Team Approach: Osseointegration Amputation Surgery.

¼ The purpose of this article was to review the multidisciplinary, team-based approach necessary for the optimal management of patients with limb loss undergoing osseointegration surgery.¼ In this study, we describe the interdisciplinary process of screening, counseling, and surgical and rehabilitation considerations with an emphasis on principles rather than specific implants or techniques.¼ Integrated perioperative management and long-term surveillance are crucial to ensure the best possible outcomes.¼ We hope this model will service as an implant-agnostic guide to others seeking to development an osseointegration center of excellence.

A Two-Stage Approach Integrating Provisional Biomaterial-Mediated Stabilization Followed by a Definitive Treatment for Managing Volumetric Muscle Loss Injuries.

Treatment of volumetric muscle loss (VML) faces challenges due to its unique pathobiology and lower priority in severe musculoskeletal injury management. Consequently, a need exists for multi-stage VML treatment strategies to accommodate delayed interventions owing to comorbidity management or prolonged casualty care in combat settings. To this end, polyvinyl alcohol (PVA) was used at concentrations of 5%, 7.5%, and 10% to generate provisional muscle void fillers (MVFs) of varying stiffness values (1.125 kPa, 3.700 kPa, and 7.699 kPa) to stabilize VML injuries as part of a two-stage approach. These were implanted into a rat model for a duration of 4 weeks, then explanted and either left untreated (control) or treated through minced muscle grafting (MMG). Additional benchmarks included acute MMG and unrepaired groups. At the MVF explant, the 7.5% PVA group exhibited superior neuromuscular function compared to the 5% and 10% PVA groups, the least fibrosis, and the largest median myofiber size among all groups at the 12-week endpoint. Despite the 7.5% PVA's superiority amongst the two-stage treatment groups, neuromuscular function was neither improved nor impaired relative to acute treatment benchmarks. This suggests that the future success of a two-stage VML treatment strategy will necessitate a more effective definitive intervention.

Refocusing the Military Health System to Support Role 4 Definitive Care in future large-scale combat operations.

ABSTRACT: The last twenty years of sustained combat operations during the Global War on Terror generated significant advancements in combat casualty care. Improvements in point-of-injury, en route, and forward surgical care appropriately aligned with the survival, evacuation, and return to duty needs of the small-scale unconventional conflict. However, casualty numbers in large-scale combat operations have brought into focus the critical need for modernized casualty receiving and convalescence: Role 4 definitive care (R4DC). Historically, World War II was the most recent conflict in which the United States fought in multiple operational theaters, with hundreds of thousands of combat casualties returned to the continental United States. These numbers necessitated the establishment of a "Zone of the Interior" which integrated military and civilian healthcare networks for definitive treatment and rehabilitation of casualties. Current security threats demand refocusing and bolstering the Military Health System's definitive care capabilities to maximize its force regeneration capacity in a similar fashion. Medical force generation, medical force sustainment and readiness, and integrated casualty care capabilities are three pillars that must be developed for MHS readiness of Role 4 definitive care in future large-scale contingencies against near-peer/peer adversaries.

Periprosthetic Joint Infection in Patients With Arthroplasty Undergoing Perioperative Colonoscopy.

Importance: Periprosthetic joint infection (PJI) is a rare but devastating complication. Most patients undergoing total joint arthroplasty (TJA) also need routine screening colonoscopy, in which transient bacteremia may be a potential source for hematogenous PJI. Patients and surgeons must decide on an optimal time span or sequence for these 2 generally elective procedures, but no such guidelines currently exist. Objective: To evaluate associations of colonoscopy with the risk of post-TJA PJI for the development of clinical practice recommendations for colonoscopy screening in patients undergoing TJA. Design, Setting, and Participants: This retrospective cohort study of Military Health System (MHS) beneficiaries older than 45 years who underwent TJA from January 1, 2010, to December 31, 2016, used propensity score matching and logistic regression to evaluate associations of colonoscopy with PJI risk. Statistical analyses were conducted between January and October 2023. Exposure: Colonoscopy status was defined by Current Procedural Terminology code for diagnostic colonoscopy within 6 months before or 6 months after TJA. Main Outcomes and Measures: Periprosthetic joint infection status was defined by a PJI International Classification of Diseases code within 1 year after TJA and within 1 year from the post-TJA index colonoscopy date. Results: Analyses included 243 671 patients (mean [SD] age, 70.4 [10.0] years; 144 083 [59.1%] female) who underwent TJA in the MHS from 2010 to 2016. In the preoperative colonoscopy cohort, 325 patients (2.8%) had PJI within 1 year postoperatively. In the postoperative colonoscopy cohort, 138 patients (1.8%) had PJI within 1 year from the index colonoscopy date. In separate analyses of colonoscopy status within 6 months before and 6 months after TJA, younger age, male sex, and several chronic health conditions (diabetes, kidney disease, and pulmonary disease) were each associated with higher PJI risk. However, no association was found with PJI risk for perioperative colonoscopy preoperatively (adjusted odds ratio, 1.10; 95% CI, 0.98-1.23) or postoperatively (adjusted odds ratio, 0.90; 95% CI, 0.74-1.08). Conclusions and Relevance: In this large retrospective cohort of patients undergoing TJA, perioperative screening colonoscopy was not associated with PJI and should not be delayed for periprocedural risk. However, health conditions were independently associated with PJI and should be medically optimized.

Mechanical loading of bone-anchored implants during functional performance tests in service members with transfemoral limb loss.

Introduction: For individuals with limb loss, bone-anchored implants create a direct structural and functional connection to a terminal prosthesis. Here, we characterized the mechanical loads distal to the abutment during several functional performance tests in Service members with transfemoral (TF) limb loss, to expand on prior work evaluating more steady-state ambulation on level ground or slopes/stairs. Methods: Two males with unilateral TF limb loss and two males with bilateral TF limb loss participated after two-stage osseointegration (24 and 12 months, respectively). Tri-directional forces and moments were wirelessly recorded through a sensor, fit distal to the abutment, during six functional tests: Timed Up and Go (TUG), Four Square Step Test (FSST), Six Minute Walk Test (6MWT), Edgren Side-Step Test (SST), T-Test (TTEST), and Illinois Agility Test (IAT). Additionally, participants performed a straight-line gait evaluation on a 15 m level walkway at a self-selected speed (0.93-1.24 m/s). Peak values for each component of force and moment were extracted from all six functional tests; percent differences compared each peak with respect to the corresponding mean peak in straight-line walking. Results: Peak mechanical loads were largest during non-steady state components of the functional tests (e.g., side-stepping during SST or TTEST, standing up from the ground during IAT). Relative to walking, peak forces during functional tests were larger by up to 143% (anterior-posterior), 181% (medial-lateral), and 110% (axial); peak moments were larger by up to 108% (flexion-extension), 50% (ab/adduction), and 211% (internal/external rotation). Conclusions: A more comprehensive understanding of the mechanical loads applied to bone-anchored implants during a variety of activities is critical to maximize implant survivability and long-term outcomes, particularly for Service members who are generally young at time of injury and return to active lifestyles.

Bone Sarcoma Survival in the US Military Health System: Comparison With the SEER Program.

BACKGROUND: Access to care is associated with cancer survival. The US Military Health System (MHS) provides universal health care to all beneficiaries. However, it is unknown whether survival among patients with bone sarcoma in a health system providing universal care is better than that in the general population. The aim of the study was to compare survival of patients with bone sarcoma in the US MHS with that of the US general population. METHODS: The MHS data were obtained from the Department of Defense Automated Central Tumor Registry (ACTUR). The US general population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. Adult patients were defined as those aged 25 years or older with a histologically confirmed musculoskeletal bone sarcoma diagnosed from January 1, 1987, to December 31, 2013. Kaplan-Meier survival curves and multivariable Cox proportional hazards models were used to compare the overall survival of the two populations. RESULTS: The final analysis included 2,273 bone sarcoma cases from ACTUR and 9,092 bone sarcoma cases from SEER. ACTUR patients had significant lower 5-year all-cause death (hazard ratio = 0.72; 95% CI, 0.66 to 0.78) after adjustment for the potential confounders. ACTUR patients with bone sarcoma also exhibited significantly lower risk of all-cause death during the entire follow-up period than the SEER patients (hazard ratio = 0.75; 95% CI, 0.6 to 0.81). CONCLUSIONS: MHS beneficiaries with bone sarcoma may have longer survival than SEER patients. Our findings support the role of universal access to high-quality care in improving bone sarcoma outcomes.

Lifetime cost-effectiveness analysis osseointegrated transfemoral versus socket prosthesis using Markov modelling.

Aims: Prior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient's quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients. Methods: Lifetime Markov models were developed evaluating active healthy middle-aged male amputees. Costs of the prostheses, associated complications, use/non-use, and annual costs of arthroplasty parts and service for both a socket and osseointegrated (OPRA) prosthesis were included. Effectiveness was evaluated using the questionnaire for persons with a transfemoral amputation (Q-TFA) until death. All costs and Q-TFA were discounted at 3% annually. Sensitivity analyses on those cost variables which affected a change in treatment (OPRA to socket, or socket to OPRA) were evaluated to determine threshold values. Incremental cost-effectiveness ratios (ICERs) were calculated. Results: For treatment-naïve patients, the lifetime ICER for OPRA was $279/quality-adjusted life-year (QALY). For treatment-refractory patients the ICER was $273/QALY. In sensitivity analysis, the variable thresholds that would affect a change in the course of treatment based on cost (from socket to OPRA), included the following for the treatment-naïve group: yearly replacement components for socket > $8,511; cost yearly replacement parts OPRA < $1,758; and for treatment-refractory group: yearly replacement component for socket of > $12,467. Conclusion: The use of the OPRA prosthesis in physically active transfemoral amputees should be considered as a cost-effective alternative in both treatment-naïve and treatment-refractory socket prosthesis patients. Disease-specific quality of life assessments such as Q-TFA are more sensitive when evaluating cost-effectiveness.

Thighplasty at the Time of Stage-1 Bone-Anchored Osseointegration Surgery.

Background: For patients with transfemoral amputations and difficulty tolerating conventional socket-based prostheses, osseointegrated (OI) implants have enabled increased prosthetic use, improved patient satisfaction, and shown promising functional outcomes1,2. Although the use of OI implants effectively eliminates the soft-tissue-related challenges that have plagued socket-based prostheses, the presence of a permanent, percutaneous implant imparts a host of new soft-tissue challenges that have yet to be fully defined. In patients undergoing OI surgery who have redundant soft tissue, we perform a thighplasty to globally reduce excess skin and fat, tighten the soft-tissue envelope, and improve the contour of the residual limb. Description: First, the orthopaedic surgical team prepares the residual femur for implantation of the OI device. After the implant is inserted, the residual hamstrings and quadriceps musculature are closed over the end of the femur, and the subcutaneous tissue and skin are closed in a layered fashion. Although the anatomic location and amount of excess soft tissue are patient-dependent, we perform a standard pinch test to determine the amount of soft tissue that can be safely removed for the thighplasty. Once the proposed area of resection is marked, we proceed with longitudinal, sharp dissection down to the level of the muscular fascia. At this point, we use another pinch test to confirm the amount of soft-tissue resection that will allow for adequate resection without undue tension3. Excess subcutaneous fat and skin are carefully removed along the previously marked incisions, typically overlying the medial compartment of the thigh in the setting of patients with transfemoral amputations. The thighplasty incision is closed in a layered fashion over 1 or 2 Jackson-Pratt drains, depending on the amount of resection. Alternatives: Depending on the amount of redundant soft tissue, thighplasty may not be necessary at the time of OI surgery; however, in our experience, excess soft tissue surrounding the transcutaneous aperture can predispose the patient to increased shear forces at the aperture, increased drainage, and increased risk of infection4. Rationale: Although superficial infectious complications are most common following OI surgery, the need for soft-tissue refashioning and excision is one of the most common reasons for reoperation1,5. Our group has been more aggressive than most in our use of a vertical thighplasty procedure to globally reduce soft-tissue motion in the residual limb to avoid reoperation. Expected Outcomes: Although much of the OI literature has focused on infectious complications, recent studies have demonstrated reoperation rates of 18% to 36% for redundant soft tissue following OI surgery1,5. We believe that thighplasty at the time of OI not only reduces the likelihood of reoperation but may also decrease infectious complications by reducing relative motion and inflammation at the skin-implant interface4,6. Important Tips: The thighplasty procedure is ideally performed as part of the first stage of the OPRA (Osseointegrated Prosthesis for the Rehabilitation of Amputees) procedure to limit the likelihood of problematic ischemia-related complications.We utilize a confirmatory pinch test both before and throughout the thighplasty procedure to ensure adequate resection without undue tension.The thighplasty excision pattern utilizes a long vertical limb designed to decrease the circumferential laxity of the residual limb. Maximal tension is borne on the vertical limb and not on the transverse extensions, as these are prone to scar widening and distortion of surrounding tissues.Closed-suction drainage is utilized liberally to decrease the likelihood of a symptomatic seroma. Acronyms and Abbreviations: OI = osseointegratedOPRA = Osseointegrated Prosthesis for the Rehabilitation of AmputeesPVNS = pigmented villonodular synovitisT-GCT = tenosynovial giant-cell tumor.BMI = body mass indexPMH = past medical history.

The influence of microbial colonization on inflammatory versus pro-healing trajectories in combat extremity wounds.

A combination of improved body armor, medical transportation, and treatment has led to the increased survival of warfighters from combat extremity injuries predominantly caused by blasts in modern conflicts. Despite advances, a high rate of complications such as wound infections, wound failure, amputations, and a decreased quality of life exist. To study the molecular underpinnings of wound failure, wound tissue biopsies from combat extremity injuries had RNA extracted and sequenced. Wounds were classified by colonization (colonized vs. non-colonized) and outcome (healed vs. failed) status. Differences in gene expression were investigated between timepoints at a gene level, and longitudinally by multi-gene networks, inferred proportions of immune cells, and expression of healing-related functions. Differences between wound outcomes in colonized wounds were more apparent than in non-colonized wounds. Colonized/healed wounds appeared able to mount an adaptive immune response to infection and progress beyond the inflammatory stage of healing, while colonized/failed wounds did not. Although, both colonized and non-colonized failed wounds showed increasing inferred immune and inflammatory programs, non-colonized/failed wounds progressed beyond the inflammatory stage, suggesting different mechanisms of failure dependent on colonization status. Overall, these data reveal gene expression profile differences in healing wounds that may be utilized to improve clinical treatment paradigms.

Utility of Thermal Imaging in Predicting Superficial Infections in Transfemoral Osseointegrated Implants.

Background: Superficial infection is a common minor complication of transcutaneous implants that can be challenging to predict or diagnose. Although it remains unclear whether superficial infections progress to deep infections (which may require implant removal), predicting and treating any infection in these patients is important. Given that flap thinning during stage II surgery requires compromising vascularity for stability of the skin penetration aperture, we hypothesized that early skin temperature changes predict long-term superficial infection risk. Methods: We obtained standardized thermal imaging and recorded surface temperatures of the aperture and overlying flaps 2 weeks postoperatively for the first 34 patients (46 limbs) treated with the Osseointegrated Prosthesis for the Rehabilitation of Amputees transfemoral implant system. We used two-sided t tests to compare temperatures surrounding the aperture and adjacent soft tissues in patients with and without subsequent infection. Results: During median follow-up of 3 years, 14 limbs (30.4%) developed 23 superficial infections. At patients' initial 2-week visit, mean skin temperature surrounding the aperture was 36.3ºC in limbs that later developed superficial infections and 36.7ºC in uninfected limbs (P = 0.35). In four patients with bilateral implants who later developed superficial infection in one limb, average temperature was 1.5ºC colder in the infected limb (P = 0.12). Conclusions: Superficial infections remain a frequent complication of transfemoral osseointegration surgery. We did not find differences in early heat signatures between limbs subsequently complicated and those not complicated by superficial infection. Further research should explore more objective measures to predict, diagnose, and prevent infections after osseointegration surgery.

Cutaneous burn injury represents a major risk factor for the development of traumatic ectopic bone formation following blast-related extremity injury.

Blast-related traumatic heterotopic ossification (tHO) impacts clinical outcomes in combat-injured patients, leading to delayed wound healing, inflammatory complications, and reduced quality of life. Blast injured patients often have significant burns. This study investigated whether a partial thickness thermal burn injury exacerbates blast-related tHO in a clinically relevant polytrauma animal model. Adult male Sprague Dawley rats were subjected to an established model involving a whole-body blast overpressure exposure (BOP), complex extremity trauma followed by hind limb amputation (CET) followed by the addition of a 10 % total body surface area (TBSA) second degree thermal burn (BU). Micro-CT scans on post-operative day 56 showed a significant increase in HO volume in the CET + BU as compared to the CET alone injury group (p < .0001; 22.83 ± 3.41 mm3 vs 4.84 ± 5.77 mm3). Additionally, CET + BU concomitant with BOP significantly increased HO (p < .0001; 34.95 ± 7.71 mm3) as compared to CET + BU alone, confirming BOP has a further synergistic effect. No HO was detectable in rats in the absence of CET. Serum analysis revealed similar significant elevated (p < .0001) levels of pro-inflammatory markers (Cxcl1 and Il6) at 6 h post-injury (hpi) in the CET + BU and BOP + CET + BU injury groups as compared to naïve baseline values. Real-time qPCR demonstrated similar levels of chondrogenic and osteogenic gene expression in muscle tissue at the site of injury at 168 hpi in both the CET + BU and BOP+CET + BU injury groups. These results support the hypothesis that a 10 % TBSA thermal burn markedly enhances tHO following acute musculoskeletal extremity injury in the presence and absence of blast overpressure. Furthermore, the influence of BOP on tHO cannot be accounted for either in regards to systemic inflammation induced from remote injury or inflammatory-osteo-chondrogenic expression changes local to the musculoskeletal trauma, suggesting that another mechanism beyond BOP and BU synergistic effects are at play. Therefore, these findings warrant future investigations to explore other mechanisms by which blast and burn influence tHO, and testing prophylactic measures to mitigate the local and systemic inflammatory effects of these injuries on development of HO.

The Scope and Distribution of Upper Extremity Nerve Injuries Associated With Combat-Related Extremity Limb Salvage.

PURPOSE: Chronic pain and functional limitations secondary to nerve injuries are a major barrier to optimal recovery for patients following high-energy extremity trauma. Given the associated skeletal and soft tissue management challenges in the polytraumatized patient, concomitant nerve injuries may be overlooked or managed in delayed fashion. Whereas previous literature has reported rates of peripheral nerve injuries at <10% in the setting of high-energy extremity trauma, in our experience, the incidence of these injuries has been much higher. Thus, we sought to define the incidence, pain sequelae, and functional outcomes following upper extremity peripheral nerve injuries in the combat-related limb salvage population. METHODS: We performed a retrospective review of all patients who underwent limb salvage procedures to include flap coverage for combat-related upper extremity trauma at a single institution between January 2011 and January 2020. We collected data on patient demographics; perioperative complications; location of nerve injuries; surgical interventions; chronic pain; and subjective, patient-reported functional limitations. RESULTS: A total of 45 patients underwent flap procedures on 49 upper extremities following combat-related trauma. All patients were male with a median age of 27 years, and 96% (n = 47) of injuries were sustained from a blast mechanism. Thirty-three of the 49 extremities (67%) sustained associated nerve injuries. The most commonly injured nerve was the ulnar (51%), followed by median (30%) and radial/posterior interosseous (19%). Of the 33 extremities with nerve injuries, 18 (55%) underwent surgical intervention. Nerve repair/reconstruction was the most common procedure (67%), followed by targeted muscle reinnervation (TMR, 17%). Chronic pain and functional limitation were common following nerve injury. CONCLUSIONS: Upper extremity peripheral nerve injury is common following high-energy combat-related trauma with high rates of chronic pain and functional limitations. Surgeons performing limb salvage procedures to include flap coverage should anticipate associated peripheral nerve injuries and be prepared to repair or reconstruct the injured nerves, when feasible. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Technical Trick: Cryoneurolysis for Subacute Pain Mitigation in Patients With Limb Loss.

SUMMARY: Pain after amputation is often managed by target muscle reinnervation (TMR) with the added benefit that TMR also provides improved myoelectric terminal device control. However, as TMR takes several months for the recipient muscles to reliably reinnervate, this technique does not address pain within the subacute postoperative period during which pain chronification, sensitization, and opioid dependence and misuse may occur. Cryoneurolysis, described herein, uses focused, extreme temperatures to essentially "freeze" the nerve, blocking nociception, and improving pain in treated nerves potentially reducing the chances of pain chronification, sensitization, and substance dependence or abuse.

Consensus and Equipose in the Management of Military Trainee Femoral Neck Stress Fractures: A Survey of Military Surgeons.

BACKGROUND: Femoral neck stress fractures (FNSFs) are a unique injury pattern not commonly treated in the civilian trauma population; however, it is particularly high with military trainees engaged in basic combat training. To date, no study has surveyed a population of military orthopedic surgeons on treatment preferences for military service members (SMs) with FNSF. QUESTIONS: We aim to evaluate the extent of clinical equipoise that exists in the management of these injuries, hypothesizing that there would be consensus in the factors dictating surgical and non-surgical intervention for FNSF. PATIENTS AND METHODS: A 27-question survey was created and sent to U.S. military orthopedic surgeon members of the Society of Military Orthopaedic Surgeons. The survey was designed in order to gather the experience among surgeons in treating FNSF and identifying variables that play a role in the treatment algorithm for these patients. In addition, seven detailed, clinical vignettes were presented to further inquire on surgeon treatment preferences. Binomial distribution analysis was used to evaluate for common trends within the surgeon's treatment preferences. RESULTS: Seventy orthopedic surgeons completed the survey, the majority of whom were on active duty status in the U.S. Military (82.86%) and having under 5 years of experience (61.43%). Majority of surgeons elected for a multiple screw construct (92.86%), however the orientation of the multiple screws was dependent on whether the fracture was open or closed. Management for compression-sided FNSF involving ≥50% of the femoral neck width, tension-sided FNSF, and stress fractures demonstrating fracture line progression had consensus for operative management. Respondents agreed upon prophylactic fixation of the contralateral hip if the following factors were involved: Complete fracture (98.57%), compression-sided fracture line >75% (88.57%), compression-sided fracture line >50-75% with hip effusion (88.57%), contralateral tension-sided fracture (87.14%), and compression-sided fracture line >50-75% (84.29%). An FNSF < 50% on the contralateral femoral neck or a hip effusion was indeterminate in surgeons indicating need for prophylactic fixation. Majority of surgeons (77.1%) utilized restricted toe-touch weight-bearing for postoperative mobility restrictions. CONCLUSIONS: Consensus exists for surgical and non-surgical management of FNSF by U.S. military orthopedic surgeons, despite the preponderance of surgeons reporting a low annual volume of FNSF cases treated. However, there are certain aspects in the operative and non-operative management of FNSF that are unanimously adhered to. Specifically, our results demonstrate that there is no clear indication on the management of FNSF when an associated hip effusion is involved. Additionally, the indications for surgically treating contralateral FNSF are unclear. LEVEL OF EVIDENCE: IV.

Severe complication after microwave thermoablation of a residual limb: multifocal full thickness cutaneous necrosis and deep venous thrombosis.

Patients with limb loss face the challenge of having an increased risk of skin disease at residual limb sites. Hyperhidrosis is a common concern for persons with amputation and excessive sweat can cause various skin pathology. Recently, microwave thermoablation (MT) was reported as an effective off-label treatment for hyperhidrosis in patients with limb loss. We present a case in which a patient following MT procedure for hyperhidrosis of a transtibial amputation developed multifocal full thickness cutaneous necrosis and deep venous thrombosis. The possible aetiologies of these complications are discussed including vascular congestion and external thermal injury.Such a case warrants the attention of individuals and providers seeking to use MT for off-label purposes, particularly for patients with limb loss, due to the large treatment surface area and potential for temporary or permanent functional loss of the amputated limb.

Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma.

Introduction: Heterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation. Methods: We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56. Results: In comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group. Discussion: Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma.

A Data-Driven Method to Discriminate Limb Salvage from Other Combat-Related Extremity Trauma.

INTRODUCTION: The aim of this study was to address and enhance our ability to study the clinical outcome of limb salvage (LS), a commonly referenced but ill-defined clinical care pathway, by developing a data-driven approach for the identification of LS cases using existing medical code data to identify characteristic diagnoses and procedures, and to use that information to describe a cohort of US Service members (SMs) for further study. METHODS: Diagnosis code families and inpatient procedure codes were compiled and analyzed to identify medical codes that are disparately associated with a LS surrogate population of SMs who underwent secondary amputation within a broader cohort of 3390 SMs with lower extremity trauma (AIS > 1). Subsequently, the identified codes were used to define a cohort of all SMs who underwent lower extremity LS which was compared with the opinion of a panel of military trauma surgeons. RESULTS: The data-driven approach identified a population of n = 2018 SMs who underwent LS, representing 59.5% of the combat-related lower extremity (LE) trauma population. Validation analysis revealed 70% agreement between the data-driven approach and gold standard SME panel for the test cases studied. The Kappa statistic (κ = 0.55) indicates a moderate agreement between the data-driven approach and the expert opinion of the SME panel. The sensitivity and specificity were identified as 55.6% (expert range of 51.8-66.7%) and 87% (expert range of 73.9-91.3%), respectively. CONCLUSIONS: This approach for identifying LS cases can be utilized to enable future high-throughput retrospective analyses for studying both short- and long-term outcomes of this underserved patient population.

Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture.

Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1ß) and Tumor Necrosis Factor-alpha (TNF-α) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-α inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg/kg/day, ANR at 100 g/kg/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (µCT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4+ agent assessed articular cartilage composition via ex vivo µCT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0-6 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p < 0.05) and tartrate-resistant acid phosphatase (TRAP, p < 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (µCT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p < 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced µCT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF.

In situ forming biomaterials as muscle void fillers for the provisional treatment of volumetric muscle loss injuries.

Volumetric muscle loss (VML) represents a devastating extremity injury which leads to chronic functional deficits and disability and is unrecoverable through normal healing pathways. When left untreated, the VML pathophysiology creates many challenges towards successful treatment, such as altered residual muscle architecture, excessive fibrosis, and contracture(s). As such, innovative approaches and technologies are needed to prevent or reverse these adverse sequelae. Development of a rationally designed biomaterial technology which is intended to be acutely placed within a VML defect - i.e., to serve as a muscle void filler (MVF) by maintaining the VML defect - could address this clinical unmet need by preventing these adverse sequelae as well as enabling multi-staged treatment approaches. To that end, three biomaterials were evaluated for their ability to serve as a provisional MVF treatment intended to stabilize a VML defect in a rat model for an extended period (28 days): polyvinyl alcohol (PVA), hyaluronic acid and polyethylene glycol combination (HA + PEG), and silicone, a clinically used soft tissue void filler. HA + PEG biomaterial showed signs of deformation, while both PVA and silicone did not. There were no differences between treatment groups for their effects on adjacent muscle fiber count and size distribution. Not surprisingly, silicone elicited robust fibrotic response resulting in a fibrotic barrier with a large infiltration of macrophages, a response not seen with either the PVA or HA + PEG. Taken together, PVA was found to be the best material to be used as a provisional MVF for maintaining VML defect volume while minimizing adverse effects on the surrounding muscle.