UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression.

Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.

Association between hemoglobin A1c, Vitamin C, and microbiome in diabetic foot ulcers and intact skin: A cross-sectional study.

Background and Aims: Diabetic foot ulcers (DFUs) add billions of dollars to the direct annual costs associated with diabetes. Despite various treatments, many DFUs do not heal and become infected. Both skin-associated microbial communities and glycemic control are believed to be important in nonhealing DFUs. Recent studies have linked serum Vitamin C levels with glycemic control and DFUs. This cross-sectional study assessed skin microbiome in DFUs, intact diabetic skin, and nondiabetic skin to identify correlations between hemoglobin A1c (HbA1c), Vitamin C, and microbial community structure. Correlations between Vitamin C, HbA1c, wound size, and ulcer duration were also determined. Methods: Participants had their DFUs or intact skin culture swabbed. HbA1c was obtained via point-of-care fingerstick testing and serum Vitamin C was obtained via venipuncture. All participants completed a dietary questionnaire. Participants with ulcers were stratified into the controlled (≤8.0%) or uncontrolled (>8.0%) HbA1c group. Analysis of microbial communities was performed via 16S ribosomal RNA (rRNA) gene amplicon sequencing and bacterial load was measured by the domain-level quantitative polymerase chain reaction of the 16S rRNA gene. Results: Forty-two patients were recruited over 6 months. Bacteria from the genera Staphylococcus and Stenotrophomonas were present in all samples and often dominant, but a shift towards anaerobic pathogenic taxa was observed in ulcers. No global significant differences were observed for HbA1c and Vitamin C levels in the microbial community structure (R < 0.013/p > 0.375). Bacterial loads were 4-5 orders of magnitude higher in ulcers than in intact skin samples. Bacterial load was not significantly higher in the uncontrolled HbA1c group (p = 0.67). Larger wound sizes (p = 0.46) were observed in the uncontrolled HbA1c group compared to the control. Lower Vitamin C levels (p = 0.002) were observed in the uncontrolled HbA1c group compared to nondiabetic controls. Conclusion: Understanding the link between Vitamin C and HbA1c and DFU microbiome may aid in new therapies.

Inhibition of CCL28/CCR10-Mediated eNOS Downregulation Improves Skin Wound Healing in the Obesity-Induced Mouse Model of Type 2 Diabetes.

Chronic, nonhealing skin wounds, such as diabetic foot ulcers (DFUs), are common in patients with type 2 diabetes. Here, we investigated the role of chemokine (C-C motif) ligand 28 (CCL28) and its receptor C-C chemokine receptor type 10 (CCR10) in downregulation of endothelial nitric (NO) oxide synthase (eNOS) in association with delayed skin wound healing in the db/db mouse model of type 2 diabetes. We observed reduced eNOS expression and elevated CCL28/CCR10 levels in dorsal skin of db/db mice and subdermal leg biopsy specimens from human subjects with type 2 diabetes. Further interrogation revealed that overexpression of CCR10 reduced eNOS expression, NO bioavailability, and tube formation of human dermal microvascular endothelial cells (HDMVECs) in vitro, which was recapitulated in mouse dorsal skin. In addition, incubation of HDMVECs with CCL28 led to internalization of the CCR10/eNOS complex and colocalization with lysosome-associated membrane protein 1. Finally, topical application of myristoylated CCR10 binding domain 7 amino acid (Myr-CBD7) peptide prevented CCR10-eNOS interaction and subsequent eNOS downregulation, enhanced eNOS/NO levels, eNOS/VEGF-R2+ microvessel density, and blood perfusion, reduced inflammatory cytokine levels, and importantly, decreased wound healing time in db/db mice. Thus, endothelial cell CCR10 activation in genetically obese mice with type 2 diabetes promotes eNOS depletion and endothelial dysfunction, and targeted disruption of CCR10/eNOS interaction improves wound healing.

Changing Perspectives: Offloading a Patient With a Diabetic Foot Ulcer as Opposed to Offloading a Diabetic Foot Ulcer.

Diabetic foot ulcers (DFUs) represent a tremendous burden to health care systems. Offloading is one of the key tenants to healing DFU and knee-high irremovable offloading devices are considered the gold standard for offloading DFU. However, the gold standard is rarely utilized in clinical practice. Patients' limited tolerance for such devices is one of a number of reasons that have been attributed to the lack of use of these devices. The practice of evidence-based medicine relies on shared decision making by pairing patients' values and preferences with the best available evidence. The present case report reviews the process of a patient-centered approach to identify the best offloading option for a patient with DFU. In consultation with the patient, a series of modalities were evaluated for offloading 2 unilateral forefoot DFUs. It is suggested that optimizing DFU offloading outcomes at the population level will require concerted efforts to employ the best offloading solution at the individual patient level. Offloading modalities are necessitated to mitigate the physical stress imparted on DFU during the weightbearing activity that patients engage in. Success is likely to be maximized by maintaining a mind-set of treating individual patients with DFUs as opposed to simply treating DFUs.Levels of Evidence: Level V: Case report.

Diabetes and Reactive Balance: Quantifying Stepping Thresholds With a Simple Spring Scale to Measure Fall-Risk in Ambulatory Older Adults.

BACKGROUND: Fall-risk assessments for patients with diabetes fail to consider reactive responses to balance loss. The purpose of this study was to assess the feasibility of using a simple clinical tool to evaluate the impact of diabetes and fall history on reactive balance in older adults. METHODS: We recruited 72 older adults with and without diabetes. Postural perturbations were applied by a waist-mounted spring scale. Stepping thresholds (STs) in the anterior and posterior directions were defined as the lowest spring-loads that induced a step. Balance was assessed via the National Institutes of Health Toolbox Standing Balance Test, and lower extremity sensation was assessed using vibratory perception threshold and Semmes-Weinstein monofilaments. Fall history over the past year was self-reported. Cox regressions and analysis of variance were used to compare hazard rates for stepping and observed STs between groups. RESULTS: Anterior STs were elicited in 42 subjects and posterior STs in 65 subjects. Hazard rates for posterior ST were significantly affected by diabetes, with greater hazards for fallers with diabetes versus control fallers and nonfallers, after accounting for balance and sensory loss. For those who stepped, ST was lower in the posterior direction for the diabetes group. Additionally, anterior but not posterior ST was lower in all fallers vs all nonfallers. CONCLUSIONS: The waist-mounted spring scale is a clinically implementable device that can assess ST in older adults with diabetes. Using the device, we demonstrated that ST was affected by diabetes and could potentially serve as a fall-risk factor independent of balance or sensory loss.

Single cell transcriptomics of human epidermis identifies basal stem cell transition states.

How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.

One-year safety, healing and amputation rates of Wagner 3-4 diabetic foot ulcers treated with cryopreserved umbilical cord (TTAX01).

An open label, multicenter 16-week trial of cryopreserved human umbilical cord (TTAX01) was previously undertaken in 32 subjects presenting with a Wagner grade 3 or 4 diabetic foot ulcer, with 16 (50%) of these having confirmed closure following a median of one product application (previous study). All but two subjects (30/32; 94%) consented to participate in this follow-up study to 1-year postexposure. No restrictions were placed on treatments for open wounds. At 8-week intervals, subjects were evaluated for adverse events (AEs) and wound status (open or closed). Average time from initial exposure to end of follow-up was 378 days (range 343-433), with 29 of 30 (97%) subjects completing a full year. AEs were all typical for the population under study, and none were attributed to prior exposure to TTAX01. One previously healed wound re-opened, one previously unconfirmed closed wound remained healed, and nine new wound closures occurred, giving 25 of 29 (86.2%) healed in the ITT population. Three of the new closures followed the use of various tissue-based products. Three subjects whose wounds were healed required subsequent minor amputations due to osteomyelitis, one of which progressed to a major amputation (1/29; 3.4%). One additional subject underwent two minor amputations prior to healing. Overall, the study found TTAX01 to be safe in long-term follow-up and associated with both a low rate of major amputation and a higher than expected rates of healing.

CCL28-induced CCR10/eNOS interaction in angiogenesis and skin wound healing.

Chemokines and their receptors play important roles in vascular homeostasis, development, and angiogenesis. Little is known regarding the molecular signaling mechanisms activated by CCL28 chemokine via its primary receptor CCR10 in endothelial cells (ECs). Here, we test the hypothesis that CCL28/CCR10 signaling plays an important role in regulating skin wound angiogenesis through endothelial nitric oxide synthase (eNOS)-dependent Src, PI3K, and MAPK signaling. We observed nitric oxide (NO) production in human primary ECs stimulated with exogenous CCL28, which also induced direct binding of CCR10 and eNOS resulting in inhibition of eNOS activity. Knockdown of CCR10 with siRNA lead to reduced eNOS expression and tube formation suggesting the involvement of CCR10 in EC angiogenesis. Based on this interaction, we engineered a myristoylated 7 amino acid CCR10-binding domain (Myr-CBD7) peptide and showed that this can block eNOS interaction with CCR10, but not with calmodulin, resulting in upregulation of eNOS activity. Importantly, topical administration of Myr-CBD7 peptide on mouse dermal wounds not only blocked CCR10-eNOS interaction, but also enhanced expression of eNOS, CD31, and IL-4 with reduction of CCL28 and IL-6 levels associated with improved wound healing. These results point to a potential therapeutic strategy to upregulate NO bioavailability, enhance angiogenesis, and improve wound healing by disrupting CCL28-activated CCR10-eNOS interaction.

Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression.

Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.

Choosing a Vibratory Test to Pair With Semmes Weinstein Monofilament Testing for Evaluating Lower Extremity Sensation in Patients With Diabetes: A Comparison of Three Vibratory Methodologies.

BACKGROUND: Numerous guidelines recommend pairing Semmes-Weinstein monofilament (SWM) testing with a secondary clinical test when screening for diabetic peripheral neuropathy, yet time is very limited in clinical practice. This study compared the time to complete and the diagnostic agreement of three vibratory sensation tests. METHODS: Sixty-five individuals (42% male; aged: 61 ± 12 years) were recruited. A single investigator administered the following tests bilaterally: 10-site SWM, traditional tuning fork (TTF), electronic tuning fork (ETF), and vibration perception threshold (VPT) via biothesiometer. Times to physically administer the tests were compared with a one-way repeated measures ANOVA. Cochran's Q test was used to compare the varied tests' diagnostic agreement. RESULTS: The ANOVA indicated there were significant (P < .001, partial eta squared = .442) differences in time to complete the varied tests. Sidak post hoc comparisons indicated the VPT (21.2 ± 14.3) testing took an intermediate time to complete, while the ETF (9.7 ± 6.5) and TTF (10.1 ± 7.5) tests took the least amount of time, and the SWM (28.6 ± 8.4) test took the longest time. There were also numerous significant differences (P ≤ .001) between the different tests in regards to neuropathy diagnoses. CONCLUSIONS: Tuning fork methods required 11 seconds less to administer than VPT testing. Although that may seem trivial, it is worth noting peripheral neuropathy screening often fails to occur in the precious few minutes clinicians are allotted per patient. Considering ETF's intrinsic control of stimulus amplitude and its ease of use with an embedded timer, the ETF is recommended over the TTF. Clinicians should also be mindful that different tests yield different diagnostic conclusions.

An open-label trial of cryopreserved human umbilical cord in the treatment of complex diabetic foot ulcers complicated by osteomyelitis.

Clinical trials of potential new therapies for diabetic foot ulcers rarely enroll patients whose wounds extend to muscle, fascia, or bone with clinical and radiographic evidence of underlying osteomyelitis. An open-label, multicenter trial of cryopreserved human umbilical cord (TTAX01) was undertaken in 32 subjects presenting with such complex wounds with a mean duration of 6.1 ± 9.0 (range: 0.2-47.1) months and wound area at screening of 3.8 ± 2.9 (range: 1.0-9.6) cm2 . Aggressive surgical debridement at baseline resulted in 17 minor amputations and an increase in mean wound area to 7.4 ± 5.8 (range: 1.1-28.6) cm2 . All subjects were placed on systemic antibiotics for at least 6 weeks in conjunction with baseline application of TTAX01. Repeat applications were made at no less than 4-week intervals over the 16-week trial. Initial closure occurred in 18 of 32 (56%) wounds, with 16 (50%) of these having confirmed closure in 16 weeks with a median of one-product application. Cases with biopsy confirmed osteomyelitis (n = 20) showed initial closure in 12 (60%) wounds and confirmed closure in 10 (50%) wounds. Four of the five ulcers presenting as recurrences experienced confirmed closure. Mean overall time to healing was 12.8 ± 4.3 weeks. Mean wound area reduction from baseline was 91% for all wounds. Of the 16 wounds without confirmed closure during the 16-week treatment period, five (31.3%) achieved 99-100% wound area reduction by their final visit. The product was well tolerated. Two minor amputations occurred during the study period due to recurrent or persistent osteomyelitis; however, there were no major amputations.

Dressings, Topical Therapy, and Negative Pressure Wound Therapy.

The current epidemic of diabetes has created a high demand for skilled wound-care professionals. Wound-care treatment begins with an appreciation of the cause of the ulceration and an adherence to the fundamental pillars of wound care. Also critical in the wound management paradigm is the optimization of the wound environment to facilitate the progression through the stages of healing. This can be accomplished through the use of different topical therapies and wound dressings to generate a favorable condition conducive to healing. This article summarizes the updated literature and best practices related to this topic.

Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis.

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Among the various molecular mechanisms implicated in osteosarcomagenesis, the RB-E2F pathway is of particular importance as virtually all cases of osteosarcoma display alterations in the RB-E2F pathway. In this study, we examined the transcription factor E2F family members that are associated with increased malignancy in Rb1-null osteosarcoma tumors. Using genetically engineered mouse models of osteosarcoma, we found that loss of activator E2Fs, E2F1 and E2F3, significantly delays tumor progression and increases the overall survival of the p53/Rb1-deficient osteosarcoma mouse model. We also studied the role of helicase, lymphoid specific (HELLS), a chromatin remodeling protein identified as a critical downstream effector of the RB-E2F signaling pathway in various cancers. In this study, we confirmed that the RB-E2F pathway directly regulates HELLS gene expression. We also found that HELLS mRNA is upregulated and its protein overexpressed in osteosarcoma. Using loss-of-function assays to study the role of HELLS in human osteosarcoma, we observed that HELLS has no effect on tumor proliferation and migration. Further, we pioneered the study of Hells in developmental tumor models by generating Hells conditional knockout osteosarcoma mouse models to examine the role of HELLS in osteosarcoma tumor development. We found that loss of Hells in osteosarcoma has no effect in tumor initiation and overall survival of mice. This suggests that while HELLS may serve as a biomarker for tumorigenesis and for RB-E2F pathway status, it is unlikely to serve as a relevant target for therapeutics in osteosarcoma.

The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells.

Osteosarcoma is the most common primary malignant neoplasm of bone and typically occurs in children and young adults. As a highly metastatic malignancy, 15-20% of osteosarcoma patients are diagnosed after the tumor has already metastasized (typically to the lungs), which translates to 5-year survival rates of <40%. Here, we tested the effect of the cyclin-dependent kinase (CDK) inhibitor flavopiridol (alvocidib) in U2OS, SaOS-2, SJSA-1, and 143B osteosarcoma tumor cells in vitro and in vivo. Our results show that flavopiridol can drastically decrease survival in these osteosarcoma cell lines at nanomolar concentrations and induce mitotic catastrophe in p53-null osteosarcomas. We also performed transcriptome analysis (RNA-seq) of flavopiridol-treated osteosarcoma cells, which revealed significant changes in genes coding for proteins involved in cell-cell and cell-matrix adhesions, including cadherin 3 (CDH3) and 4 (CDH4). These transcriptional changes translated to a striking reduction in the ability of osteosarcoma cells to migrate and invade in vitro. Further, in vivo assessment of the effects of flavopiridol on osteosarcoma metastasis resulted in a significant reduction in the number of lung metastases in mice treated with flavopiridol at concentrations that are physiologically tolerable. This study suggests that flavopiridol, likely in combination with other cytotoxic chemotherapeutic agents, may be a promising drug for the treatment of osteosarcoma.

Control of lower extremity edema in patients with diabetes: Double blind randomized controlled trial assessing the efficacy of mild compression diabetic socks.

AIMS: Persons with diabetes frequently present with lower extremity (LE) edema; however, compression therapy is generally avoided for fear of compromising arterial circulation in a population with a high prevalence of peripheral arterial disease. This double blind randomized controlled trial (RCT) assessed whether diabetic socks with mild compression could reduce LE edema in patients with diabetes without negatively impacting vascularity. METHODS: Eighty subjects with LE edema and diabetes were randomized to receive either mild-compression knee high diabetic socks (18-25mmHg) or non-compression knee high diabetic socks. Subjects were instructed to wear the socks during all waking hours. Follow-up visits occurred weekly for four consecutive weeks. Edema was quantified through midfoot, ankle, and calf circumferences and cutaneous fluid measurements. Vascular status was tracked via ankle brachial index (ABI), toe brachial index (TBI), and skin perfusion pressure (SPP). RESULTS: Seventy-seven subjects (39 controls and 38 mild-compression subjects) successfully completed the study. No statistical differences between the two groups in terms of age, body mass index, gender, and ethnicity. Repeated measures analysis of variance and Sidak corrections for multiple comparisons were used for data analyses. Subjects randomized to mild-compression diabetic socks demonstrated significant decreases in calf and ankle circumferences at the end of treatment as compared to baseline. LE circulation did not diminish throughout the study with no significant decreases in ABI, TBI or SPP for either group. CONCLUSIONS: Results of this RCT suggest that mild compression diabetic socks may be effectively and safely used in patients with diabetes and LE edema.

Safety and efficacy of intramuscular human placenta-derived mesenchymal stromal-like cells (cenplacel [PDA-002]) in patients who have a diabetic foot ulcer with peripheral arterial disease.

The objective of this study was to examine the safety of cenplacel (PDA-002) in patients with peripheral arterial disease (PAD) and a diabetic foot ulcer (DFU). Cenplacel is a mesenchymal-like cell population derived from full-term human placenta. This phase 1, dose-escalation study investigated cenplacel in diabetic patients with chronic DFUs (Wagner grade 1 or grade 2) and PAD [ankle-brachial index (ABI) >0·5 and ≤0·9], enrolled sequentially into each of four dose cohorts (3 × 106 , 10 × 106 , 30 × 106 and 100 × 106 cells; administered intramuscularly on study days 1 and 8 in combination with standard of care). Overall, cenplacel was well tolerated in all 15 patients in the study. Before enrollment, nine patients had an ulcer for ≥6 months and 11 had an ABI of 0·7-0·85. No patient met dose-limiting toxicity criteria and no treatment-related serious adverse events were reported. There was preliminary evidence of ulcer healing in seven patients (five complete; two partial) within 3 months of cenplacel treatment, and circulating endothelial cell levels (a biomarker of vascular injury in PAD) were decreased within 1 month. Cenplacel was generally safe and well tolerated in patients with chronic DFUs and PAD. Outcomes from this study informed the doses, endpoints, biomarkers and patient population for an ongoing phase 2 trial.

Preliminary Evaluation of a Cycling Cleat Designed for Diabetic Foot Ulcers.

BACKGROUND: Offloading devices for diabetic foot ulcers (DFU) generally restrict exercise. In addition to traditional health benefits, exercise could benefit DFU by increasing blood flow and acting as thermotherapy. This study functionally evaluated a cycling cleat designed for forefoot DFU. METHODS: Fifteen individuals at risk of developing a DFU used a recumbent stationary bicycle to complete one 5-minute cycling bout with the DFU cleat on their study foot and one 5-minute bout without it. Foot stress was evaluated by plantar pressure insoles during cycling. Laser Doppler perfusion monitored blood flow to the hallux. Infrared photographs measured foot temperature before and after each cycling bout. RESULTS: The specialized cleat significantly reduced forefoot plantar pressure (9.9 kPa versus 62.6 kPa, P < .05) and pressure time integral (15.4 versus 76.4 kPa*sec, P < .05). Irrespective of footwear condition, perfusion to the hallux increased (3.97 ± 1.2 versus 6.9 ± 1.4 tissue perfusion units, P < .05) after exercise. Infrared images revealed no changes in foot temperature. CONCLUSIONS: The specialized cleat allowed participants to exercise with minimal forefoot stress. The observed increase in perfusion suggests that healing might improve if patients with active DFU were to use the cleat. Potential thermotherapy for DFU was not supported by this study. Evaluation of the device among individuals with active DFU is now warranted.

Human acellular dermal wound matrix: evidence and experience.

A chronic wound fails to complete an orderly and timely reparative process and places patients at increased risk for wound complications that negatively impact quality of life and require greater health care expenditure. The role of extracellular matrix (ECM) is critical in normal and chronic wound repair. Not only is ECM the largest component of the dermal skin layer, but also ECM proteins provide structure and cell signalling that are necessary for successful tissue repair. Chronic wounds are characterised by their inflammatory and proteolytic environment, which degrades the ECM. Human acellular dermal matrices, which provide an ECM scaffold, therefore, are being used to treat chronic wounds. The ideal human acellular dermal wound matrix (HADWM) would support regenerative healing, providing a structure that could be repopulated by the body's cells. Experienced wound care investigators and clinicians discussed the function of ECM, the evidence related to a specific HADWM (Graftjacket(®) regenerative tissue matrix, Wright Medical Technology, Inc., licensed by KCI USA, Inc., San Antonio, TX), and their clinical experience with this scaffold. This article distills these discussions into an evidence-based and practical overview for treating chronic lower extremity wounds with this HADWM.