Scarring and Skin Fibrosis Reversal with Regenerative Surgery and Stem Cell Therapy.

Skin scarring and fibrosis affect millions of people worldwide, representing a serious clinical problem causing physical and psychological challenges for patients. Stem cell therapy and regenerative surgery represent a new area of treatment focused on promoting the body's natural ability to repair damaged tissue. Adipose-derived stem cells (ASCs) represent an optimal choice for practical regenerative medicine due to their abundance, autologous tissue origin, non-immunogenicity, and ease of access with minimal morbidity for patients. This review of the literature explores the current body of evidence around the use of ASCs-based regenerative strategies for the treatment of scarring and skin fibrosis, exploring the different surgical approaches and their application in multiple fibrotic skin conditions. Human, animal, and in vitro studies demonstrate that ASCs present potentialities in modifying scar tissue and fibrosis by suppressing extracellular matrix (ECM) synthesis and promoting the degradation of their constituents. Through softening skin fibrosis, function and overall quality of life may be considerably enhanced in different patient cohorts presenting with scar-related symptoms. The use of stem cell therapies for skin scar repair and regeneration represents a paradigm shift, offering potential alternative therapeutic avenues for fibrosis, a condition that currently lacks a cure.

Portable three-dimensional imaging to monitor small volume enhancement in face, vulva, and hand: A comparative study.

Multiple handheld three-dimensional (3D) systems are available on the market, but data regarding their use in detecting small volumes are limited. The aim of this study was to compare different portable 3D technologies in detecting small volumetric enhancement on a mannequin model and a series of patients. Five portable 3D systems (Artec Eva, Crisalix, Go!Scan, LifeViz Mini, and Vectra H1) were tested in a controlled environment with standardised volumes and in a clinical setting with patients undergoing small volume fat grafting to face, vulva, and hand. Accuracy was assessed with absolute and relative technical error measurement (TEM and rTEM); precision with intra- and inter-observer reliability (rp and ICC); and usability in clinical practice with the following parameters: portability, suitability of use in operating theatre/clinic, ease of use of hardware and software, speed of capture, image quality, patient comfort, and cost. All tested devices presented overall good accuracy in detecting small volumetric changes ranging from 0.5 to 4 cc. Structured-light laser scanners (Artec Eva and Go!Scan) showed high accuracy, but their use in clinical practice was limited by longer capture time, multiple wiring, and complex software for analysis. Crisalix was considered the most user-friendly, less bothering for patients, and truly portable, but its use was limited to the face because the software does not include vulva and hand. Three-dimensional technologies exploiting the principle of passive stereophotogrammetry such as LifeViz Mini and Vectra H1 were the most versatile for assessing accurately multiple body areas, representing overall the best long-term value for money. Therefore, 3D portable technology is a non-invasive, accurate, and reproducible method to assess the volumetric outcome after facial, vulval, and hand injectables. The choice of the 3D system should be based on the clinical need and resources available.

Regenerative Strategy for Persistent Periprosthetic Leakage around Tracheoesophageal Puncture: Is It an Effective Long-Term Solution?

Autologous tissue-assisted regenerative procedures have been considered effective to close different types of fistula, including the leakage around tracheoesophageal puncture. The aim of this study was to retrospectively review 10 years of lipotransfer for persistent periprosthetic leakage in laryngectomized patients with voice prosthesis. Clinical records of patients who experienced periprosthetic leakage from December 2009 to December 2019 were reviewed. Patients receiving fat grafting were included. The leakage around the prosthesis was assessed with a methylene blue test. Twenty patients experiencing tracheoesophageal fistula enlargement were treated with fat grafting. At the one-month follow-up, all patients were considered improved with no leakage observed. At six months, a single injection was sufficient to solve 75% of cases (n 15), whereas 25% (n 5) required a second procedure. The overall success rate was 80% (n 16). Results remained stable for a follow-up of 5.54 ± 3.97 years. Fat grafting performed around the voice prosthesis, thanks to its volumetric and regenerative properties, is a valid and lasting option to solve persistent periprosthetic leakage.

The usefulness of the IMAP propeller flap for trachea and tracheostome reconstruction after resection of parastomal recurrence of squamous cell carcinoma following salvage total laryngectomy.

PURPOSE: Parastomal recurrence of squamous cell carcinoma (SCC) with tracheal involvement following salvage total laryngectomy after prior concurrent chemoradiotherapy is one of the most insidious challenges in head and neck surgery because a complex reconstruction is often required for covering a large area of skin loss, filling the dead space beneath, tracheal reconstruction and suspension, and tracheostome resurfacing. The aim is to describe our experience with the internal mammary artery perforator (IMAP) propeller flap for tracheal and tracheostome reconstruction and neck resurfacing after parastomal and cervical trachea resection, especially for suspension and anchoring the stump of the residual distal trachea to the island flap itself. METHODS: We describe IMAP flap reconstruction after resection of parastomal recurrence of SCC requiring cervical trachea resection in five patients between January 1, 2005 and August 30, 2019. RESULTS: IMAP propeller flap was successfully used for reconstruction after complex resection of parastomal recurrence of SCC with cervical trachea involvement in all cases. The mean length and width were, respectively, 16.8 cm (range 13-23) and 6.9 cm (range 5.5-8). We did not report complications of both the donor and the recipient site. Pharyngo-cutaneous or tracheoesophageal fistulas and wound dehiscence were not observed. CONCLUSIONS: to the best of our knowledge, this is the first report about the use of the IMAP propeller flap in this more complex clinical setting and we provide the message that this surgical procedure is worthy of consideration.

Measuring Differential Volume Using the Subtraction Tool for Three-Dimensional Breast Volumetry: A Proof of Concept Study.

Background. Three-dimensional (3D) photography provides a promising means of breast volumetry. Sources of error using a single-captured surface to calculate breast volume include inaccurate designation of breast boundaries and prediction of the invisible chest wall generated by computer software. An alternative approach is to measure differential volume using subtraction of 2 captured surfaces. Objectives. To explore 3D breast volumetry using the subtraction of superimposed images to calculate differential volume. To assess optimal patient positioning for accurate volumetric assessment. Methods. Known volumes of breast enhancers simulated volumetric changes to the breast (n = 12). 3D photographs were taken (3dMDtorso) with the subject positioned upright at 90° and posteriorly inclined at 30°. Patient position, breathing, distance and camera calibration were standardised. Volumetric analysis was performed using 3dMDvultus software. Results. A statistically significant difference was found between actual volume and measured volumes with subjects positioned at 90° (P < .05). No statistical difference was found at 30° (P = .078), but subsequent Bland-Altman analysis showed evidence of proportional bias (P < .05). There was good correlation between measured and actual volumes in both positions (r = .77 and r = .85, respectively). Univariate analyses showed breast enhancer volumes of 195 mL and 295 mL to incur bias. The coefficient of variation was 5.76% for single observer analysis. Conclusion. Positioning the subject at a 30° posterior incline provides more accurate results from better exposure of the inferior breast. The subtraction tool is a novel method of measuring differential volume. Future studies should explore methodology for application into the clinical setting.

Development and Validation of a Clinical Grading Scale to Assess the Vulvar Region: The Vulvar Architecture Severity Scale.

BACKGROUND: The vulva is composed of aesthetic units that can be affected differently by vulvar conditions. A reliable, comprehensive, and quick-to-use clinical scoring system is required to assess the disease extent in the vulvar area. OBJECTIVES: The aim of this study was to develop and validate a grading scale based on the aesthetic unit principle to evaluate the extent of vulvar lichen sclerosus (VLS). METHODS: After reviewing photographs of 100 patients affected by VLS, the authors targeted the aesthetic units most frequently affected. The disease signs were recorded and graded in 4 levels of severity (none, mild, moderate, severe) taking into account the vulvar architecture and skin involvement. To validate the scale, 14 observers were asked to apply it to photographs of 25 VLS patients on 2 different occasions. Intra- and inter-observer reliabilities were determined employing Pearson's and intraclass correlation coefficients. RESULTS: A 6-region, 4-point grading system was designed and identified as the Vulvar Architecture Severity Scale (VASS). In all 6 areas, the Pearson's r was greater than 0.9 (mean, 0.994; 95% confidence interval [CI] = 0.992), indicating that the intra-observer reliability of the VASS was consistent over time (P < 0.001). Intraclass correlation at time 1 was 0.928 (95% CI = 0.910, 0.943) and at time 2 was 0.944 (95% CI = 0.931, 0.996), indicating a high reliability level among different observers. CONCLUSIONS: The VASS is a reliable scale to assess the severity of VLS, and it might be considered as an outcome measure in future VLS trials.

Fat Grafting Improves Fibrosis and Scarring in Vulvar Lichen Sclerosus: Results From a Prospective Cohort Study.

OBJECTIVE: The aim of the study was to evaluate the effect of lipotransfer in women presenting with fibrosis and scarring due to lichen sclerosus. MATERIALS AND METHODS: This prospective cohort study included 33 women attending the vulvar clinic of a public hospital. Patients received one lipotransfer treatment. Validated measures were used prospectively to assess the sexual function (Female Sexual Function Index, Female Sexual Distress Scale); symptoms (visual analog scale for itching, burning, soreness), pain (Pain Anxiety Symptoms Scale 20); psychological status and quality of life (Hospital Anxiety and Depression Scale, Relationship Assessment Scale, Wound Management Questionnaire Revised); physician-based disease signs (Vulvar Architecture Severity Scale). Data were analyzed using paired t test with nonparametric Wilcoxon matched-pairs signed rank test and unpaired t test with nonparametric Mann-Whitney test (Prism6 Software). RESULTS: The mean (SD) follow-up was 12.9 (3.5) months. Sexual function improved after treatment (p < .001), as well as the distress associated with sexuality (p < .0001). A significant improvement was reported in itching (p < .001), burning (p < .05), soreness (p < .001), and pain (p < .0001). Patients reported a significant improvement in romantic relationship (p < .05), anxiety (p < .0001), and depression (p < .0001). Improvement was not significant in the self-care associated with self-disgust assessment (p = .42). The clinical physician-based score showed an overall improvement in all the treated areas to lesser or greater extent. CONCLUSIONS: The use of fat grafting in lichen sclerosus is promising. Further studies are required to rule out a potential placebo effect and to better understand the underlying molecular mechanism of action.

Impact of internal mammary artery perforator propeller flap in neck resurfacing and fistula closure after salvage larynx cancer surgery: Our experience.

BACKGROUND: Salvage total laryngectomy (TL) and laryngopharyngectomy (LP) after chemoradiotherapy may produce disfiguring defects with severe complications that require complex reconstructions. METHODS: Between January 2012 and December 2018, we enrolled 25 patients who underwent internal mammary artery perforator (IMAP) flap reconstruction after salvage TL or LP. We performed retrospective review of clinical charts to collect information such as history, timing of reconstruction, type of defect, follow-up, donor and recipient site complications, and overall flap survival (OFS) rate. Three years overall survival (OS), relapse-free survival (RFS), and disease-specific survival (DSS) were calculated. RESULTS: The OFS rate was 95%. One partial flap necrosis was recorded. No donor-site complications were found. The mean follow-up was 18 months. Three years OS was 44%, RFS was 47%, and DSS was 54%. CONCLUSIONS: IMAP flap appears to be safe, versatile, and easy to harvest, with minimal donor site morbidity. It is a reliable option in Head&Neck reconstruction, in salvage surgery as well.

Evaluation of the efficacy of lipotransfer to manage radiation-induced fibrosis and volume defects in head and neck oncology.

BACKGROUND: Multimodality treatment for head and neck cancer leads to substantial functional and esthetic impairment mainly manifested as radiation-induced skin fibrosis (RIF) in combination with volumetric defects and reduction in neck mobility. This study assessed the impact of lipotransfer as part of secondary surgical procedure(s) in patients treated for head and neck malignancies. METHODS: Retrospective analysis was performed between 2005 and 2016. All patients with a history of head and neck malignancy, multimodal treatment including at least surgery or radiotherapy, and at least 2-year disease-free survival were included. Thirty-eight patients (22 men, 16 women) matched the inclusion criteria. RESULTS: Thirty seven (97%) reported esthetic and functional improvements in their RIF and volumetric defect at follow-up of 32 months. Major improvement in esthetic and functional outcome was reported by 24 (63%) patients and surgeons and minor by 13 patients and surgeons (34%) without causing any complications. Lipotransfer was also found to significantly improve patient's psychological health postoperatively as showed by significant improvements in Derriford Appearance Scale (DAS24), Short Form Health Survey (SF-36), and University of Washington Quality of Life Questionnaire (UW-QOL V4) scores (P < .001). CONCLUSIONS: Lipotransfer is effective for volume restoration and treating scar and RIF from head and neck defects.

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis.

Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- ß1 (TGF ß-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-ß1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-ß (PDGF-ß) and Integrin Subunit Beta 6 (ITG-ß6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-ß1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.

Characteristics and Immunomodulating Functions of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells Across Defined Human Leukocyte Antigen Barriers.

BACKGROUND: Vascularized composite allotransplantation opens new possibilities in reconstructive transplantation such as hand or face transplants. Lifelong immunosuppression and its side-effects are the main drawbacks of this procedure. Mesenchymal stem cells (MSCs) have clinically useful immunomodulatory effects and may be able to reduce the burden of chronic immunosuppression. Herein, we assess and compare characteristics and immunomodulatory capacities of bone marrow- and adipose tissue-derived MSCs isolated from the same human individual across defined human leukocyte antigen (HLA) barriers. MATERIALS AND METHODS: Samples of omental (o.) adipose tissue, subcutaneous (s.c.) adipose tissue, and bone marrow aspirate from 10 human organ donors were retrieved and MSCs isolated. Cells were characterized by flow cytometry and differentiated in three lineages: adipogenic, osteogenic, and chondrogenic. In mixed lymphocyte reactions, the ability of adipose-derived mesenchymal stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BMSCs) to suppress the immune response was assessed and compared within individual donors. HLA mismatched or mitogen stimulations were analyzed in co-culture with different MSC concentrations. Supernatants were analyzed for cytokine contents. RESULTS: All cell types, s.c.ASC, o.ASC, and BMSC demonstrated individual differentiation potential and cell surface markers. Immunomodulating effects were dependent on dose and cell passage. Proliferation of responder cells was most effectively suppressed by s.c.ASCs and combination with BMSC resulted in highly efficient immunomodulation. Immunomodulation was not cell contact-dependent and cells demonstrated a specific cytokine secretion. CONCLUSION: When human ASCs and BMSCs are isolated from the same individual, both show effective immunomodulation across defined HLA barriers in vitro. We demonstrate a synergistic effect when cells from the same biologic system were combined. This cell contact-independent function underlines the potential of clinical systemic application of MSCs.

Adipose stem cells enhance excisional wound healing in a porcine model.

BACKGROUND: Adipose-derived stem cells (ASCs) are capable of secreting regenerative growth factors and replacing multiple tissue types. Although current literature suggests that ASCs accelerate wound healing and reduce scarring, the dose-response relationship has not been adequately investigated in large animals. We sought to establish a porcine model to optimize dose and delivery. METHODS: Four-centimeter circular, full thickness excisional wounds were created on the backs of Yorkshire pigs. Fluorescently labeled allogeneic porcine ASCs were injected into the superficial wound bed and around the wound perimeter at high (3.0 × 106 cells/cm2; n = 8), medium (1.0 × 106 cells/cm2; n = 8), and low (0.3 × 106 cells/cm2; n = 8) doses. Control wounds received saline injections (n = 8) or no treatment (n = 8). Dressings were changed twice per week, and wound closure was tracked by surface area tracing. Animals were sacrificed at 1 and 2 wk. Wounds were harvested for real-time quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and ASC tracking. RESULTS: Labeled ASCs integrated into treated wounds by 1 wk in a dose-dependent fashion. Epithelial coverage was achieved by 14 d in all wounds. Wounds receiving high-dose ASCs exhibited thicker granulating neodermis at 7 d and greater wound contraction at 14 d. real-time quantitative reverse transcriptase polymerase chain reaction revealed improved collagen 1:collagen 3 (Col1:Col3) ratio in the medium-dose group and enhanced α-smooth muscle actin in the high-dose group at 14 d. Western blot demonstrated increased cluster of differentiation 31 protein at 2 wk in wounds receiving >106 cells/cm2. CONCLUSIONS: Doses up to 3.0 × 106 cells/cm2 were well-tolerated. High-dose ASCs accelerate wound contraction, enhance neovascularization, and may improve scar quality in excisional wounds healing by secondary intention. Doses greater than those previously used may be necessary to achieve desired effects.

Use of Lipotransfer in Scleroderma.

Lipotransfer for soft tissue filling is a well-established plastic and aesthetic surgical technique. Elective fat grafting is considered a safe and well-tolerated procedure. Coleman and others have reported that fat grafting may have tissue regenerative properties and not only serve as a soft tissue filler. There have been reports from our group and others that it may improve fibrosis secondary to many different pathological aetiologies including scleroderma, burn injury, lichen sclerosis, graft vs host disease, and radiation. The mechanism of action remains unclear but has been postulated that is adipose derived stem cells (ADSCs) related. Lipoaspirate has been characterised and shown to contain several cell populations including fibroblasts, endothelial cells, and ADSCs. The ADSCs have shown to secrete angiogenic, immunodulatory, and antiapoptotic factors as well as proliferate and differentiate into different cell types similarly to other stem cell sources. We have shown that ADSCs are functionally different in scleroderma patients but despite this lipotransfer produces a significant reversal in the effects of fibrosis in these patients. The advantage of lipoaspirate containing a valuable source of regenerative properties, ease of access, isolation, and processing may serve a significant future role in the treatment of fibrotic conditions.

Management of complication after breast augmentation with methacrylate.

INTRODUCTION: Several alloplastic biomaterials are available for injection to the breast, nevertheless not all of them are approved for biomedical use. Although in North America and Western Europe experience with synthetic biomaterials for breast augmentation is very limited, migratory streams might expose physicians worldwide to manage the related complications of these procedures. The aim of this study was to share with other surgeons the case of a patient presenting complications after breast augmentation with an unknown synthetic substance containing methacrylate. PRESENTATION OF CASE: A 33-years old Asian woman presented to our Institution with breast deformities, lumps and chest pain. The patient referred previous breast injection "with hospital fat" performed in China six years before. She was not aware about the details of the procedure, and language barriers limited communication. Clinical examination and ultrasounds revealed the irregular distribution of an unknown substance in both breasts. The material was surgically removed and replaced in the same session with polyurethane implants. Chemical analysis revealed the presence of methacrylate. DISCUSSION: With a growing demand for non-invasive cosmetic surgery, has been reported a growing population of untrained and unlicensed personnel performing cosmetic surgery in many countries where there are no laws that restrict the use of cosmetic procedures to physicians with appropriate training and with approved materials. Surgical removal of this substances can be extremely challenging and an open procedure with surgical debridement is recommended. CONCLUSION: Breast augmentation with non-absorbable biomaterials can lead to severe complications, in particular for patients intending to breastfeed.

Platelet-rich plasma mixed-fat grafting: a reasonable prosurvival strategy for fat grafts?

BACKGROUND: One of the most interesting developments in practical applications of fat grafting in recent years is the use of prosurvival strategies to improve maintenance of volume. Platelet-rich plasma (PRP) plays a decisive role in the repair and regeneration of different tissues via the activation and secretion of a great variety of growth factors and other cytokines stored in the alpha-granules of the platelets. This review aimed to assess the efficacy of PRP mixed-fat grafting as a prosurvival strategy for fat grafts. METHODS: Online searches of the Cochrane Library and MEDLINE until January 2014 were conducted. The review included studies with at least one clinical end point in which the effect of PRP on the absorption and viability of the fat graft could be assessed. RESULTS: The review comprised 6 preclinical studies with a control group and 9 clinical studies of humans. It also included comparative studies performed with other prosurvival strategies for fat grafts, such as combination with the stromal vascular fraction and second-generation PRP, also called "platelet-rich fibrin." The results indicate that PRP may have a dose-dependent positive effect on fat grafts and suggest low complication rates. CONCLUSIONS: The development of new growth factor delivery systems or cell therapies to enrich fat grafts is an area that merits further research.

Health care for immigrant women in Italy: are we really ready? A survey on knowledge about female genital mutilation.

BACKGROUND: Because of immigration, female genital mutilation (FGM) is an issue of increasing concern in western countries. Nevertheless operators without a specific training may ignore the health condition of women subjected to this practice and fail to provide them adequate assistance. The purpose of the study was to estimate the current knowledge about FGM among social and health care assistants working with asylum seeker. MATERIAL AND METHODS: From October to December 2012, a questionnaire was used to interview 41 operators working in CARA (Shelter for Refugees and Asylum Seekers) in central and southern Italy. RESULTS: Only 7.3% of respondents states to know well FGM, while 4.9% do not know it at all. 70.7% declare to have never met or assisted a woman with FGM, nevertheless all respondents work with asylum seeker from countries where FGM are performed. CONCLUSIONS: Migration fluxes to Italy over the past decade created a healthcare challenge: women with FGM have specific medical and psychological problems that doctors, nurses and social assistants without specific training are not usually able to manage.