Gabriel J. Pavey

Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model

Heterotopic ossification (HO) involves formation of endochondral bone at non-skeletal sites, is prevalent in severely wounded service members, and causes significant complications and delayed rehabilitation. As common prophylactic treatments such as anti-inflammatory drugs and irradiation cannot be used after multi-system combat trauma, there is an urgent need for new remedies. Previously, we showed that the retinoic acid receptor γ agonist Palovarotene inhibited subcutaneous and intramuscular HO in mice, but those models do not mimic complex combat injury. Thus, we tested Palovarotene in our validated rat trauma-induced HO model that involves blast-related limb injury, femoral fracture, quadriceps crush injury, amputation and infection with methicillin-resistant Staphylococcus aureus from combat wound infections. Palovarotene was given orally for 14days at 1mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes were monitored for up to 84days post injury. Compared to vehicle-control animals, Palovarotene significantly decreased HO by 50 to 60% regardless of when the treatment started and if infection was present. Histological analyses showed that Palovarotene reduced ectopic chondrogenesis, osteogenesis and angiogenesis forming at the injury site over time, while fibrotic tissue was often present in place of ectopic bone. Custom gene array data verified that while expression of key chondrogenic and osteogenic genes was decreased within soft tissues of residual limb in Palovarotene-treated rats, expression of cartilage catabolic genes was increased, including matrix metalloproteinase-9. Importantly, Palovarotene seemed to exert moderate inhibitory effects on wound healing, raising potential safety concerns related to dosing and timing. Our data show for the first time that Palovarotene significantly inhibits HO triggered by blast injury and associated complications, strongly indicating that it may prevent HO in patients at high risk such as those sustaining combat injuries and other forms of blast trauma.

Risk of Anterior Cruciate Ligament Injury in Athletes on Synthetic Playing Surfaces: A Systematic Review

Background: The effect of synthetic playing surfaces on the risk of injury in athletes is frequently debated in the orthopaedic literature. Biomechanical studies have identified increased frictional force at the shoe-surface interface, theoretically increasing the risk of injury relative to natural grass. This increase in frictional force is potentially relevant for the risk of anterior cruciate ligament (ACL) rupture, where noncontact mechanisms are frequent. However, clinical studies examining this issue have shown mixed results. Hypothesis/Purpose: The purpose of this study was to systematically review the available literature on risk of ACL rupture on natural grass versus artificial turf. We hypothesized that the risk of ACL rupture on synthetic playing surfaces would not be higher than that of natural grass playing surfaces. Study Design: Systematic review. Methods: A systematic keyword search was performed of OVID, EMBASE, the Cochrane Library of Systematic Reviews, and the PROSPERO International Prospective Register of Systematic Reviews. Candidate articles were included if they reported the risk ratio of ACL rupture on natural grass versus synthetic playing surfaces, were of level 3 evidence or better, and included only ACL injuries sustained during organized athletic events. Exclusion criteria included a study with non-field-related sports and the use of historical cohorts for calculating risk ratios. Results: A total of 10 studies with 963 ACL injuries met criteria for inclusion, all of which reported on soccer and football cohorts. Among these, 4 studies (753 ACL injuries) found an increased risk of ACL injury on artificial playing surfaces. All 4 of these articles were conducted using American football cohorts, and they included both earlier-generation surfaces (AstroTurf) and modern, 3rd-generation surfaces. Only 1 study in football players found a reduced risk of ACL injury on synthetic playing surfaces. No soccer cohort found an increased risk of ACL injury on synthetic surfaces. Conclusion: High-quality studies support an increased rate of ACL injury on synthetic playing surfaces in football, but there is no apparent increased risk in soccer. Further study is needed to clarify the reason for this apparent discrepancy.

Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma-induced heterotopic ossification: VANCOMYCIN SUPPRESSES TRAUMA-INDUCED HO

Heterotopic ossification (HO) is a debilitating sequela of high‐energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat‐injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast‐related, post‐traumatic HO. Male Sprague‐Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin‐resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD‐0, n = 34) or on postoperative day‐3 (POD‐3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12‐weeks post‐injury by micro‐CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post‐injury. Vancomycin treatment on POD‐0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro‐inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management.

An Analysis of Research from Faculty at U.S. Adult Reconstruction Fellowships

We reviewed all articles published in three major orthopaedic journals from January 2010 to December 2014. Any article focusing on adult reconstruction of the hip or knee was reviewed for first and last authorship, institution, and level of evidence. Three institutions had authored work from arthroplasty faculty that fell within the top five most published institutions in all three journals, while one institution ranked first in all three journals. 43 of 67 (64.2%) reconstruction fellowships had at least one publication included in this study. The majority of the adult reconstruction literature published by faculty at U.S. reconstruction fellowships stems from a few academic centers with the ten most prolific institutions accounting for 65.9% of all U.S. fellowship publications.

Rehabilitation of Lower Extremity Trauma: a Review of Principles and Military Perspective on Future Directions

The rehabilitation of individuals with lower extremity injury is a common but complex problem for the surgical and rehabilitative teams. Basic science tenets of fracture and soft tissue reconstruction and healing guide postoperative weight-bearing and range of motion protocols. In addition to the physiological complications associated with the injury severity, patient outcomes are often influenced by other factors such as patient compliance, pain, depression, and the negative effects of immobility. As a result, novel rehabilitative protocols to include early weight bearing, continuous passive motion, psychosocial intervention, and multimodal pain management are becoming more popular to facilitate rehabilitation and improved patient outcomes. Further supporting the need for this shift in paradigm thinking are outcome studies of both civilian and military trauma patients that demonstrate the negative impact that psychological, social, and economical factors have on outcomes. This report highlights the experience that our team has had in instituting comprehensive rehabilitation strategies to treat injured service members with complex lower extremity trauma from combat.

Heterotopic ossification and lessons learned from fifteen years at war: A review of therapy, novel research, and future directions for military and civilian orthopaedic trauma

Heterotopic ossification, the formation of bone in soft tissues, is a common complication of the high-energy extremity trauma sustained in modern armed conflict. In the past 15years, military treatment facilities and aligned laboratories have been in a unique position to study and treat this process due to the high volume of patients with these injuries secondary to blast trauma. The devastating nature of these wounds has limited traditional therapeutic options, necessitating alternative solutions to prophylaxis and initial treatment producing substantial advances in modeling, prophylaxis, detection, and therapy. Specific developments include establishment of an animal model that reproduces the systemic and local tissue injury of blast injuries, the use of molecular assays and predictive modeling in clinical decision making, advances in early detection including Raman spectroscopy, and investigation of prophylactic and therapeutic pharmacotherapy targeting the molecular pathways of aberrant bone formation. In this review article, we will present the literature to date, ongoing studies, and future directions for investigation of heterotopic ossification, with a focus on military-specific research.

Intrawound Antibiotic Powder Decreases Frequency of Deep Infection and Severity of Heterotopic Ossification in Combat Lower Extremity Amputations

Background Amputations sustained owing to combat-related blast injuries are at high risk for deep infection and development of heterotopic ossification, which can necessitate reoperation and place immense strain on the patient. Surgeons at our institution began use of intrawound antibiotic powder at the time of closure in an effort to decrease the rate of these surgical complications after initial and revision amputations, supported by compelling clinical evidence and animal models of blast injuries. Antibiotic powder may be useful in reducing the risk of these infections, but human studies on this topic thus far have been inconclusive. Purpose We sought to determine whether administration of intrawound antibiotic powder at the time of closure would (1) decrease the risk of subsequent deep infections of major lower-extremity combat-related amputations, and (2) limit formation and decrease severity of heterotopic ossification common in the combat-related traumatic residual limb. Methods Between 2009 and 2015, 252 major lower extremity initial and revision amputations were performed by a single surgeon. Revision cases were excluded if performed specifically to address deep infection, leaving 223 amputations (88.5%) for this retrospective analysis. We reviewed medical records to collect patient information, returns to the operating room for subsequent infection, and microbiologic culture results. We also reviewed radiographs taken at least 3 months after surgery to determine the presence and severity of heterotopic ossification using the Walter Reed classification system. We grouped cases according to whether limbs underwent initial or revision amputations, and whether the limbs had a history of a prior infection. Apart from the use of antibiotic powder and duration of followup, the groups did not differ in terms of age, mechanism of injury, or sex. We then calculated the absolute risk reduction for infection and heterotopic ossification and the number needed to treat to prevent an infection. Results Overall, administration of antibiotic powder resulted in a 13% absolute risk reduction of deep infection (14 of 82 [17%] versus 42 of 141 [30%]; p = 0.03; 95% CI, 0.20%-24.72%). In revision amputation surgery, the absolute risk reduction of infection with antibiotic powder use was 16% overall (eight of 58 versus 17 of 57; 95% CI, 1.21%-30.86%), and 25% for previously infected limbs (eight of 46 versus 14 of 33; 95% CI, 4.93%-45.14%). The number needed to treat to prevent one additional deep infection in amputation surgery is eight in initial amputations, seven in revision amputations, and four for revision amputation surgery on previously infected limbs. With the numbers available, we observed no reduction in the risk of heterotopic ossification with antibiotic powder use, but severity was decreased in the treatment group in terms of the number of residual limbs with moderate or severe heterotopic ossification (three of 12 versus 19 of 34; p = 0.03). Conclusions Our findings show that administration of intrawound antibiotic powder reduces deep infection in residual limbs of combat amputees, particularly in the setting of revision amputation surgery in apparently aseptic residual limbs at the time of the surgery. Furthermore, administration of antibiotic powder for amputations at time of initial closure decreases the severity of heterotopic ossification formation, providing a low-cost adjunct to decrease the risk of two complications common to amputation surgery. Level of Evidence Level III, therapeutic study

Soft Tissue Injuries and Amputations

The wars in Iraq and Afghanistan have produced a devastating but survivable injury pattern termed dismounted complex blast injury (DCBI) which is characterized by proximal lower extremity amputations and peri-pelvic trauma. The potential for massive blood loss from major vessel hemorrhage requires expedient battlefield intervention and coordinated casualty evacuation that balances aggressive debridement and soft tissue management with forward-minded action to preserve limb length and maximize function. Despite and possibly as a result of these attempts, the limbs of DCBI patients are wrought with early and late complications. Infection mitigation remains difficult despite serial debridements, early antibiosis, and delayed closures that utilize negative pressure wound dressings and antibiotic- and antifungal-impregnated cement beads. Invasive fungal infection, in particular, has high mortality and requires aggressive debridement as a lifesaving measure. Efforts to preserve amputation level necessitate novel approaches to soft tissue management to include rotational and free flaps, tissue expanders, and regenerative xenograft tissue matrices that push the limits of the orthoplastic reconstructive ladder. Heterotopic ossification is nearly ubiquitous in the residual limbs of DCBI causalities and when symptomatic can delay rehabilitation and require morbid surgery making prophylaxis a primary focus of military surgeons and scientists. While the functional outcomes of combat amputees surpass those of civilian traumatic amputees, innovative treatments such as targeted muscle reinnervation and osseointegration offer promise for those amputees who are limited by neuromas and poorly tolerated conventional prostheses. These advances may have wide-reaching clinical application beyond military treatment facilities and veteran’s hospitals to those who sustain traumatic amputations from conventional trauma, natural disaster, or terrorism.

Military personnel sustaining Lisfranc injuries have high rates of disability separation

Objectives Lisfranc injuries are relatively uncommon midfoot injuries disproportionately affecting young, active males. Previous studies in civilian populations have reported relatively good results with operative treatment. However, treatment results have not been specifically examined in military personnel, who may have higher physical demands than the general population. The purpose of this study was to examine rates of return to military duty following surgical treatment of isolated Lisfranc injuries. Methods Surgical records and radiographic images from all active duty US military personnel treated for an isolated Lisfranc injury between January 2005 and July 2014 were examined. Demographic information, injury data, surgical details and subsequent return to duty information were recorded. The primary outcome was ability to return to unrestricted military duty following treatment. The secondary outcome was secondary conversion to a midfoot arthrodesis following initial open reduction internal fixation. Results Twenty-one patients meeting inclusion criteria were identified. Median patient age was 23 years, and mean follow-up was 43 months. Within this cohort, 14 patients were able to return to military service, while seven required a disability separation from the armed forces. Of the 18 patients who underwent initial fixation, eight were subsequently revised to midfoot arthrodesis for persistent pain. Discussion Military personnel sustaining Lisfranc injuries have high rates of persistent pain and disability, even after optimal initial surgical treatment. Military surgeons should counsel patients on the career-threatening nature of this condition and high rates of secondary procedures.