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The ability of the extracellular matrix (ECM) to instruct progenitor cell differentiation has generated excitement for the development of materials-based regenerative solutions. Described a nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) material capable of inducing in vivo skull regeneration without exogenous growth factors or ex vivo progenitor cell-priming is described previously. Here, the contribution of titrating stiffness to osteogenicity is evaluated by comparing noncrosslinked (NX-MC) and crosslinked (MC) forms of MC-GAG. While both materials are osteogenic, MC demonstrates an increased expression of osteogenic markers and mineralization compared to NX-MC. Both materials are capable of autogenously activating the canonical BMPR signaling pathway with phosphorylation of Smad1/5. However, unlike NX-MC, human mesenchymal stem cells cultured on MC demonstrate significant elevations in the major mechanotransduction mediators YAP and TAZ expression, coincident with β-catenin activation in the canonical Wnt signaling pathway. Inhibition of YAP/TAZ activation reduces osteogenic expression, mineralization, and β-catenin activation in MC, with less of an effect on NX-MC. YAP/TAZ inhibition also results in a reciprocal increase in Smad1/5 phosphorylation and BMP2 expression. The results indicate that increasing MC-GAG stiffness induces osteogenic differentiation via the mechanotransduction mediators YAP/TAZ and the canonical Wnt signaling pathway, whereas the canonical BMPR signaling pathway is activated independent of stiffness., (© 2020 Wiley-VCH GmbH.)

Background: Minimally-invasive methods to treat scars address a common pathway of altering collagen structure, leading to collagen remodeling., Objective: In this study, we employed in situ redox chemistry to create focal pH gradients in skin, altering dermal collagen, in a process we refer to as electrochemical therapy (ECT). The effects of ECT to induce biochemical and structural changes in ex vivo porcine skin were examined., Methods: During ECT, two platinum electrodes were inserted into fresh porcine skin, and following saline injection, an electrical potential was applied. pH mapping, high frequency ultrasonography, and two photon excitation microscopy and second harmonic generation (SHG) microscopy were used to evaluate treatment effects. Findings were correlated with histology., Results: Following ECT, pH mapping depicted acid and base production at anode and cathode sites respectively, with increasing voltage and application time. Gas formation during ECT was observed with ultrasonography. Anode sites showed significant loss of SHG signal, while cathode sites showed disorganized collagen structure with fewer fibrils emitting an attainable signal. Histologically, collagen denaturation at both sites was confirmed., Conclusion: We demonstrated the production of in situ acid and base in skin occurring via ECT. The effects chemically and precisely alter collagen structure through denaturation, giving insight on the potential of ECT as a simple, low-cost, and minimally-invasive means to remodel skin and treat scars., Competing Interests: Declaration of Competing Interest The authors have no financial interests to declare., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Objectives: Injury to healthy dermis and the dermoepidermal junction initiates a robust healing process consisting of fibrous tissue overgrowth, collagen deposition, and scar formation. The conventional management of scars and other skin injuries has largely relied upon surgical soft tissue transfer to resurface and/or replace damaged and dysmorphic tissue with new skin. However, these strategies are invasive, expensive, and may further exacerbate integumentary injury. In this study, we examine the creation of in situ redox generated pH changes in fresh human skin. We believe this process of "electrochemical therapy" (ECT) leads to changes in collagen matrix structure. Our objective is to map local tissue pH landscapes and image changes in collagen structure of non-injured skin following ECT., Study Design: Ex vivo human study involving ECT of human skin., Methods: Remnant fresh ex vivo human facial skin from facelift operations was enveloped in saline-soaked gauze for a maximum of 2 hours prior to ECT and imaging. ECT was performed by inserting platinum-plated needle electrodes connected to a DC power supply. Voltage (4, 5, or 6 V) and time (3, 4, or 5 minutes) were varied systematically. High frequency ultrasound (25 MHz) was performed immediately after ECT on each sample. Treated samples were also imaged using multiphoton microscopy (MPM) with second harmonic generation (SHG) to specifically visualize collagen fibers in the dermis. The pH landscapes were mapped using indicator dyes in bisected specimens and the MPM images were compared with histologic findings., Results: Above 4 V and 3 minutes, a profound reduction in dermal collagen SHG signal was observed at the anode. Although there was less blunting of SHG signal seen at the cathode, a decrease in the fluorescence of the dermoepidermal junction was observed. The pH application suggests ECT spatial selectivity and a direct relationship between voltage and application time. Ultrasound demonstrated gas formation between the anode and cathode, which is consistent with ECT's mechanism of action. Importantly, these electrochemical changes occurred without disrupting dermal and epidermal histologic architecture., Conclusion: ECT alters tissue pH leading to dermal collagen structural change. These results offer additional insight into the translational potential of ECT to locally remodel the soft-tissue matrix. Future directions aim to expand into a skin injury model to determine if similar collagen effects are observed in vivo. ECT is incredibly inexpensive (~$5) and may be a means to treat soft tissue injuries using simple needle-based devices and DC battery power supplies. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Electromechanical reshaping is a novel, minimally invasive means to induce mechanical changes in connective tissues, and has the potential to be utilized in lieu of current orthopedic therapies that involve tendons and ligaments. Electromechanical reshaping delivers an electrical current to tissues while under mechanical deformation, causing in situ redox changes that produce reliably controlled and spatially limited mechanical and structural changes. In this study, we examine the feasibility of altering Young's modulus and inducing a shape deformation using an ex vivo bovine Achilles tendon model. Tendon was mechanically deformed in two different modes: (1) elongation to assess for tensile modulus and (2) compression to assess for compressive modulus. Electromechanical reshaping was applied to tendon specimens via flat plate platinum electrodes (6 V, 3 min) while simultaneously under mechanical strain for 15 min. In elongation mode, post-electromechanical reshaping samples demonstrated a significant decrease in Young's modulus compared to pretreatment samples (66.02 and 45.12 MPa, respectively, p < 0.0049). In compression mode, posttreatment samples illustrated a significant shape change, with an increase in diameter (10.62 to 11.36 mm, p < 0.05) and decrease in thickness (4.13 to 3.62 mm, p < 0.05). Results demonstrated a tissue softening effect without lengthening deformation during elongation, and a shortening effect without compromising compressive stiffness during compression. Electromechanical reshaping's reliable, low-cost, and efficacious methodology in inducing mechanical and structural connective tissue modifications illustrates a potential for future alternative orthopedic applications. Future studies will optimize and refine electromechanical reshaping to address clinically relevant geometries and methods such as needle techniques. • In elongation, post-electromechanical reshaping tendon samples decreased in Young's modulus. • In compression, post-electromechanical reshaping tendon samples increased in diameter and decreased in thickness. • Electromechanical reshaping has potential utility for orthopedic applications involving tendon and ligament stiffness. [ABSTRACT FROM AUTHOR]