Transgenic skin biomechanical properties following first lifesaving epidermal regeneration using combined gene and cell therapy.

BACKGROUND: In 2017, we reported the first life-saving regeneration of virtually an entire epidermis by combined gene and stem cell therapy. Recently, we demonstrated excellent long-term stability of this transgenic epidermis. Skin quality in this experimental approach and its potential application in other conditions were elucidated here regarding long-term outcomes of biomechanical properties. PATIENTS AND METHODS: Analysis of biomechanical properties including skin elasticity, anisotropy and friction was performed on multiple body sites 24, 36 and 60 months following transplantation. Firstly, the sites were matched against and compared to remaining stable non-transgenic areas as well as to a control group of 13 healthy subjects. Parameters for skin elasticity, deformation and friction were assessed non-invasively. RESULTS: Biomechanical properties of the transgenic epidermis showed encouraging results in comparison to both the remaining stable non-transgenic skin as well as healthy controls. Skin elasticity was comparable to the controls. Skin friction showed some decrease in both transgenic and non-transgenic areas as compared to the controls. CONCLUSIONS: The excellent functional outcomes of the transgenic epidermis demonstrate stable long-term results of this novel combined gene and stem cell therapy for epidermal regeneration. Thus, other applications for this technology, such as treatment of specific burns, should be explored.

Characteristics and Patient Reported Outcome Measures in Lipedema Patients-Establishing a Baseline for Treatment Evaluation in a High-Volume Center.

Lipedema patients suffer not only from visual stigma but also reduction in their quality of life through pain and performance loss in daily life. In clinical practice, it is still difficult to reliably diagnose the disease. This study aims to provide further insights into the characteristics of lipedema patients of all stages and provide a baseline prior to surgery for a surgical treatment evaluation by means of patient-reported outcome measures. METHODS: Patients completed a lipedema-specific questionnaire containing 50 items, the World Health Organization Quality of Life BREF (WHOQOL-BREF) and the Patient Health Questionnaire 9 (PHQ-9). The data were analyzed using SPSS statistics 27. Patients who had already received liposuction were excluded. RESULTS: Five hundred and eleven patients were included, of whom 337 completed the PHQ9 and 333 completed the WHOQOL-BREF questionnaires. The general characteristics of lipedema patients, especially the daily symptoms, are described. Previous observations, such as the frequent occurrence of hypothyroidism and the low rate of type 2 diabetes, were confirmed. Over 49% suffer from severe impairments in their jobs, whereby the disease shows a familial accumulation. The results of the WHOQOL-BREF and the PHQ-9 suggest a high level of mental stress. DISCUSSION: As surgical intervention in lipedema patients is gaining traction, its effects should be well-documented. Therefore, a comprehensive baseline needs to be established prior to surgical treatment. The psychological components are just as important as the inclusion of daily impairments.

Geographical differences in carpometacarpal joint osteoarthritis treatment of the thumb: A survey of 1138 hand surgeons from the USA and Europe.

BACKGROUND: Carpometacarpal osteoarthritis of the thumb (CMC OA) is treated with various therapeutic approaches. However, the literature remains inconclusive regarding the ideal procedure for each disease stage. In this study, we assessed the international application of surgical treatment options including CMC I implants and non-surgical treatment options for CMC OA depending on the disease stage, with a strong focus on the detection of geographical disparities. METHODS: We conducted a large international online survey with members of hand surgical societies of the International Federation of Societies for Surgery of the Hand (IFSSH). The first part of the survey asked about general therapy options of CMC OA depending on the severity of the disease, whereas the second part specifically dealt with the use of prostheses. RESULTS: We could include 10 of 56 IFSSH member societies (6807 surgeons) and received answers from 1138 members (16.7%). Significant differences were detected in an increased use of corticosteroid injections in the USA, and a growing frequency of fat injections in Europe. Regarding use and frequency of the resection arthroplasty, we found similar results in all participating countries. Prosthetic implantation showed a significant difference between the USA and Europe, with far larger numbers stated by European hand surgeons. CONCLUSION: CMC OA is treated differently in the participating countries depending on the stage of the disease. We give an insight into geographical differences in treatment paradigms, with corticosteroid injections being more prevalent in the USA, and prosthesis implantation being more frequently chosen in the selected European countries.

Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation.

BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts. OBJECTIVES: The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo. METHODS: We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis. RESULTS: In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses. CONCLUSIONS: The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.

The Usage of Pedicled or Free Muscle Flaps Represents a Beneficial Approach for Periprosthetic Infection After Knee Arthroplasty.

INTRODUCTION: Periprosthetic joint infection (PJI) is a severe complication after a total knee replacement that is primarily associated with soft tissue defects. Finding an appropriate therapy for PJI is a major challenge because of the lack of guidelines and research comparing treatment options. METHODS: In this study, we retrospectively compared 78 patients who had a knee prosthetic infection within a mean follow-up period of 24 months. Group A received a soft tissue coverage in addition to orthopedic surgical therapy with or without a component replacement (CR) of the prosthesis. Group B received the same orthopedic treatment without plastic surgery for soft tissue coverage. RESULTS: Only 21% of the patients in group A received a CR compared with 70% in group B (P = 0.0001). In group A, 83% did not have a recurrent infection, and in group B, 57% of the patients had no further infection and regained joint function (P = 0.0376). In group A, only 15% of the patients who received a CR had a significant complication within the follow-up period of 2 years, whereas in group B, 75% of patients exhibiting a major complication (P = 0.0048*). CONCLUSIONS: Soft tissue coverage improves the outcome after PJI of the knee with soft tissue defects. Patients who simultaneously needed plastic surgery for defect coverage and orthopedic surgery for CR had the lowest number of complications overall. Based on the results of this study, a therapy algorithm could be identified considering the soft tissue defect grade leading to the lowest major complication rates and maximizing the outcome of knee prosthesis infection therapies.

Polydioxanone Threads for Facial Rejuvenation: Analysis of Quality Variation in the Market.

BACKGROUND: Beside botulinum-toxin injections and hyaluronic acid fillers, thread lifts have established themselves as the third column of minimally invasive facial rejuvenation. Most commonly, barbed threads for this approach are made out of polydioxanone, a material known for decades from application in resorbable sutures. The clinical efficacy and the putative material safety of polydioxanone have fueled the popularity of thread lifts. METHODS: The present study highlights significant variation among six commercially available threads in microstructure, tensile strength, elasticity, anchoring capacity in human tissue, and biocompatibility. RESULTS: Despite their license to be marketed and sold in the European Union, some products performed significantly worse than others on material testing, and even displayed cytotoxic characteristics. CONCLUSION: The results of this study are highly relevant for clinicians and may be linked to various typical side effects of polydioxanone threads for facial rejuvenation.

New Insights on Lipedema: The Enigmatic Disease of the Peripheral Fat.

BACKGROUND: Although a large number of adult women worldwide are affected by lipedema, the physiologic conditions triggering onset and progression of this chronic disease remain enigmatic. In the present study, a descriptive epidemiologic situation of postoperative lipedema patients is presented. METHODS: The authors developed an online survey questionnaire for lipedema patients in Germany. The survey was conducted on 209 female patients who had been diagnosed with lipedema and had undergone tumescent liposuction. RESULTS: Most of the participants (average age, 38.5 years) had noticed a first manifestation of the disease at the age of 16. It took a mean of 15 years to accomplish diagnosis. Liposuction led to a significant reduction of pain, swelling, tenderness, and easy bruising as confirmed by the majority of patients. Hypothyroidism [n = 75 (35.9 percent) and depression [n = 48 (23.0 percent)] occurred at a frequency far beyond the average prevalence in the German population. The prevalence of diabetes type 1 [n = 3 (1.4 percent)], and diabetes type 2 [n = 2 (1 percent)] was particularly low among the respondents. Forty-seven of the lipedema patients (approximately 22.5 percent) suffered from a diagnosed migraine. Following liposuction, the frequency and/or intensity of migraine attacks became markedly reduced, as stated by 32 patients (68.1 percent). CONCLUSIONS: Quality of life increases significantly after surgery with a reduction of pain and swelling and decreased tendency to easy bruising. The high prevalence of hypothyroidism in lipedema patients could be related to the frequently observed lipedema-associated obesity. The low prevalence of diabetes, dyslipidemia, and hypertension appears to be a specific characteristic distinguishing lipedema from lifestyle-induced obesity.

The impact of repetitive oocyte retrieval on the ovarian reserve: a retrospective cohort study.

PURPOSE: To investigate a possible influence of repetitive micro-traumata on the ovaries in the course of oocyte retrieval during IVF/ICSI treatment on serum anti-Müllerian hormone (AMH) levels. METHODS: The study included retrospectively collected data from women who underwent three or more consecutive IVF/ICSI treatments between 2007 and 2017. The primary endpoint of the study was to evaluate changes in serum AMH levels on cycle days 1-3 during the course of repetitive IVF/ICSI treatments. RESULTS: A total of 125 patients were included in this study. Median AMH levels before the first, second and third IVF/ICSI cycles were 3.8 ng/mL (IQR 1.8-7.1), 3.3 ng/mL (IQR 1.8-6.1) and 3.0 ng/mL (IQR 1.6-5.3), respectively (p = n.s.). In patients who underwent IVF/ICSI due to polycystic ovary syndrome (PCOS), we found a significant decrease in AMH serum levels between the first [AMH 9.7 ng/mL (IQR 7.4-14.4)] and the third [AMH 5.3 ng/mL (IQR 3.3-10.4)] IVF/ICSI cycles (p = 0.026). When performing a generalized linear model, we found PCOS to be an independent predictor for serum AMH decrease during the course of three oocyte retrievals (p < 0.001). CONCLUSIONS: When comparing the indications for IVF/ICSI, we observed a significant decrease in AMH serum levels after repetitive oocyte retrievals only in women with PCOS, while the decrease in AMH was not significant in patients with tubal factor, endometriosis, male factor and unexplained infertility. This finding leads us to hypothesize that repetitive micro-traumata on the ovarian cortex might diminish/normalize functional ovarian reserve in women with PCOS. Further prospective studies are highly warranted to allow firm conclusions.

Lipofilling of Fingertips for Volume Defects after Fingertip Injuries.

INTRODUCTION: Regardless of the good outcomes of conservatively treated fingertip injuries, many patients complain about volume defects and hypoesthesia. Injection of autologous fat into the defect zone may resolve the volume problem and stimulate digital nerve regeneration by adipose derived stem cell transplantation. METHODS: We analyzed 5 volume defects resulting from conservatively treated fingertip injuries in 4 patients (male to female ratio, 2:2), 6 months after the injection of autologous abdominal fat into the defect zone retrospectively. The fat transplantation was performed after complete wound healing was achieved (2.5-13.5 months; mean, 6.5 months). Assessment of 2-point discrimination; finger pulp circumference; the Disability of the Arm, Shoulder, and Hand score; visual analog scale score; and a questionnaire regarding the treatment satisfaction were carried out both preoperatively and at a 6 month follow-up according to the standard of our clinic. RESULTS: In 3 patients, one session of lipofilling was sufficient to correct the contour, whereas 1 patient with 2 fingertip injuries was treated a second time. There was no significant change in finger pulp circumference, in the 2-point discrimination values and the Disability of the Arm, Shoulder, and Hand score results. There was a significant improvement in the visual analog scale scores in 4 of 5 cases, and all patients were very satisfied with the results of the procedure regarding the improvement in hand function in sports, at work and their daily routine. CONCLUSIONS: Lipofilling can be performed with little operative risks, might alleviate the patient's symptoms and reduce pain after conservative treatment of fingertip injuries.

Fibrin Glue Enhances Adipose-Derived Stromal Cell Cytokine Secretion and Survival Conferring Accelerated Diabetic Wound Healing.

INTRODUCTION: Although chronic wounds are a major personal and economic burden, treatment options are still limited. Among those options, adipose-derived stromal cell- (ASC-) based therapies rank as a promising approach but are restricted by the harsh wound environment. Here we use a commercially available fibrin glue to provide a deliverable niche for ASCs in chronic wounds. MATERIAL AND METHODS: To investigate the in vitro effect of fibrin glue, cultivation experiments were performed and key cytokines for regeneration were quantified. By using an established murine chronic diabetic wound-healing model, we evaluated the influence of fibrin glue spray seeding on cell survival (In Vivo Imaging System, IVIS), wound healing (wound closure kinetics), and neovascularization of healed wounds (CD31 immunohistochemistry). RESULTS: Fibrin glue seeding leads to a significantly enhanced secretion of key cytokines (SDF-1, bFGF, and MMP-2) of human ASCs in vitro. IVIS imaging showed a significantly prolonged murine ASC survival in diabetic wounds and significantly accelerated complete wound closure in the fibrin glue seeded group. CD31 immunohistochemistry revealed significantly more neovascularization in healed wounds treated with ASCs spray seeded in fibrin glue vs. ASC injected into the wound bed. CONCLUSION: Although several vehicles have shown to successfully act as cell carrier systems in preclinical trials, regulatory issues have prohibited clinical usage for chronic wounds. By demonstrating the ability of fibrin glue to act as a carrier vehicle for ASCs, while simultaneously enhancing cellular regenerative function and viability, this study is a proponent of clinical translation for ASC-based therapies.