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Title: Towards Topical Antifibrotics in Tissue Engineering and Repair
Keywords: Fibrosis, Angiogenesis, Macromolecular crowding, Biomaterials, Collagen, HIF-1a
Issue Date: 3-Dec-2010
Citation: CHEN ZHEN CHENG, CLARICE (2010-12-03). Towards Topical Antifibrotics in Tissue Engineering and Repair. ScholarBank@NUS Repository.
Abstract: Fibrosis represents a major global disease burden, yet a potent antifibrotic compound is still not in sight. Part of the explanation for this situation is the difficulties that both academic laboratories and R&D departments in the pharmaceutical industry have been facing in re-enacting the fibrotic process in vitro for screening procedures prior to animal testing. Effective in vitro characterization of antifibrotic compounds has been hampered by cell culture settings that are lacking crucial cofactors or are not holistic representations of the biosynthetic and depositional pathway leading to the formation of an insoluble pericellular collagen matrix. Only when collagen has formed a fibrillar matrix that becomes cross-linked, invested with ligands, and can be remodeled and resorbed, the complete picture of fibrogenesis can be reflected in vitro. We developed the Scar-in-a-Jar, which implements for the first time in vitro the complete biosynthetic cascade of collagen matrix formation including complete conversion of procollagen by collagen C-proteinase/BMP-1, its subsequent extracellular deposition and lysyl oxidase-mediated cross-linking. This is achieved by applying the biophysical principle of macromolecular crowding. Collagen matrix deposition velocity and morphology can be controlled using negatively charged crowders in a rapid (2 days) mode and a mixture of neutral crowders in a novel accelerated (6 days) mode. Combined together with quantitative optical bioimaging, this novel system allows for in situ assessment of the area of deposited collagen(s)/cell. A well thought-out in vitro fibrogenesis system represents the missing link between brute force chemical library screens and rational animal experimentation, thus providing both cost-effectiveness and streamlined procedures towards the development of better antifibrotic drugs. Only upon identification of effective compounds will we then be able to address the current bottleneck in tissue engineering, peri-implantational fibrosis, which not only impede the implant¿s original remedial purpose, but also exacerbates the problem. Compounds from the prolyl-4-hydroxylase inhibitor (PHi) substance class were shown to have antifibrotic potential by the Scar-in-a-Jar, and are further known to stimulate angiogenesis. We believe that local delivery of 2,4-pyridinedicarboxylic acid (PDCA), ciclopirox olamine (CPX) and hydralazine (HDZ) via a material will elicit both antifibrotic and angiogenic tissue behaviour. Besides delivering drugs, some design considerations of such a material include its ability to support cell attachment, proliferation and infiltration, which was attained by our composite material comprising coelectrospun micron-sized medical grade poly(e-caprolactone)/collagen (mPCL/Col) with codeposited HeprasilTM, a hyaluronic acid hydrogel containing heparin. mPCL/Col-Hep was used to deliver PHi in two modes, via HeprasilTM (mode 1), or the microfibers (mode 2). Mode 1 was tested in a rat renal pouch model and fibrosis was not apparent around the implanted materials within 7 days, even in controls without PHi. Concentrations of 10 mM PDCA and 10 µM HDZ showed blood vessel infiltration comparable to VEGF delivery, and at this point, served as a proof-of-concept that local delivery of PHi can aid angiogenesis.
Appears in Collections:Ph.D Theses (Open)

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