Muwaffak, Saja; (2020) Design and Formulation of an In-situ Gelling Collagen for Tissue Specific Modified Drug Release and Cell Therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Much research is dedicated to developing biomedical materials that can be utilised by minimally invasive techniques. Collagen is a good candidate for further development. It was hypothesised that an injectable collagen hydrogel could be developed for use in drug delivery and pharmaceutical research. Initial experiments examined different collagen and hyaluronic acid (HA) hydrogels. Collagen type I and tyramine substituted HA hydrogels were prepared and characterised mechanically and by in-vitro 3D cell cultures. The possibility of formulating an injectable artificial vitreous substitute was studied by photochemical crosslinking of HA and collagen. A potential vitreous substitute was prepared using riboflavin 5’-phosphate and blue light at 4 mW/cm2. The in-situ preparation of the vitreous substitute showed a significant reduction in cell viability in ARPE-19 cells due the generation of reactive oxygen species (ROS). However, there may be potential to use the crosslinked material as a simulated vitreous fluid for pharmaceutical research. A lyophilisable in-situ polymerisable collagen (IPC) designed for injectability with tuneable mechanical properties (500 - 2500 Pa) was then prepared. The IPC was prepared by dialysis of collagen type I against EDTA following an optimised process. Solid drug powder IPC gel formulations of the anti-scarring agents: ilomastat and AZ 8955 were investigated to mediate healing after eyelid surgery for trichiasis. A 100 µL depot which could potentially be injected into the subconjunctival space at the surgical site in the eyelid achieved a 2-week in vitro release profile at therapeutic concentrations. Drug release profiles were dependent by depot volume or the drug loading. Drug release profiles were primarily dependent on drug solubility. Poorly soluble drugs were mixed with the IPC as powder suspensions for the purpose of localising drug in the tissue and to minimise the risk of localised foreign body reactions. A moderately soluble anti-scarring drug, pirfenidone was mixed into the IPC as a solution but release was too rapid, so pirfenidone was pre-encapsulated into PLGA particles by an electrospray process and then incorporated into the IPC. The antibody, bevacizumab which is widely used to treat ocular angiogenesis and can mediate post-surgical healing was also formulated with the IPC and displayed a release profile of 30 days in the presence of high molecular weight HA (2 mg/mL). The IPC was also utilised as a vehicle to establish a method for preparing an injectable cellular delivery formulation using human tenon fibroblasts (HTF). IPC-based 3D cultures of HTF cells showed excellent cell viability (>90%) and attachment after 7 days.

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