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Title: Collagen-mimetic peptide-modifiable scaffolds for musculoskeletal tissue regeneration
Author: Parmar, Paresh Ashok
ISNI:       0000 0004 7656 8233
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The development of tissue-engineered articular cartilage through the use of scaffold systems to repair and regenerate damaged and/or diseased tissue has gained momentum in recent years. However, tissue engineering strategies for repairing and regenerating articular cartilage face significant challenges to recapitulate the highly dynamic and complex biochemical microenvironment that is deemed important for its multiple biochemical and biomechanical functions. Recently, there has been a growing interest towards taking advantage of the native tissue environment by using or mimicking specific components and using them in scaffold designs and thus, to further recreate a native-like pericellular microenvironment for cells. One approach to mimic the biochemical complexity of articular cartilage is through the use of recombinant bacterial collagens as they provide a well-defined biological 'blank template' that can be easily modified to incorporate multiple and different bioactive and/or biodegradable peptide sequences within a precisely defined three-dimensional (3D) system. The backbone of a recombinantly synthesised Streptococcal collagen-like 2 protein was customised with different bioactive peptide moieties designed to specifically and non-covalently bind biomolecules present in articular cartilage, such as hyaluronic acid, chondroitin sulphate, and heparin, and these were either tethered to the protein backbone or genetically incorporated as part of the protein backbone to mediate cellular behaviour. These glycosaminoglycans (GAGs) were not covalently functionalised to the proteins as it was believed the chemical modification could negatively interfere or inhibit their bioactivity. GAG-binding peptides have been shown to improve their bioactivity possibly through mimicking native-like protein-GAG interactions. Enzymatically cleavable motifs were used to generate 3D biodegradable systems tailored to the temporal expression pattern of specific enzymes secreted by human mesenchymal stem cells (hMSCs). Variations of these proteins functionalised with bioactive and/or biodegradable peptide sequences were fabricated into hydrogels and foams tuned to the chondrogenic differentiation of encapsulated hMSCs to improve and modulate articular cartilage-specific extracellular matrix (ECM) deposition and elaboration. The optimised scaffold systems also demonstrated a delayed or inhibited hypertrophic behaviour by hMSCs, which is a fundamental engineering challenge. The scaffold development work culminated into a system that displayed a temporal balance between scaffold degradation and matrix accumulation by hMSCs undergoing chondrogenesis. This system is the first demonstration of a multi-modal bioactive and enzymatically degradable natural platform. As such, this novel bioactive peptide-functionalised collagen-mimetic protein, cross-linked via multiple enzymatically cleavable peptides, provides a highly adaptable well- defined platform to recapitulate a high degree of biological complexity, which could be applicable to other regenerative medicine and tissue engineering applications.
Supervisor: Stevens, Molly Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral