Intersections of Fibrodysplasia Ossificans Progressiva and Traumatic Heterotopic Ossification.

Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.

Burn Patient Metabolism and Nutrition.

Following severe burns, patients have unique metabolic derangements that make adequate nutritional support imperative for their survival and recovery. Patients with burns have persistent and prolonged hypermetabolic states that lead to increased catabolism following injury. During rehabilitation, catabolism leads to increased muscle wasting and cachexia. Failure to adequately meet the patient's increased nutritional requirements can lead to poor wound healing, increased infections, and overall organ dysfunction. Because of these risks, adequate assessment and provision of nutritional needs are imperative to care for these patients.

Neutrophil and NETosis Modulation in Traumatic Heterotopic Ossification.

OBJECTIVE: To characterize the role of neutrophil extracellular traps (NETs) in heterotopic ossification (HO) formation and progression and to use mechanical and pharmacological methods to decrease NETosis and mitigate HO formation. BACKGROUND: Traumatic HO is the aberrant osteochondral differentiation of mesenchymal progenitor cells after traumatic injury, burns, or surgery. While the innate immune response has been shown to be necessary for HO formation, the specific immune cell phenotype and function remain unknown. Neutrophils, one of the earliest immune cells to respond after HO-inducing injuries, can extrude DNA, forming highly inflammatory NETs. We hypothesized that neutrophils and NETs would be diagnostic biomarkers and therapeutic targets for the detection and mitigation of HO. METHODS: C57BL6J mice underwent burn/tenotomy (a well-established mouse model of HO) or a non-HO-forming sham injury. These mice were either (1) ambulated ad libitum, (2) ambulated ad libitum with daily intraperitoneal hydroxychloroquine, ODN-2088 (both known to affect NETosis pathways), or control injections, or (3) had the injured hind limb immobilized. Single-cell analysis was performed to analyze neutrophils, NETosis, and downstream signaling after the HO-forming injury. Immunofluorescence microscopy was used to visualize NETosis at the HO site and neutrophils were identified using flow cytometry. Serum and cell lysates from HO sites were analyzed using enzyme-linked immunosorbent assay for myeloperoxidase-DNA and ELA2-DNA complexes to identify NETosis. Micro-computerized tomography was performed on all groups to analyze the HO volume. RESULTS: Molecular and transcriptional analyses revealed the presence of NETs within the HO injury site, which peaked in the early phases after injury. These NETs were highly restricted to the HO site, with gene signatures derived from both in vitro NET induction and clinical neutrophil characterizations showing a high degree of NET "priming" at the site of injury, but not in neutrophils in the blood or bone marrow. Cell-cell communication analyses revealed that this localized NET formation coincided with high levels of toll-like receptor signaling specific to neutrophils at the injury site. Reducing the overall neutrophil abundance within the injury site, either pharmacologically through treatment with hydroxychloroquine, the toll-like receptor 9 inhibitor OPN-2088, or mechanical treatment with limb offloading, results in the mitigation of HO formation. CONCLUSIONS: These data provide a further understanding of the ability of neutrophils to form NETs at the injury site, clarify the role of neutrophils in HO, and identify potential diagnostic and therapeutic targets for HO mitigation.

A Review of Laser Therapies for the Treatment of Scarring and Vascular Anomalies.

Significance: Laser use has become part of the gold standard of treatment as an effective adjuvant in multimodal therapy for pathologic scarring caused by burns, trauma, acne, and surgery, as well as vascular anomalies. Understanding indications and applications for laser therapy is essential for physicians to improve patient outcomes. Recent Advances: Since the 1980s, the medical use of lasers has continuously evolved with improvements in technology. Novel lasers and fractionated technologies are currently being studied in the hopes to improve treatment efficacy, while reducing complications. Recent advancements include acne treatment with novel picosecond lasers, new hypertrophic scar therapies with simultaneous laser and intense pulsed light use, and novel systems such as lasers with intralesional optical fiber delivery devices. In addition, optimizing the timing of laser therapy and its use in multimodal treatments continue to advance the field of photothermolysis. Critical Issues: Selecting the correct laser for a given indication is the fundamental decision when choosing a laser balancing effective treatment with minimal complications. This article covers the principles of laser therapy, the preferred lasers used for the treatment of scarring and vascular anomalies, and discusses the current evidence behind these laser choices. Future Directions: To optimize laser therapy, larger randomized control trials and split scar studies are needed. Continued advancement through better randomized controlled studies will help to improve patient outcomes on a broader scale.

Discoidin domain receptor 2 regulates aberrant mesenchymal lineage cell fate and matrix organization.

Extracellular matrix (ECM) interactions regulate both the cell transcriptome and proteome, thereby determining cell fate. Traumatic heterotopic ossification (HO) is a disorder characterized by aberrant mesenchymal lineage (MLin) cell differentiation, forming bone within soft tissues of the musculoskeletal system following traumatic injury. Recent work has shown that HO is influenced by ECM-MLin cell receptor signaling, but how ECM binding affects cellular outcomes remains unclear. Using time course transcriptomic and proteomic analyses, we identified discoidin domain receptor 2 (DDR2), a cell surface receptor for fibrillar collagen, as a key MLin cell regulator in HO formation. Inhibition of DDR2 signaling, through either constitutive or conditional Ddr2 deletion or pharmaceutical inhibition, reduced HO formation in mice. Mechanistically, DDR2 perturbation alters focal adhesion orientation and subsequent matrix organization, modulating Focal Adhesion Kinase (FAK) and Yes1 Associated Transcriptional Regulator and WW Domain Containing Transcription Regulator 1 (YAP/TAZ)-mediated MLin cell signaling. Hence, ECM-DDR2 interactions are critical in driving HO and could serve as a previously unknown therapeutic target for treating this disease process.

Macrophage TGF-ß signaling is critical for wound healing with heterotopic ossification after trauma.

Transforming growth factor-ß1 (TGF-ß1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGF-ß1 signaling in macrophages, and not mesenchymal stem/progenitor cells, is critical in HO formation. In-depth single-cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrated increased TGF-ß1 signaling in early infiltrating macrophages, with open chromatin regions in TGF-ß1-stimulated genes at binding sites specific for transcription factors of activated TGF-ß1 (SMAD2/3). Genetic deletion of TGF-ß1 receptor type 1 (Tgfbr1; Alk5), in macrophages, resulted in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor, we administered a systemic treatment with TGF-ß1/3 ligand trap TGF-ßRII-Fc, which resulted in decreased HO formation and a delay in macrophage infiltration to the injury site. Overall, our data support the role of the TGF-ß1/ALK5 signaling pathway in HO.

Contemporary perspectives on heterotopic ossification.

Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.

How We Did It: Implementing a Trainee-Focused Surgical Research Curriculum and Infrastructure.

OBJECTIVE: To describe the implementation of a department-wide research curriculum and infrastructure created to promote academic collaboration and productivity, particularly amongst trainees and junior investigators involved in basic, translational, clinical, quality, or education research. DESIGN: Description of UT Southwestern Medical Center's (UTSW) surgical research resources and infrastructure and the development of a didactic curriculum focused on research methods, writing skills, and optimizing academic time and effort. SETTING: The collaboration was initiated by UTSW Department of Surgery residents who were on dedicated research time (DRT) and grew to include trainees and faculty at all levels of the institution. Guest lecturers from institutions around the country were incorporated via virtual meeting platforms. PARTICIPANTS: Medical students, residents, and clinical and research faculty from the Department of Surgery were invited to attend research meetings, didactics, and the guest-lecture series. Additionally, all groups were given access to shared resources and encouraged to share their own work. RESULTS: A robust set of resources including data analysis tools, manuscript and grant writing templates, funding opportunities, and a comprehensive list of surgical conferences was created and made accessible to UTSW Surgery team members. Moreover, a curriculum of lectures covering a broad variety of topics for all types of research was created and has thus far reached an audience of over 40 UTSW Surgery trainees and staff. CONCLUSIONS: A comprehensive set of lectures and resources targeted toward facilitating surgical research was designed and implemented at one of the largest surgical training programs in the country. This effort represents a low-cost, feasible, and accessible way to improve academic productivity and enhance the training of surgeon-scientists and can serve as a blueprint for other institutions around the country.

Relationship Between Pregnancy Complications and Subsequent Coronary Artery Disease Assessed by Coronary Computed Tomographic Angiography in Black Women.

BACKGROUND: Maternal pregnancy complications, particularly preeclampsia and gestational diabetes mellitus, are described to increase the risk for subsequent coronary artery disease (CAD). In addition, black women are at higher risk for CAD. The objective of this study was to compare the prevalence and extent of CAD as detected by coronary computed tomographic angiography (CCTA) in black women with and without a history of prior pregnancy complications. METHODS: We retrospectively evaluated patient characteristics and CCTA findings in groups of black women with a prior history of preterm delivery (n=154), preeclampsia (n=137), or gestational diabetes mellitus (n=148), and a matched control group of black women who gave birth without such complications (n=445). Univariate and multivariate analyses were performed to assess risk factors of CAD. RESULTS: All groups with prior pregnancy complications showed higher rates of any (≥20% luminal narrowing) and obstructive (≥50% luminal narrowing) CAD (preterm delivery: 29.2% and 9.1%; preeclampsia: 29.2% and 7.3%; and gestational diabetes mellitus: 47.3% and 15.5%) compared with control women (23.8% and 5.4%). After accounting for confounding factors at multivariate analysis, gestational diabetes mellitus remained a strong risk factor of any (odds ratio, 3.26; 95% CI, 2.03-5.22; P<0.001) and obstructive CAD (odds ratio, 3.00; 95% CI, 1.55-5.80; P<0.001) on CCTA. CONCLUSIONS: Black women with a history of pregnancy complications, particularly gestational diabetes mellitus, have a higher prevalence of CAD on CCTA while only a history of gestational diabetes mellitus was independently associated with any and obstructive CAD on CCTA.