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Significance: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis (RIF) of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations and esthetic concerns and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for RIF of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and esthetic outcomes, and even as prophylaxis for RIF. Recent Advances: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of RIF. The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy. Critical Issues: Various animal models of RIF demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood. Future Directions: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through (1) augmentation of fat grafts with platelet-rich plasma and (2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.

Topical patch delivery of deferoxamine (DFO) has been studied as a treatment for this fibrotic transformation in irradiated tissue. Efficacy of a novel cream formulation of DFO was studied as a RIF therapeutic in unwounded and excisionally wounded irradiated skin. C57BL/6J mice underwent 30 Gy of radiation to the dorsum followed by 4 weeks of recovery. In a first experiment, mice were separated into six conditions: DFO 50 mg cream (D50), DFO 100 mg cream (D100), soluble DFO injections (DI), DFO 1 mg patch (DP), control cream (Vehicle), and irradiated untreated skin (IR). In a second experiment, excisional wounds were created on the irradiated dorsum of mice and then divided into four treatment groups: DFO 100 mg Cream (W-D100), DFO 1 mg patch (W-DP), control cream (W-Vehicle), and irradiated untreated wounds (W-IR). Laser Doppler perfusion scans, biomechanical testing, and histological analysis were performed. In irradiated skin, D100 improved perfusion compared to D50 or DP. Both D100 and DP enhanced dermal characteristics, including thickness, collagen density and 8-isoprostane staining compared to untreated irradiated skin. D100 outperformed DP in CD31 staining, indicating higher vascular density. Extracellular matrix features of D100 and DP resembled normal skin more closely than DI or control. In radiated excisional wounds, D100 facilitated faster wound healing and increased perfusion compared to DP. The 100 mg DFO cream formulation rescued RIF of unwounded irradiated skin and improved excisional wound healing in murine skin relative to patch delivery of DFO., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: A significant gap exists in the translatability of small-animal models to human subjects. One important factor is poor laboratory models involving human tissue. Thus, the authors have created a viable postnatal human skin xenograft model using athymic mice., Methods: Discarded human foreskins were collected following circumcision. All subcutaneous tissue was removed from these samples sterilely. Host CD-1 nude mice were then anesthetized, and dorsal skin was sterilized. A 1.2-cm-diameter, full-thickness section of dorsal skin was excised. The foreskin sample was then placed into the full-thickness defect in the host mice and sutured into place. Xenografts underwent dermal wounding using a 4-mm punch biopsy after engraftment. Xenografts were monitored for 14 days after wounding and then harvested., Results: At 14 days postoperatively, all mice survived the procedure. Grossly, the xenograft wounds showed formation of a human scar at postoperative day 14. Hematoxylin and eosin and Masson trichome staining confirmed scar formation in the wounded human skin. Using a novel artificial intelligence algorithm using picrosirius red staining, scar formation was confirmed in human wounded skin compared with the unwounded skin. Histologically, CD31 + immunostaining confirmed vascularization of the xenograft. The xenograft exclusively showed human collagen type I, CD26 + , and human nuclear antigen in the human scar without any staining of these human markers in the murine skin., Conclusion: The proposed model demonstrates wound healing to be a local response from tissue resident human fibroblasts and allows for reproducible evaluation of human skin wound repair in a preclinical model., Clinical Relevance Statement: Radiation-induced fibrosis is a widely prevalent clinical phenomenon without a well-defined treatment at this time. This study will help establish a small-animal model to better understand and develop novel therapeutics to treat irradiated human skin., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: As visibility of the transgender patient population and utilization of online resources increases, it is imperative that web-based gender-affirming surgery (GAS) materials for patients are readable, accessible, and of high quality., Methods: A search trends analysis was performed to determine frequency of GAS-related searches over time. The top 100 most common results for GAS-related terms were analyzed using six readability formulas. Accessibility of patient-facing GAS sources was determined by categorizing types of search results. Frequency of article types was compared in low- and high-population dense areas. Quality was assigned to GAS web-based sources using the DISCERN score., Results: Search engine trend data demonstrates increasing occurrence of searches related to GAS. Readability scores of the top 100 online sources for GAS were discovered to exceed recommended levels for patient proficiency. Availability of patient-facing online information related to GAS was found to be 60%, followed by information provided by insurance companies (17%). Differences in availability of online resources in varying dense cities were found to be minimal. The average quality of sources determined by the DISCERN score was found to be 3, indicating "potential important shortcomings.", Conclusions: Despite increasing demand for web-based GAS information, the readability of online resources related to GAS was found to be significantly greater than the grade level of proficiency recommended for patients. A high number of nonpatient-facing search results appear in response to GAS search terms. Quality sources are still difficult for patients to find, as search results have a high incidence of low-quality resources., Competing Interests: All authors declared that there are no conflicts of interest. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Wound dehiscence, oftentimes a result of the poor tensile strength of early healing wounds, is a significant threat to the post-operative patient, potentially causing life-threatening complications. Vanadate, a protein tyrosine phosphatase inhibitor, has been shown to alter the organisation of deposited collagen in healing wounds and significantly improve the tensile strength of incisional wounds in rats. In this study, we sought to explore the effects of locally administered vanadate on tensile strength and collagen organisation in both the early and remodelling phases of excisional wound healing in a murine model. Wild-type mice underwent stented excisional wounding on their dorsal skin and were divided equally into three treatment conditions: vanadate injection, saline injection control and an untreated control. Tensile strength testing, in vivo suction Cutometer analysis, gross wound measurements and histologic analysis were performed during healing, immediately upon wound closure, and after 4 weeks of remodelling. We found that vanadate treatment significantly increased the tensile strength of wounds and their stiffness relative to control wounds, both immediately upon healing and into the remodelling phase. Histologic analysis revealed that these biomechanical changes were likely the result of increased collagen deposition and an altered collagen organisation composed of thicker and distinctly organised collagen bundles. Given the risk that dehiscence poses to all operative patients, vanadate presents an interesting therapeutic avenue to improve the strength of post-operative wounds and unstable chronic wounds to reduce the risk of dehiscence., (© 2022 The Wound Healing Society.)

Objective: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to improve these soft tissue defects through the promotion of adipogenesis. These matrices are decellularized by a combination of physical, chemical, and enzymatic methods to minimize their immunologic effects while promoting their regenerative effects. In this study, we aimed at exploring the regenerative ability of a DAM (renuva ® ; MTF biologics, Edison, NJ) in radiation-induced soft tissue injury. Approach: Fresh human lipoaspirate or DAM was injected into the irradiated scalp of CD-1 nude mice, and volume retention was monitored radiographically over 8 weeks. Explanted grafts were histologically assessed, and overlying skin was examined histologically and biomechanically. Irradiated human skin was also evaluated from patients after fat grafting or DAM injection. However, integrating data between murine and human skin in all cohorts is limited given the genetic variability between the two species. Results: Volume retention was found to be greater with fat grafts, though DAM retention was, nonetheless, appreciated at irradiated sites. Improvement in both mouse and human irradiated skin overlying fat and DAM grafts was observed in terms of biomechanical stiffness, dermal thickness, collagen density, collagen fiber networks, and skin vascularity. Innovation: This is the first demonstration of the use of DAMs for augmenting the regenerative potential of irradiated mouse and human skin. Conclusions: These findings support the use of DAMs to address soft tissue atrophy after radiation therapy. Morphological characteristics of the irradiated skin can also be improved with DAM grafting.

Significance: Skin inevitably heals with the formation of a fibrotic scar. Patients affected by skin scarring suffer from long-term psychological and physical burdens. Recent Advances: Since the discovery of fetal scarless skin-wound healing, research has hoped to identify and mimic scarless healing for adult skin. Oral mucosa healing in adults provides the closest example to fetal scarless healing. Injuries to the oral mucosa heal with very minimal scarring. Understanding the mechanisms through which this process occurs may bring us closer to achieving scarless healing in adults. Critical Issues: In this review, we summarize the current evidence that illustrates distinct mechanisms involved in oral mucosal healing. We discuss the role of the oral niche in contributing to wound repair. The intrinsic properties of immune cells, fibroblasts, and keratinocytes within the oral mucosa that support regenerative repair are provided. We highlight the contribution of cytokines, growth factors, and chemokine secretion in permitting a scarless mucosal environment. Furthermore, we discuss the role of stem cell-like progenitor populations in the mucosa that may contribute to wound healing. We also provide suggestions for future studies that are needed to achieve scarless healing in adults. Future Directions: Many characteristics of the oral mucosa have been shown to contribute to decreased scarring, but the specific mechanism(s) is unclear. Advancing our understanding of oral healing may yield therapeutic therapies that can be used to overcome dermal scarring.

Background: Treatments for radiation-induced fibrosis range from vitamin E (VE) and pentoxifylline (PTX) systemically to deferoxamine and fat grafting locally. Regarding fat grafting, volume retention hinders its long-term functionality and is affected by 2 factors: inflammation and necrosis secondary to hypovascularity., Objective: The authors aimed to simultaneously improve fat graft retention and radiation-induced fibrosis by integrating VE and PTX into fat grafts locally., Methods: Forty adult CD-1 nude male mice, 6 weeks old, underwent scalp irradiation and recovered for 4 weeks to allow for development of fibrosis. Mice received 200 μL of donor human fat graft to the scalp. Mice were separated into 4 conditions: no grafting, fat graft without treatment, graft treated with PTX, and graft treated with VE. Fat graft volume retention was monitored in vivo with micro-computed tomography scans at weeks 0, 1, 2, 4, 6, and 8 after grafting. Histological and cytokine analysis of the scalp skin and fat grafts were performed., Results: VE-treated grafts had significant improvement in dermal thickness and collagen density of overlying skin compared with all other groups. VE decreased 8-isoprostane and increased CD31+ staining compared with the other grafted groups. Cytokine analysis revealed decreased inflammatory and increased angiogenic markers in both the fat graft and overlying skin of the VE group. Fat graft volume retention was significantly improved in the VE group starting at 1 week post grafting., Conclusions: Radiation-induced fibrosis and fat graft volume retention are both simultaneously improved with local administration of VE., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin., Methods: Wild-type mice received 30 Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions., Results: Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds., Conclusion: Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy., (© 2022. The Author(s).)

Objective: Skin fibrosis places an enormous burden on patients and society, but disagreement exists over methods to quantify severity of skin scarring. A suction cutometer measures skin elasticity in vivo , but it has not been widely adopted because of inconsistency in data produced. We investigated variability of several dimensionless parameters generated by the cutometer to improve their precision and accuracy. Approach: Twenty adult human subjects underwent suction cutometer measurement of normal skin (NS) and fibrotic scars (FS). Using Mode 1, each subject underwent five trials with each trial containing four curves. R0/2/5/6/7 and Q1/2/3 data were collected. Analyses were performed on these calculated parameters. Results: R0/2/5/6/7 and Q1/2 parameters from curves 1 to 4 demonstrated significant differences, whereas these same parameters were not significantly different when only using curves 2-4. Individual analysis of all parameters between curve 1 and every subsequent curve was statistically significant for R0, R2, R5, R6, R7, Q1, and Q2. No differences were appreciated for parameter Q3. Comparison between NS and FS were significantly different for parameters R5, Q1, and Q3. Innovation: Our study is the first demonstration of accurate comparison between NS and FS using the dimensionless parameters of a suction cutometer. Conclusions: Measured parameters from the first curve of each trial were significantly different from subsequent curves for both NS and FS. Precision and reproducibility of data from dimensionless parameters can therefore be improved by removing the first curve. R5, Q1, and Q3 parameters differentiated NS as more elastic than FS.

Objective: Mandibular distraction osteogenesis (MDO) is frequently performed to address airway obstruction in patients with Pierre Robin sequence (PRS), though more recently the technique of orthodontic airway plating (OAP) has gained traction. We aimed to evaluate OAP compared to MDO for airway obstruction in PRS., Design: A systematic literature search across PubMed, Embase, and Google Scholar identified all studies published in English, which involved MDO or any form of OAP as treatments for PRS. All relevant articles were reviewed in detail and reported on, adhering to PRISMA guidelines., Main Outcome Measures: Airway (tracheostomy avoidance, decannulation rate), feeding (full oral feeding tolerance)., Results: Literature search identified 970 articles, of which 42 MDO studies and 9 OAP studies met criteria for review. A total of 1159 individuals were treated with MDO, and 322 individuals were treated with OAP. Primary outcomes appear similar for MDO and OAP at face value; however, this must be interpreted with different pretreatment contexts in mind., Conclusions: Orthodontic airway plating may be considered for airway obstruction in PRS, as some airway-related and feeding-related outcomes appear similar with MDO, per existing evidence in the literature. However, since PRS severity differed between studies, OAP cannot be uniformly considered a replacement for MDO. Further research is required to more comprehensively assess these treatment modalities inclusive of metrics that allow for direct comparison.

Objective: It is important for health care education materials to be easily understood by caretakers of children requiring craniofacial surgery. This study aimed to analyze the readability of Google search results as they pertain to "Cleft Palate Surgery" and "Palatoplasty." Additionally, the study included a search from several locations globally to identify possible geographic differences., Design: Google searches of the terms "Cleft Palate Surgery" and "Palatoplasty" were performed. Additionally, searches of only "Cleft Palate Surgery" were run from several internet protocol addresses globally., Main Outcome Measures: Flesch-Kincaid Grade Level and Readability Ease, Gunning Fog Index, Simple Measure of Gobbledygook (SMOG) index, and Coleman-Liau Index., Results: Search results for "Cleft Palate Surgery" were easier to read and comprehend compared to search results for "Palatoplasty." Mean Flesch-Kincaid Grade Level scores were 7.0 and 10.11, respectively ( P = .0018). Mean Flesch-Kincaid Reading Ease scores were 61.29 and 40.71, respectively ( P = .0003). Mean Gunning Fog Index scores were 8.370 and 10.34, respectively ( P = .0458). Mean SMOG Index scores were 6.84 and 8.47, respectively ( P = .0260). Mean Coleman-Liau Index scores were 12.95 and 15.33, respectively ( P = .0281). No significant differences were found in any of the readability measures based on global location., Conclusions: Although some improvement can be made, craniofacial surgeons can be confident in the online information pertaining to cleft palate repair, regardless of where the search is performed from. The average readability of the top search results for "Cleft Palate Surgery" is around the seventh-grade reading level (US educational system) and compares favorably to other health care readability analyses.

Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy., (© 2021 John Wiley & Sons Ltd.)

The iron chelator, deferoxamine (DFO), has been shown to potentially improve dermal radiation-induced fibrosis (RIF) in mice through increased angiogenesis and reduced oxidative damage. This preclinical study evaluated the efficacy of two DFO administration modalities, transdermal delivery and direct injection, as well as temporal treatment strategies in relation to radiation therapy to address collateral soft tissue fibrosis. The dorsum of CD-1 nude mice received 30 Gy radiation, and DFO (3 mg) was administered daily via patch or injection. Treatment regimens were prophylactic, during acute recovery, post-recovery, or continuously throughout the experiment (n = 5 per condition). Measures included ROS-detection, histology, biomechanics and vascularity changes. Compared with irradiated control skin, DFO treatment decreased oxidative damage, dermal thickness and collagen content, and increased skin elasticity and vascularity. Metrics of improvement in irradiated skin were most pronounced with continuous transdermal delivery of DFO. In summary, DFO administration reduces dermal fibrosis induced by radiation. Although both treatment modalities were efficacious, the transdermal delivery showed greater effect than injection for each temporal treatment strategy. Interestingly, the continuous patch group was more similar to normal skin than to irradiated control skin by most measures, highlighting a promising approach to address detrimental collateral soft tissue injury following radiation therapy., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)