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Title: Manipulating the mechanical strength and biological stability of collagen-based scaffolds for tissue engineering
Author: Busby, Grahame
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2013
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Collagen, the most abundant structural protein in the body, has become the most widely used matrix for tissue engineering. Implanted collagen undergoes a constant process of remodelling, and it is the balance of collagen synthesis and its gradual breakdown by the cells of the body that will determine its strength and effectiveness as a scaffold. It has been shown that collagen for implantation is degraded more quickly than cells are able to synthesise new collagen, resulting in a rapid reduction in matrix strength. The collagen is broken down by tissue/cell derived collagenases, which are members of the matrix metalloproteinase (MMP) family of enzymes. Angiotensin converting enzyme (ACE) inhibitors have long been used successfully to treat hypertension. More recently, some ACE inhibitors have also been shown to inhibit certain MMPs. The purpose of this thesis was to investigate the potential of the ACE inhibitors captopril and enalapril to inhibit enzymatic collagen degradation, and ultimately slow down the rate at which collagen is degraded by cells of the body. Both captopril and enalapril were shown to inhibit enzymatic collagen degradation in a dose-dependent manner, at concentrations that are non-toxic to cells in culture. To determine whether the ACE inhibitors were able to affect the mechanical properties of fibroblast-populated collagen lattices (FPCLs), a technique was developed for the characterisation of their time-dependent properties. The technique, which facilitates estimation of the stiffness and hydraulic permeability of hydrogel samples via confined compression and biphasic theory, may also be suitable for characterising other inherently weak hydrated tissues, and therefore may be of great value to anyone interested in doing so. Having demonstrated that the technique was sensitive to small variations in collagen content, it was used to compare the mechanical properties of FPCLs, where it was shown that FPCLs treated with captopril or enalapril were stiffer than control FPCLs after 6 days in culture. It seems likely that the retention of matrix stiffness is attributable to a reduction in the rate of substrate degradation by collagenolytic enzymes, which in turn can be attributed to their inhibition by the ACE inhibitors, though the mechanism of inhibition is still not fully understood. The potential to manipulate the strength and stability of collagen implants by treating them with ACE inhibitors has major implications throughout the fields of tissue engineering, regenerative medicine and cosmetic surgery.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Eng.D.) Qualification Level: Doctoral