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Item 51 Wireless Electroceutical Dressing for the Treatment of Biofilm Infected Burn Wounds(Oxford University Press, 2022) Nuutila, Kristo; Diaz, Victoria; Anselmo, Kristin; Steiner, Shomita; Sen, Chandan K.; Carlsson, Anders H.; Chan, Rodney K.; Roy, Sashwati; Surgery, School of MedicineIntroduction: Burn injuries are common to all military conflicts. In combat, eradication and prevention of burn wound infection is complicated by high rates of soft tissue contamination and prolonged delays to definitive stateside care. Furthermore, in the battlefield setting the salvage rate for infected burned extremities is low. Therefore, a simple, easy, non-invasive and rapid method to protect the wound, while also inhibiting infection, would represent a significant advance in the treatment of combat burn wounds. The purpose of this clinical trial was to investigate the efficacy of an FDA approved disposable and easily portable, wireless electroceutical dressing (WED) in the treatment of burn wounds. The hypothesis was that a low electric field generated by the moisture-activated WED will reduce infection load, improve graft survival and take, enhance wound healing and restore skin barrier function of biofilm infected wounds. Methods: A phase I, prospective, randomized, controlled clinical trial was performed to evaluate the efficacy of the WED dressing as compared to the standard of care (SoC) dressing to prevent and disrupt biofilms. Subjects were screened from inpatient admissions for traumatic burns >300cm2 in size. In total 38 subjects were enrolled to the study. Subject burn wounds were divided into two parts and randomized to receive either the SoC dressing or the WED dressing. Dressings were changed on day 4, removed on day 7 and the burns were followed for 30 days. Small biopsies were collected on days 4 and 7 for histology, SEM examination of biofilm and for quantitative bacteriological analysis. In addition, non-invasive wound imaging techniques were utilized to study wound healing. Furthermore, Vancouver scar scale and patient observer scar assessment were used to evaluate quality of healing. Results: The results showed that at the time of dressing removal, non-grafted burns that were treated with the WED dressing presented statistically significantly less biofilm in comparison to the SoC treated burns (p < 0.05). The results also demonstrated that the WED dressing was more efficient at eradicating biofilm than the SoC dressing. At the time of the dressing removal, biofilm score [0-3] had decreased in 48% of the WED dressing treated burns in comparison to 28% in the SoC treated burns. In terms of wound healing and quality of healing no significant differences were observed between the WED and the SoC dressings. Conclusions: This trial demonstrated that the WED dressing was more efficient against biofilm infection than the SoC dressing. In addition, the study concluded that the WED dressing performed equally well as the SoC in terms of burn wound healing.Item Adipose stromal cells enhance keratinocyte survival and migration in vitro, and graft revascularization in mouse wound healing model(2013-12-11) Knowles, Kellen Alexander; Berbari, Edward J.; March, Keith Leonard, 1963-; Ji, JulieIn the US, more than 1 million burn injuries are reported annually. About 45,000 injuries due to fires and burns result in hospitalization and ten percent of these result in death every year. Advances in burn treatment have led to a reduction in mortality rate over the last decades. Since more patients are surviving the initial resuscitation phase even with very large areas of skin being burned away, wound care has become increasingly important to ensure continued patient survival and improvement. While currently a common treatment for third degree burn wounds, skin grafts have several drawbacks. The availability of donor sites for autografts may be limited, especially in incidences of extensive skin loss. The rejection associated with the use of allografts and xenografts may render them inadequate or undesirable. Even if a suitable graft is found, poor retention due to infection, hematoma, and low vascularity at the recipient site are other drawbacks associated with the use of skin grafts as a primary treatment for severe burn wounds. As such, research has been done into alternative treatments, which include but are not limited to artificial skin, cell therapy, and growth factor application. We propose the delivery of adipose derived stem cells (ASC) in combination with endothelial progenitor cells (EC) via Integra Dermal Regenerative Template (DRT) to promote faster graft vascularization and thus faster healing of wounds. Integra DRT is an acellular skin substitute that consists of a dermal layer composed of bovine collagen and chondroitin-6-sulfate glycosaminoglycan, and an "epidermal" layer, which consists of silicone polymer. This silicone layer is removed after the collagen matrix is adequately vascularized (usually takes 2-3 weeks), and then a thin layer autograft is applied to the top of the neo-dermis. ASC are derived from the stromal-vascular fraction (SVF) of adipose tissue and are a readily available, pluripotent, mesenchymal cell known to promote angiogenesis. They are being explored as a treatment for a myriad of diseases and conditions, including wound healing. In combination with ECs, they form stable microvessel networks in vitro and in vivo. In our work, we found that ASC+EC form stable microvessel networks when cultured on Integra DRT. Also, ASC and ASC+EC conditioned media promoted both survival and migration of human epidermal keratinocytes compared to control medium. In a full thickness wound healing model, using healthy NSG mice, the ASC+EC case showed a significantly higher rate of wound closure compared to control. Based on best linear unbiased estimates (BLUE), the difference between the healing rates of ASC alone treatment and the Control treatment group is -0.45 +/- 0.22 mm²/day (p=0.041), which is not less than 0.025 and thus not statistically significant (Bonferroni Adjusted). However, the BLUE for the difference between the ASC+EC group and the Control group healing rates is -0.55 +/- 0.28 mm²/day (p = 0.017<0.025, Bonferroni Adjusted), which is statistically significant. Histology revealed a significantly higher number of vessels compared to control in both ASC alone and ASC+EC case. CD31 staining revealed the presence of human vessels in ASC+EC treatment scaffolds. We conclude that the combination of ASC and EC can be used to accelerate healing of full-thickness wounds when delivered to site of the wound via Integra. This result is especially compelling due to the fact that the mice used were all healthy. Thus our treatment shows an improvement in healing rate even compared to normal wound healing.Item Adult skin fibroblast state change in murine wound healing(Springer Nature, 2023-01-17) Gharbia, Fatma Z.; Abouhashem, Ahmed S.; Moqidem, Yomna A.; Elbaz, Ahmed A.; Abdellatif, Ahmed; Singh, Kanhaiya; Sen, Chandan K.; Azzazy, Hassan M. E.; Surgery, School of MedicineWound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotypes have been identified in patients with chronic wounds. In this work, we analyzed scRNA-seq datasets of normal and wounded skin from mice at day 4 post-wound to investigate fibroblast heterogeneity during the proliferative phase of wound healing. Compositional analysis revealed a specific subset of fibroblast (cluster 3) that primarily increased in wounded skin (14%) compared to normal skin (3.9%). This subset was characterized by a gene signature marked by the plasma membrane proteins Sfrp2 + Sfrp4 + Sfrp1 + and the transcription factors Ebf1 + Prrx1 + Maged1 + . Differential gene expression and enrichment analysis identified epithelial to mesenchymal transition (EMT) and angiogenesis to be upregulated in the emerging subset of fibroblasts of the wounded skin. Using two other datasets for murine wounded skin confirmed the increase in cluster 3-like fibroblasts at days 2, 7 and 14 post-wounding with a peak at day 7. By performing a similarity check between the differential gene expression profile between wounded and normal skin for this emerging fibroblast subset with drug signature from the ConnectivityMap database, we identified drugs capable of mimicking the observed gene expression change in fibroblasts during wound healing. TTNPB, verteprofin and nicotinic acid were identified as candidate drugs capable of inducing fibroblast gene expression profile necessary for wound healing. On the other hand, methocarbamol, ifosfamide and penbutolol were recognized to antagonize the identified fibroblast differential expression profile during wound healing which might cause delay in wound healing. Taken together, analysis of murine transcriptomic skin wound healing datasets suggested a subset of fibroblasts capable of inducing EMT and further inferred drugs that might be tested as potential candidates to induce wound closure.Item Biofilm Management in Wound Care(Wolters Kluwer, 2021) Sen, Chandan K.; Roy, Sashwati; Mathew-Steiner, Shomita S.; Gordillo, Gayle M.; Surgery, School of MedicineLearning objectives: After studying this article, the participant should be able to: 1. Understand the basics of biofilm infection and be able to distinguish between planktonic and biofilm modes of growth. 2. Have a working knowledge of conventional and emerging antibiofilm therapies and their modes of action as they pertain to wound care. 3. Understand the challenges associated with testing and marketing antibiofilm strategies and the context within which these strategies may have effective value. Summary: The Centers for Disease Control and Prevention estimate for human infectious diseases caused by bacteria with a biofilm phenotype is 65 percent and the National Institutes of Health estimate is closer to 80 percent. Biofilms are hostile microbial aggregates because, within their polymeric matrix cocoons, they are protected from antimicrobial therapy and attack from host defenses. Biofilm-infected wounds, even when closed, show functional deficits such as deficient extracellular matrix and impaired barrier function, which are likely to cause wound recidivism. The management of invasive wound infection often includes systemic antimicrobial therapy in combination with débridement of wounds to a healthy tissue bed as determined by the surgeon who has no way of visualizing the biofilm. The exceedingly high incidence of false-negative cultures for bacteria in a biofilm state leads to missed diagnoses of wound infection. The use of topical and parenteral antimicrobial therapy without wound débridement have had limited impact on decreasing biofilm infection, which remains a major problem in wound care. Current claims to manage wound biofilm infection rest on limited early-stage data. In most cases, such data originate from limited experimental systems that lack host immune defense. In making decisions on the choice of commercial products to manage wound biofilm infection, it is important to critically appreciate the mechanism of action and significance of the relevant experimental system. In this work, the authors critically review different categories of antibiofilm products, with emphasis on their strengths and limitations as evident from the published literature.Item Bone Morphogenetic Protein-2 Rapidly Heals Two Distinct Critical Sized Segmental Diaphyseal Bone Defects in a Porcine Model(Oxford University Press, 2023) McKinley, Todd O.; Childress, Paul; Jewell, Emily; Griffin, Kaitlyn S.; Wininger, Austin E.; Tucker, Aamir; Gremah, Adam; Savaglio, Michael K.; Warden, Stuart J.; Fuchs, Robyn K.; Natoli, Roman M.; Shively, Karl D.; Anglen, Jeffrey O.; Chu, Tien-Min Gabriel; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineIntroduction: Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. Materials and methods: Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. Results: BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P < .0001). mRUST scores increased from 8.2 (±1.1) in ORIF40 Cont to 14.3 (±1.0) in ORIF40 BMP specimens (P < .01). CT scans confirmed all BMP-2 specimens had healed and none of the control specimens had healed in both IMN and ORIF groups. BMP-2 restored 114% and 93% of intact torsional stiffness in IMN25 BMP and ORIF40 BMP specimens. Conclusions: We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.Item Clinical Features, Prognostic Factors, and Treatment Interventions for Ulceration in Patients With Infantile Hemangioma(American Medical Association, 2021) Faith, Esteban Fernández; Shah, Sonal; Witman, Patricia M.; Harfmann, Katya; Bradley, Flora; Blei, Francine; Pope, Elena; Alsumait, Anwar; Gupta, Deepti; Covelli, Isabela; Streicher, Jenna L.; Cotton, Colleen; Tollefson, Megha; Nguyen, Henry; Hunt, Raegan; Moore-Clingenpeel, Melissa; Frieden, Ilona J.; Dermatology, School of MedicineImportance: Ulceration is a common complication of infantile hemangioma (IH), which leads to substantial morbidity. Ulceration in IH has not been systematically studied since the advent of β-blocker therapy for IH. Objectives: To examine treatment interventions used for ulceration in IH and identify clinical prognostic indicators of healing time. Design, setting, and participants: A retrospective, multicenter cohort study was conducted on 436 consecutive patients with a clinical diagnosis of ulcerated IH and available clinical photographs. Patients receiving care at tertiary referral centers evaluated between 2012 and 2016 were included; statistical and data analysis were performed from February 7 to April 27, 2020. Exposures: Clinical characteristics, treatment interventions, course, complications, and resource use were analyzed. Treatment interventions for ulceration in IH included local (wound care, topical), systemic (β-blocker, corticosteroids), and procedural (pulsed-dye laser). Main outcomes and measures: The primary end point was time to complete or nearly complete ulceration healing. Clinical characteristics were analyzed to determine the responses to most common interventions and prognostic factors for healing of ulceration. Results: Of the 436 patients included in the study, 327 were girls (75.0%); median age at ulceration was 13.7 weeks (interquartile range, 8.86-21.30 weeks). The median heal time was 4.79 weeks (95% CI, 3.71-5.86 weeks) with wound care alone, 5.14 weeks (95% CI, 4.57-6.00 weeks) with timolol, 6.36 weeks (95% CI, 5.57-8.00 weeks) with a systemic β-blocker, and 7.71 weeks (95% CI, 6.71-10.14 weeks) with multimodal therapy. After adjusting for IH size, a dose of propranolol less than or equal to 1 mg/kg/d was associated with shorter healing time compared with higher propranolol doses (hazard ratio, 2.04; 95% CI, 1.11 to 3.73; P = .02). Size of the IH was identified as a significant prognostic factor for healing time in multivariable analysis. Increasing size of IH portends a proportionately longer time to heal of the ulceration. Conclusions and relevance: Despite the use of β-blockers, this cohort study found that a subset of patients with IH ulceration continued to experience prolonged IH healing times. Larger IH size appears to be a poor prognostic factor for time to heal. For patients requiring systemic therapy, initiation of propranolol at lower doses (≤1 mg/kg/d) should be considered.Item Collagen in Wound Healing(MDPI, 2021-05-11) Mathew-Steiner, Shomita S.; Roy, Sashwati; Sen, Chandan K.; Medicine, School of MedicineNormal wound healing progresses through inflammatory, proliferative and remodeling phases in response to tissue injury. Collagen, a key component of the extracellular matrix, plays critical roles in the regulation of the phases of wound healing either in its native, fibrillar conformation or as soluble components in the wound milieu. Impairments in any of these phases stall the wound in a chronic, non-healing state that typically requires some form of intervention to guide the process back to completion. Key factors in the hostile environment of a chronic wound are persistent inflammation, increased destruction of ECM components caused by elevated metalloproteinases and other enzymes and improper activation of soluble mediators of the wound healing process. Collagen, being central in the regulation of several of these processes, has been utilized as an adjunct wound therapy to promote healing. In this work the significance of collagen in different biological processes relevant to wound healing are reviewed and a summary of the current literature on the use of collagen-based products in wound care is provided.Item Computational Mechanobiology Model Evaluating Healing of Postoperative Cavities Following Breast-Conserving Surgery(bioRxiv, 2023-04-28) Harbin, Zachary; Sohutskay, David; Vanderlaan, Emma; Fontaine, Muira; Mendenhall, Carly; Fisher, Carla; Voytik-Harbin, Sherry; Buganza Tepole, Adrian; Surgery, School of MedicineBreast cancer is the most commonly diagnosed cancer type worldwide. Given high survivorship, increased focus has been placed on long-term treatment outcomes and patient quality of life. While breast-conserving surgery (BCS) is the preferred treatment strategy for early-stage breast cancer, anticipated healing and breast deformation (cosmetic) outcomes weigh heavily on surgeon and patient selection between BCS and more aggressive mastectomy procedures. Unfortunately, surgical outcomes following BCS are difficult to predict, owing to the complexity of the tissue repair process and significant patient-to-patient variability. To overcome this challenge, we developed a predictive computational mechanobiological model that simulates breast healing and deformation following BCS. The coupled biochemical-biomechanical model incorporates multi-scale cell and tissue mechanics, including collagen deposition and remodeling, collagen-dependent cell migration and contractility, and tissue plastic deformation. Available human clinical data evaluating cavity contraction and histopathological data from an experimental porcine lumpectomy study were used for model calibration. The computational model was successfully fit to data by optimizing biochemical and mechanobiological parameters through the Gaussian Process. The calibrated model was then applied to define key mechanobiological parameters and relationships influencing healing and breast deformation outcomes. Variability in patient characteristics including cavity-to-breast volume percentage and breast composition were further evaluated to determine effects on cavity contraction and breast cosmetic outcomes, with simulation outcomes aligning well with previously reported human studies. The proposed model has the potential to assist surgeons and their patients in developing and discussing individualized treatment plans that lead to more satisfying post-surgical outcomes and improved quality of life.Item Computational Mechanobiology Model Evaluating Healing of Postoperative Cavities Following Breast-Conserving Surgery(Elsevier, 2023) Harbin, Zachary; Sohutskay, David; Vanderlaan, Emma; Fontaine, Muira; Mendenhall, Carly; Fisher, Carla; Voytik-Harbin, Sherry; Buganza Tepole, Adrian; Surgery, School of MedicineBreast cancer is the most commonly diagnosed cancer type worldwide. Given high survivorship, increased focus has been placed on long-term treatment outcomes and patient quality of life. While breast-conserving surgery (BCS) is the preferred treatment strategy for early-stage breast cancer, anticipated healing and breast deformation (cosmetic) outcomes weigh heavily on surgeon and patient selection between BCS and more aggressive mastectomy procedures. Unfortunately, surgical outcomes following BCS are difficult to predict, owing to the complexity of the tissue repair process and significant patient-to-patient variability. To overcome this challenge, we developed a predictive computational mechanobiological model that simulates breast healing and deformation following BCS. The coupled biochemical-biomechanical model incorporates multi-scale cell and tissue mechanics, including collagen deposition and remodeling, collagen-dependent cell migration and contractility, and tissue plastic deformation. Available human clinical data evaluating cavity contraction and histopathological data from an experimental porcine lumpectomy study were used for model calibration. The computational model was successfully fit to data by optimizing biochemical and mechanobiological parameters through Gaussian process surrogates. The calibrated model was then applied to define key mechanobiological parameters and relationships influencing healing and breast deformation outcomes. Variability in patient characteristics including cavity-to-breast volume percentage and breast composition were further evaluated to determine effects on cavity contraction and breast cosmetic outcomes, with simulation outcomes aligning well with previously reported human studies. The proposed model has the potential to assist surgeons and their patients in developing and discussing individualized treatment plans that lead to more satisfying post-surgical outcomes and improved quality of life.Item Deficient functional wound closure as measured by elevated trans-epidermal water loss predicts chronic wound recurrence: An exploratory observational study(Springer Nature, 2024-10-09) Chattopadhyay, Debarati; Sinha, Mithun; Kapoor, Akshay; Kumar, Manoj; Singh, Kanhaiya; Mathew-Steiner, Shomita S.; Sen, Chandan K.; Surgery, School of MedicineA single-center, prospective, observational pilot study was performed to evaluate wound healing endpoint and recurrence by measuring transepidermal water loss (TEWL) post-closure at the site of wound repair. Patients with clinically-defined chronic wounds (such as pressure ulcers, diabetic ulcers, and trauma wounds) who visited the Plastic Surgery outpatient department or were in-patients at the All India Institute of Medical Sciences, Rishikesh, India, and were referred for chronic wound management, were enrolled. Non-invasive point-of-care TEWL measurements were obtained, from closed wound-site and contralateral healthy skin site, starting from confirmation of closure (post-closure, V0) continuing every 2 weeks for a maximum of five visits or until the wound recurred. Statistical analyses of the data involved logistic regression and likelihood ratio chi-square tests to assess differences in TEWL at visit 0 (V0) between the closed wound site and reference skin, with the TEWL score as the sole predictor of recurrence. Of the 72 subjects that completed the study, 44 (61%) showed no recurrence and 28 (39%) had wounds that recurred over a period of 12 weeks. A significant association was found between the V0 (post-closure) TEWL score and the odds of wound recurrence, both in univariate analysis (OR [95%CI] = 1.26[1.14,1.42] (p < 0.001) and after adjusting for covariates in multivariable analysis (OR [95%CI] = 1.34[1.19,1.61] (p < 0.001). The likelihood ratio chi-square analysis demonstrated that the V0 TEWL score is a significant universal predictor of recurrence across all wound types studied. Cases of closed wounds with subsequent recurrence showed an overall higher post-closure V0 TEWL score, compared to those who did not have a wound recurrence, across visits. The TEWL score cut-off value predictive of recurrence was 24.1 g.m-2.h-1 (AUC = 0.967). The outcome of this pilot study on a wide range of chronic wounds leads to the hypothesis that post-closure TEWL at the site of wound healing is a reliable biomarker of wound recurrence. It also raises the question whether the clinical endpoint of wound closure should include re-establishment of skin barrier function as additional criterion. The current standard of care wound closure endpoint calls for re-epithelialization of the wound with no discharge for two consecutive weeks disregarding the functional parameter of restoration of skin barrier function at the wound-site.
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