Ma, Yingchang; (2024) Hyaluronic Acid-Tyramine Hydrogel Platform for Prolonged Release of Small Molecule Drugs and Extracellular Vesicles. Doctoral thesis (Ph.D), UCL (University College London).

Text Yingchang Ma-17048801-PhD Thesis.pdf - Submitted Version Access restricted to UCL open access staff until 1 October 2025. Download (22MB)

Abstract

In situ formed hydrogels potentially offer a versatile platform for delivering biological substances and drugs through needles, thereby avoiding implantation surgeries. This approach also allows for better mixing of polymers with large vesicles. Hyaluronic acid (HA), a biocompatible polymer with high water retention, was used in this study to form enzymatically crosslinked HA-TA (tyramine-modified HA) hydrogels. DMTMM is an efficient coupling agent to achieve tyramine conjugation to HA, ranging from 1.75-3.21 % tyramine substitution. HA-TA formed in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2), allowing tuning of gelation time and crosslinking density. Upon characterisation, the hydrogel displayed high porosity and biodegradability, with in vitro assays confirming their non-cytotoxicity. To evaluate the potential of HA-TA hydrogels, a semi-interpenetrating network (semi-IPN) was developed using premixed HA-TA and β-cyclodextrin (β-CD) polymers, which were then crosslinked for sustained release of water-soluble drug sunitinib malate (SUM). NMR spectroscopy confirmed the inclusion complex formation of SUM and β-CD with molar ratios of 1:1 or 1:2. These semi-IPN hydrogels demonstrated enhanced mechanical strength, denser networks and water absorption, enabling higher drug loading and extended release over 20 days in an in vitro flow rig model, ideal for extended drug delivery. HA-TA hydrogels were further examined for the formulation of extracellular vesicles (EVs). EVs are small membrane vesicles and are a promising therapeutic modality, which unfortunately faces challenges like rapid clearance and susceptibility to degradation. HA-TA (2.58 % TA) crosslinked with 2 U/mL HRP and 0.05 mM H2O2 displayed rapid gelation within one minute when injected in situ. Isolated EVs from HEK293T cells were incorporated into these hydrogels while preserving their protein bioactivity and displaying extended release over seven days determined by a CD9 ELISA kit. The release profile can also be tailored by modifying the hydrogel concentration, which constrains EV movement and diffusion.

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