies, 66% reported significantly decreased anterior-posterior laxity when hybrid fixation methods were employed, with the remainder showing no difference. CONCLUSION: Hybrid methods of tibial-sided graft fixation in ACL reconstruction result in stronger initial fixation and less side-to-side laxity after healing but do not change patient-reported outcomes at 1- to 3-year follow-up. REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews No. 42014015464.