Effective treatment strategies for skin wound repair are the focus of numerous studies. New pharmacological approaches appear necessary to guarantee a correct and healthy tissue regeneration. For these reasons, we purposed to investigate the effects of the combination between heparan sulfate and growth factors further adding the heparinase enzyme. Interestingly, for the first time, we have found that this whole association retains a marked pro-healing activity when topically administered to the wound. In detail, this combination significantly enhances the motility and activation of the main cell populations involved in tissue regeneration (keratinocytes, fibroblasts and endothelial cells), compared with single agents administered without heparinase. Notably, using an experimental C57BL/6 mouse model of skin wounding, we observed that the topical treatment of skin lesions with heparan sulfate + growth factors + heparinase promotes the highest closure of wounds compared to each substance mixed with the other ones in all the possible combinations. Eosin/hematoxylin staining of skin biopsies revealed that treatment with the whole combination allows the formation of a well-structured matrix with numerous new vessels. Confocal analyses for vimentin, FAP1α, CK10 and CD31 have highlighted the presence of activated fibroblasts, differentiated keratinocytes and endothelial cells at the closed region of wounds. Our results encourage defining this combined treatment as a new and appealing therapy expedient in skin wound healing, as it is able to activate cell components and promote a dynamic lesions closure.

2023-07-01·International Urogynecology Journal

Effects of mesenchymal stem cells and heparan sulfate mimetics on urethral function and vaginal wall biomechanics in a simulated rat childbirth injury model

Article

作者: Janssen, Kristine ; van Ruiten, Geertruida W ; Eijkelkamp, Niels ; Damaser, Margot S ; van der Vaart, Carl H

AbstractIntroduction and hypothesisNew treatments are needed for pelvic floor disorders. ReGeneraTing Agent® (RGTA®) is a promising regenerative therapy. Therefore, the objective of this study was to compare regenerative abilities of mesenchymal stem cells (MSCs) and RGTA® on regeneration after simulated childbirth injury in rats.MethodsRats underwent pudendal nerve crush and vaginal distension (PNC+VD) or sham injury. Rats that underwent PNC+VD were treated intravenously with vehicle, MSCs or RGTA® 1 h, 7 days, and 14 days after surgery. Sham rats received 1 ml vehicle at all time points. After 21 days, urethral function and pudendal nerve function were tested. Vaginal tissues were harvested for biomechanical testing and histology. Biaxial testing was performed to measure tissue stiffness.ResultsPNC+VD decreased urethral and pudendal nerve function compared with sham. Vaginal wall stiffness was significantly decreased in longitudinal and transverse tissue axes after PNC+VD compared with sham. MSC or RGTA® did not restore urethral or pudendal nerve function. However, MSC treatment resolved loss in vaginal wall stiffness in both tissue axes and improved collagen content within the vaginal wall. RGTA® treatment increased vaginal wall anisotropy by increasing relative stiffness in the longitudinal direction. PNC+VD (with vehicle or MSCs) enhanced elastogenesis, which was not observed after RGTA® treatment.ConclusionsTreatment with MSCs facilitated recovery of vaginal wall biomechanical properties and connective tissue composition after PNC+VD, whereas treatment with RGTA® resulted in anisotropic biomechanical changes. This indicates that MSCs and RGTA® promote different aspects of vaginal tissue regeneration after simulated childbirth injury.

2023-06-01·Journal of drugs in dermatology : JDD

Reduction of Erythema in Moderate-Severe Rosacea by a Low Molecular Weight Heparan Sulfate Analog (HSA).

Article

作者: Brown, Madeline ; Byrd, Angel S ; Cohen, Joel L ; Gallo, Richard L ; George, Rosalyn ; Okeke, Chidubem A V

Rosacea changes are a result of an immune mediated response and the angiogenic properties of the LL-37 peptide. This peptide induces an inflammatory signal that activates the NLRP3-mediated inflammasome, triggering rosacea pathogenesis. Research findings show that LL-37 peptide is inhibited by binding to a cell surface glycosaminoglycan, heparan sulfate. Heparan Sulfate Analog (HSA) is a proprietary low molecular weight analog of heparan sulfate that has been formulated into a Dermal Repair Cream (DRC), specifically to aid in such immune mediated responses. Herein, in vitro studies using human epidermal keratinocytes showed an increase in HSA decreased LL-37 toxicity and IL-8 cytokine release. A single-center, randomized double-blind trial included 16 subjects (Fitzpatrick skin types I-IV) with a clinical diagnosis of type 1 rosacea and moderate to severe facial erythema, who were undergoing Pulsed Dye Laser (PDL) treatment. The clinical improvements of their facial erythema were assessed at baseline, 2 weeks, 4 weeks, and 8 weeks. Results revealed that low molecular weight HSA significantly improves the clinical signs of rosacea during the 8 weeks of use likely resulting from inhibition of LL-37 induced IL-8 cytokine release. These findings support the use of DRC in rosacea topical treatment regimens as it demonstrates visible skin benefits and improves tolerability of PDL therapy in a shorter duration of time as compared with PDL alone.George R, Gallo RL, Cohen JL, et al. Reduction of erythema in moderate-severe rosacea by a low molecular weight Heparan Sulfate Analog (HSA). J Drugs Dermatol. 2023;22(6):546-553. doi:10.36849/JDD.7494.

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