Sethi, Kamaljit Kaur; (1999) Control of fibroblast-mediated collagen contaction: Importance and mechanism of cell attachment in the contraction process. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The repair of damaged adult tissue is achieved by the production of scar tissue. Irregular healing can lead to hypertrophic scarring, where the healed scar continues to contract after wound closure, producing 'scar contracture'. Current understanding of mechanisms leading to both wound contraction and scar contracture are limited. This study aimed to investigate and modify early phase cell-matrix attachment and contraction mechanisms, using a 3-dimensional in vitro model of wound contraction, the Culture Force Monitor (CFM). Three areas of research were pursued: Firstly, cell-matrix interaction and contraction was manipulated using neutralising antibodies, synthetic peptides and specific protein depleted sera. As well as the CFM, effect of such modifications were monitored by observing changes in cytoskeletal proteins, using confocal microscopy. Secondly, effect of the potent cytokine, TGFβ1, on early phase contraction was tested. TGFβ1 related changes in cellular morphology and integrin expression were also monitored. The final part of the study used Photodynamic Therapy (PDT) to manipulate cell-matrix attachment and subsequent contraction. Drug dose, wavelength and time of irradiation was optimised using a cell viability assay, to find conditions that were minimally toxic to fibroblasts. Contraction was then monitored using untethered (free floating) and tethered (CFM) gels. Results suggest a sequential role for fibronectin, vitronectin, and collagen mediated attachment during fibroblast-mediated contraction. Studies have shown that TGFβ1 may promote early granulation tissue contraction, by directly upregulating specific integrin expression. Data shows that PDT successfully reduced cell-matrix attachment and contraction, and thus, may be of value in an in vivo situation. Mechanisms through which contraction may be controlled are discussed. In order to potentially regulate the process of collagen contraction in tissue repair or in tissue engineering, and to formulate potential therapeutic regimes to control scar contracture, it would seem that clinical intervention is required at a very early stage.

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