The use of NovoSorb biodegradable temporising matrix in wound management: a literature review and case series.

OBJECTIVE: NovoSorb (Poly-Novo Ltd, Australia) biodegradable temporising matrix (BTM) is a novel artificial dermal matrix. Previous literature is weighted towards its use in burns reconstruction; however, this paper describes its use within a range of wound aetiologies. The authors present one of the largest and most diverse case series to date, and aim to provide an independent benchmark of clinical practice. METHOD: A retrospective observational study was performed. Patient demographics and clinical data (wound aetiology, site, total body surface area (TBSA), wound bed, number of debridements, time to BTM integration, time to skin grafting) were collected and subgroup analysis preformed. RESULTS: The cohort consisted of 37 patients (acute trauma wounds, n=19; hard-to-heal wounds, n=9; acute infections, n=6; cancer, n=3). Successful BTM integration, allowing subsequent split-thickness skin grafting (STSG), occurred in 70% of cases, despite an overall complication rate of 51%. Mean time from BTM application to STSG was 53 days. There was no difference in STSG outcomes when grafting was performed either before or after the six-week BTM application period. There was no difference when various wound beds (fascia, tendon, periosteum) were compared. Patients >65 years of age were more likely to experience complications; however, this did not affect the speed of integration. The relation of diabetes and smoking to overall integration had no statistical significance. CONCLUSION: In comorbid patients in particular, the time between BTM application and STSG may be longer than the manufacturer's recommendation. Furthermore, data suggest greater wound bed optimisation and closer interval monitoring in hard-to-heal/malignant wounds, and in older patients and patients with comorbidities. However, BTM appears robust (even in infection) and is showing promise as a useful reconstructive tool.

The management of partial extensor tendon lacerations of the hand and forearm: A systematic review.

Injuries to the extensor mechanism of the hand and forearm are common and cause significant functional disability. Complete tendon lacerations are managed with surgical repair, whereas selected partial tendon injuries may be managed without repair but with splinting and physiotherapy alone. There is limited evidence to support the management of partial lacerations, in particular the decision of whether to repair or not. We aimed to systematically review the literature to determine the optimal management of partial extensor tendon lacerations in the hand and forearm. A protocol for the systematic review was developed prospectively and registered with PROSPERO (CRD42021250431). PubMed, EMBASE, clinicaltrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1990 to 27/05/2022. 4565 studies were screened, of which 88 underwent full text review. Five studies were included, one randomised control trial and four cohort studies. One study examined outcomes of partial lacerations treated without repair; the other four studies examined outcomes following repair. Pinch and grip strength and time to return to work were similar regardless of management. Adverse outcomes were reported for patients undergoing surgical repair; none were observed in those managed without repair. Meta-analysis was precluded by study heterogeneity and high risk of bias. There is limited evidence to support the management of partial extensor tendon lacerations, with some low-quality evidence that non-operative management of selected partial lacerations is safe. There is a pressing need for pragmatic, multicentre randomised trials to assess the cost-effectiveness of current treatments.

COVID-19 Countermeasures: An Algorithm to Stay Unlocked.

We describe a visual algorithm to help prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contagion as well as manage COVID-19 disease according to categories of clinical severity. The algorithm is timely, with multiple countries worldwide declaring repeat surges in SARS-CoV-2 infections following the easing of lockdown measures. Its flowchart assimilates key effective interventions in a visual manner that will assist healthcare workers to manage COVID-19 disease algorithmically, and policymakers to suppress further SARS-CoV-2 waves. Importantly, we include the innovative use of topical p-menthane-3,8-diol spray by the British Army for COVID-19 Support Force personnel, which in light of its coronavirucidal properties, deserves wider dissemination. This algorithm has the potential to be updated as numerous studies are concluded globally.

Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis.

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.

Systematic review of non-surgical treatments for early dupuytren's disease.

BACKGROUND: Dupuytren's disease is a common fibrotic disorder of the palm characterized by the development of progressive flexion deformities in the digits, leading to significant functional impairment. Surgical excision remains the most common treatment. However, this is only indicated in patients with established contractures rather than those with early disease. Early disease is generally characterized by the presence of palmar nodules with limited or no contracture of the fingers. The ideal treatment would be directed at patients with early progressive disease to prevent future deterioration. Various non-surgical treatment modalities have been described but there is currently no systematic assessment of the role and efficacy of these treatments in patients with early disease. METHODS: Using a PICOS analysis we reviewed publications of studies of patients with early disease who had received physical therapies, pharmacological treatment, or radiotherapy. Following PRISMA guidelines titles and abstract were screened using predefined criteria to identify those reporting outcomes specifically relating to the treatment of early disease. In the absence of a definition of early disease studies were included if early DD was described clinically, with digital contractures not exceeding 30°, Tubiana grades N to 1, and which reported identifiable data. Studies were excluded if data for early DD patients could not be extracted for analysis. RESULTS: In this systematic review, 26 studies were identified and analyzed to evaluate the effect of pharmacological therapy (n = 11), physical therapy (n = 5) and radiotherapy (n = 10) on early Dupuytren's disease. The studies comprised 20 case series, 1 cohort study with the remainder reporting case studies. All publications were graded level of evidence 4 or 5 assessed using the Oxford Centre for Evidence Based Medicine grading. Narrative descriptions of the data are presented. CONCLUSIONS: Physical therapies were the most robustly assessed, using objective measures but the studies were under powered, providing insufficient evidence of efficacy. Intralesional steroid injection and radiotherapy appeared to lead to softening of nodules and to retard disease progression but lacked rigorous evaluation and studies were poorly designed. There is an urgent need for adequately powered double blinded randomized trials for this common disorder which affects 4 % of the population. TRIAL REGISTRATION: The protocol was registered ( CRD42015008986 16 November 2015) with the PROSPERO international prospective register of systematic reviews.

Donor site morbidity of the medial plantar artery flap studied with gait and pressure analysis.

BACKGROUND: The medial plantar artery flap (MPA) allows transfer of both glabrous (smooth and free from hair) and sensate tissue. It has been suggested that the non-weight bearing instep area of the foot provides tissue for transfer with minimal donor morbidity. However the abductor hallucis muscle and plantar fascia are dissected during flap harvest which may affect foot mechanics. METHODS: Patients were included who had undergone MPA flap harvest and were walking unaided. The majority of the patients studied had problems with soft tissues of their heels rather than trauma as a starting point. Laboratory normals and the patient's contralateral limb were used as controls. Gait and pressure analysis were performed using 3D gait analysis and high resolution pressure analysis. RESULTS: This study included 6 patients, with 5 chronic wounds (4 ipsilateral, 1 contralateral) and 1 traumatic ankle defect. QUESTIONNAIRE RESULTS: Enneking scores: 67.9% return to function; Foot Function Index scores: 39.1% loss of function. GAIT ANALYSIS: Significant differences were seen in kinetic and kinematic data. PRESSURE ANALYSIS: The donor site group had significantly less pressure in the great toe (38.1kPa vs. 78.1kPa, p=0.013), significantly slower transition through the midfoot (445.2ms vs. 352.07ms, p=0.016) and increased impulse in the heel (3.1kPa/s vs. 11.7kPa/s, p=0.038). CONCLUSIONS: This study demonstrates subjective and objective evidence of MPA donor site morbidity. Comparison to other studies looking at gait and pressure changes seen after flap reconstruction of the plantar region suggest that much of this difference may be attributable to ipsilateral reconstruction. As the majority had chronic problems with the soft tissues over the heel some of these biomechanical responses could be related to learned behaviour preoperatively or continued discomfort in the heel pad. Nonetheless it demonstrates accurately the effect of the technique overall on the function of the foot. The changes in the region of the great toe may be solely attributable to MPA harvest. These results suggest that MPA harvest is not free of donor morbidity.

Isometric contraction of Dupuytren's myofibroblasts is inhibited by blocking intercellular junctions.

Myofibroblasts (MFs) are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human MFs derived from patients with Dupuytren's disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three-dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive, or gap junctions effectively inhibited contraction of the collagen matrices and downregulated the MF phenotype. Our data indicate that MFs in part function as a coordinated cellular syncytium, and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells.

Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target.

Dupuytren's disease is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function. The cell responsible for development of the disease is the myofibroblast. There is currently no treatment for early disease or for preventing recurrence following surgical excision of affected tissue in advanced disease. Therefore, we sought to unravel the signaling pathways leading to the development of myofibroblasts in Dupuytren's disease. We characterized the cells present in Dupuytren's tissue and found significant numbers of immune cells, including classically activated macrophages. High levels of proinflammatory cytokines were also detected in tissue from Dupuytren's patients. We compared the effects of these cytokines on contraction and profibrotic signaling pathways in fibroblasts from the palmar and nonpalmar dermis of Dupuytren's patients and palmar fibroblasts from non-Dupuytren's patients. Exogenous addition of TNF, but not other cytokines, including IL-6 and IL-1ß, promoted differentiation into specifically of palmar dermal fibroblasts from Dupuytren's patients in to myofibroblasts. We also demonstrated that TNF acts via the Wnt signaling pathway to drive contraction and profibrotic signaling in these cells. Finally, we examined the effects of targeted cytokine inhibition. Neutralizing antibodies to TNF inhibited the contractile activity of myofibroblasts derived from Dupuytren's patients, reduced their expression of α-smooth muscle actin, and mediated disassembly of the contractile apparatus. Therefore, we showed that localized inflammation in Dupuytren's disease contributes to the development and progression of this fibroproliferative disorder and identified TNF as a therapeutic target to down-regulate myofibroblast differentiation and activity.

Fasciocutaneous flaps of the subscapular artery axis to reconstruct large extremity defects.

INTRODUCTION: The scapular, parascapular and thoracodorsal artery perforator (TDAP) flaps represent fasciocutaneous flaps derived from the subscapular artery axis. These flaps can be harvested individually or combined as conjoint flaps, tailored to reconstruct a wide variety of defects in the extremities. ANALYSIS AND METHODS: All patients undergoing free-flap reconstruction at North Bristol trust with a fasciocutaneous flap of the subscapular axis from April 2006 until April 2010 were included. This cohort of 45 patients was retrospectively analysed. The Enneking score for return of limb function was used as an outcome measure after reconstruction. Donor-site morbidity analysis was carried out prospectively using Oxford Medical Research Council (MRC) score, Vancouver Scar Scale and disability of arm, shoulder and hand questionnaire (DASH) scores. RESULTS: A total of 45 patients had extremity reconstruction using flaps of the subscapular artery axis following severe limb trauma, often comprising open tibial fractures. A total of 42 patients had lower limb injuries and three had upper limb injuries. All flaps survived. The mean Injury Severity Score (ISS) was 9.3, the mean Enneking score was 27 at 12 months mean follow-up. In the nine conjoint flaps, the mean area of tissue resurfaced was 257 cm2. CONCLUSIONS: In this case series of fasciocutaneous flaps of the subscapular artery axis, we establish that these flaps are robust and versatile. They replace 'like-with-like' and have good patient satisfaction. The donor site can be closed primarily, is discrete and has minimal donor morbidity. The conjoint flaps can be used for reconstruction of very large defects without the need to sacrifice functionally important muscle.