No / Following traumatic injury, skin has the capacity to repair itself through a complex cascade of biochemical change. The dermis, which contains a load-bearing collagenous network structure, is remodelled over a long period of time, affecting its mechanical behaviour. This study examines the nanomechanical and viscoelastic properties of the upper dermis from human skin that includes both healthy intact and scarred tissue. Extensive nanoindentation analysis shows that the dermal scar tissue exhibits stiffer behaviour than the healthy intact skin. The scar skin also shows weaker viscoelastic creep and capability to dissipate energy at physiologically relevant frequencies than the adjacent intact skin. These results are discussed in conjunction with a visual change in the orientation of collagenous fibrils in the scarred dermis compared with normal dermis, as shown by atomic force microscopy imaging.

no / This study aimed at determining the role of the transforming growth factor-beta (TGF-β) isomers and their combinations in bone cell behaviour using MG63 cells. The work examined how TGF-β1, 2 and 3 and their solvent and carrier (HCl and BSA, respectively) effected cell morphology, cell proliferation and integrin expression. This study also aimed at examining how the TGF-βs and their solvent and carrier influenced wound closure in an in vitro wound closure model and how TGF-βs influence extracellular matrix (ECM) secretion and integrin expression. The wound healing response in terms of healing rate to the TGF-βs and their solvent/carrier was investigated in 300 μm ± 10–30 μm SD wide model wounds induced in fully confluent monolayers of MG63 bone cells. The effect of different TGF-β isomers and their combinations on proliferation rate and cell length of human bone cells were also assessed. Immunostaining was used to determine if TGF-βs modifies integrin expression and ECM secretion by the bone cells. Imaging with WSPR allowed observation of the focal contacts without the need for immunostaining. The wound healing results indicated that TGF-β3 has a significant effect on the wound healing process and its healing rate was found to be higher than the control (p < 0.001), TGF-β1 (p < 0.001), TGF-β2 (p < 0.001), BSA/HCl (p < 0.001) and HCl (p < 0.001) in ascending order. It was also found that TGF-β1 and TGF-β2 treatment significantly improved wound closure rate in comparison to the controls (p < 0.001). All TGF-β combinations induced a faster healing rate than the control (p < 0.001). It was expected that the healing rate following treatment with TGF-β combinations would be greater than those healing rates following treatments with TGF-β isomers alone, but this was not the case. The results also suggest that cell morphological changes were observed significantly more in cells treated with TGF-β(2 + 3) and TGF-β(1 + 3) (p < 0.001). Any cell treated with TGF-β1, TGF-β(1 + 2) and TGF-β(1 + 2 + 3) showed significantly less elongation compared to the control and other TGF-β isomers. In terms of proliferation rate, TGF-β3 and TGF-β(2 + 3) increased cell numbers more than TGF-β1, TGF-β2 and other combinations. TGF-β1 and its combinations did not show significant proliferation and attachment compared to the control. Immunostaining indicated that treatment with TGF-β3 significantly enhanced the secretion of collagen type I, fibronectin and integrins α3 and β1. The WSPR experiments also indicated that TGF-βs influenced the distribution of focal contacts. In conclusion, combining TGF-β3 with any other TGF-β isomer resulted in a faster model wound closure rate (p < 0.001), while treatment with TGF-β1 in any TGF-β combination reduced the healing rate (p < 0.001). It can therefore be concluded that the presence of TGF-β1 has an inhibitory effect on bone wound healing while TGF-β3 had the opposite effect and increased the rate of wound closure in a 2 dimensional cell culture environment. / Emailed Mansour for final draft 27/06/2016

KS0365 activated recombinant and native mouse TRPV3 more potently and with a higher efficacy compared with 2-APB and did not activate TRPV2 or TRPV4 channels. The activation of TRPV3 by KS0365 super-additively accelerated the EGF-induced keratinocyte migration, which was inhibited by the TRP channel blocker ruthenium red or by siRNA-mediated TRPV3 knockdown. Moreover, KS0365 induced strong Ca2+ responses in migrating front cells and in leading edges of keratinocytes.

Yes / Antibacterial hydrogels have been intensively studied due to their wide practical potential in wound healing. However, developing an antibacterial hydrogel that is able to integrate with exceptional mechanical properties, cell affinity, and adhesiveness will remain a major challenge. Herein, a novel hydrogel with antibacterial and superior biocompatibility properties was developed using aluminum ions (Al3+) and alginate− dopamine (Alg-DA) chains to cross-link with the copolymer chains of acrylamide and acrylic acid (PAM) via triple dynamic noncovalent interactions, including coordination, electrostatic interaction, and hydrogen bonding. The cationized nanofibrillated cellulose (CATNFC), which was synthesized by the grafting of long-chain quaternary ammonium salts onto nanofibrillated cellulose (NFC), was utilized innovatively in the preparation of antibacterial hydrogels. Meanwhile, alginate-modified dopamine (Alg-DA) was prepared from dopamine (DA) and alginate. Within the hydrogel, the catechol groups of Alg-DA provided a decent fibroblast cell adhesion to the hydrogel. Additionally, the multitype cross-linking structure within the hydrogel rendered the outstanding mechanical properties, self-healing ability, and recycling in pollution-free ways. The antibacterial test in vitro, cell affinity, and wound healing proved that the as-prepared hydrogel was a potential material with all-around performances in both preventing bacterial infection and promoting tissue regeneration during wound healing processes. / This work was supported by the National Natural Science Foundation of China (32070826 and 51861165203), the Chinese Postdoctoral Science Foundation (2019M650239, 2020T130762), the Sichuan Science and Technology Program (2019YJ0125), the State Key Laboratory of Polymer Materials Engineering (sklpme2019-2-19), the Chongqing Research Program of Basic Research and Frontier Technology (cstc2018jcyjAX0807), Chongqing Medical Joint Research Project of Chongqing Science and Technology Committee & Health Agency (2020GDRC017), and the RCUK China-UK Science Bridges Program through the Medical Research Council, and the Fundamental Research Funds for the Central Universities.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第25315号 / 農博第2581号 / 新制||農||1103(附属図書館) / 学位論文||R6||N5487 / DFAM / 京都大学大学院農学研究科農学専攻 / (主査)教授 白岩 立彦, 教授 那須田 周平, 教授 田中 千尋 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

2024 / Fibrotic diseases affect thousands of individuals across various organs, yet there is no standard of care or curative option available when it comes to treatment. Fibrosis displays significant heterogeneity in its cause, onset timeline and severity across patients and tissues. Despite these differences, the foundation of fibrosis development remains consistent. It is caused by a dysregulated wound healing response to inflammation due to tissue injury. This inflammatory stimulus can result from infection, toxins, physical damage, autoimmunity or arise idiopathically. The normal healing processes become overactive, resulting in deposition of stiff extracellular matrix (ECM) proteins that causes the tissue to become impaired and lose functionality. In all forms of fibrosis, patient quality of life is impacted, whether from uncomfortable and unattractive scars on the skin, or loss of internal organ function resulting in death. Through various complex and interconnected positive feedback mechanisms, fibrotic signaling cascades and ECM build-up are constantly stimulated, making prevention and early treatment critical to success. In this work, we address some of the challenges of treating fibrotic diseases using the endogenous peptide hormone, human relaxin-2 (RLX-2), combined with mechanisms to enhance its therapeutic potential and antifibrotic efficacy. RLX-2 is a natural antifibrotic and antifibrogenic with the ability to both inhibit pathways responsible for fibrosis development and upregulate enzymes to degrade the stiffened matrix, making it poised as both a prophylactic and a treatment for established disease. However, RLX-2 has failed in previous clinical trials due to lack of efficacy. We hypothesize that these failures were due to inadequate concentration at the target tissue due to systemic delivery, as well as fibrosis-specific alterations to the RLX-2 receptor, RXFP1. We explore the antifibrotic effects of RLX-2 and methods to improve its efficacy in three different fibrotic diseases. First, we encapsulate RLX-2 into a polymeric microparticle formulation for the treatment of shoulder arthrofibrosis. Second, we are developing a sustained-release hydrogel for RLX-2 application to deep dermal wounds for the prevention and potential reversal of hypertrophic and keloid scars. Last, we explore RXFP1 gene expression in scleroderma patient dermal fibroblasts and demonstrate use of a corticosteroid to upregulate RXFP1 and potentiate the antifibrotic effects of RLX-2. Through targeted delivery strategies and understanding the pathology of the disease and target, these studies demonstrate methods to improve RLX-2’s therapeutic potential to treat fibroses. / 2027-02-12T00:00:00Z

No description available.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctorate of Philosophy. / Senecio serratuloides is widely used for wound healing in South Africa but minimal information regarding its efficacy is available. Furthermore toxic pyrrolizidine alkaloids may be present. The following investigation sought firstly to evaluate the efficacy and safety of Senecio serratuloides in a porcine wound model; secondly to assess for a potential mechanism and finally isolate and identify fractions in in-vitro assays. Assessment of Efficacy and Safety Materials and Methods: Deep partial thickness and full thickness wounds were created on 9 pigs. Treatment included an occlusive dressing (negative control), activated carbon, or the Senecio preparation. Wounds were monitored using photographic documentation, pH measurement and histological analysis (skin thickness and collagen content). Toxicity was monitored on blood and liver samples. Results and Discussion: Efficacy of Senecio serratuloides was established with a significantly thicker epidermis, maximal at day 7 post-operative, 2 days before the controls. Effects on collagen content was negligible with no toxicity detected. Mechanistic investigation Materials and Methods: Wound fluid was analysed for IL-10, IL-12, IL-1β, IL-6, IL-8, TNF-α using flow cytometry based assays. Tyrosine phosphorylation and cellular proliferation was assessed using dual immunofluorescence staining. Results and Discussion: IL-1β levels were significantly greater in the Senecio treatment. Tyrosine phosphorylation increased to day 9 post-operative where it stabilised in all groups. In the same period, cellular proliferation was sustained in the Senecio treated wounds but not in the controls. Keratinocyte proliferation was identified as the target for in-vitro assays. Extraction, Isolation and Partial Identification using In-vitro Proliferation Assays. Materials and Methods: The plant was fractionated using solid phase extraction cartridges. Keratinocytes were grown under standard conditions in 96-well plates. Cellular proliferation was assessed spectrophotometrically using a resazurin dye technique. Active fractions were analysed using gas chromatography and mass spectrometry. Results and Discussion: Identified fractions increased the rate of proliferation by 300- 400%. Potential lead compounds were identified. Importantly, pyrrolizidine alkaloids could not be detected. Conclusion Senecio serratuloides is efficacious in treating deep partial thickness wounds without inducing liver toxicity. Sustained keratinocyte proliferation linked to tyrosine phosphorylation may be an underlying mechanism. Although successful, in-vitro detection of active fractions requires further characterisation.

No description available.

No / Increasing pressure on health care budgets highlights the need for clinicians to understand the true costs of wound care, in order to be able to defend services against indiscriminate cost cutting. Our aim was to develop and test a straightforward method of measuring treatment costs, which is feasible in routine practice. The method was tested in a prospective study of leg ulcer patients attending three specialist clinics in the UK. A set of ulcer-related health state descriptors were defined on the basis that they represented distinct and clinically relevant descriptions of wound condition ['healed', 'progressing'; 'static''deteriorating; 'severe' (ulcer with serious complications)]. A standardised data-collection instrument was used to record information for all patients attending the clinic during the study period regarding (i) the health state of the ulcer; (ii) treatment received during the clinic visit and (iii) treatment planned between clinic visits. Information on resource use was used to estimate weekly treatment costs by ulcer state. Information was collected at 827 independent weekly observations from the three study centres. Treatment costs increased markedly with ulcer severity: an ulcer which was 'deteriorating' or 'severe' cost between twice and six times as much per week as an ulcer which was progressing normally towards healing. Higher costs were driven primarily by more frequent clinic visits and by the costs of hospitalisation for ulcers with severe complications. This exercise has demonstrated that the proposed methodology is easy to apply, and produces information which is of value in monitoring healing and in potentially reducing treatment costs.