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Doctoral thesis
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Hyaluronan-Based Hydrogel Formulations for Therapeutic Applications

Number of pages319
Imprimatur date2022-12-05
Defense date2022-11-23
Abstract

Numerous and diversified industrial applications have been proposed and investigated for native hyaluronic acid (HA) and related derivatives, non-exhaustively comprising drug delivery, wound treatment, ophthalmology, arthrology, urology, and cosmetic applications. Specifications or target parameter ranges for therapeutic products based on hyaluronan strongly depend on the intended application and use. In this thesis, we propose a new class of hyaluronic-based copolymer gels incorporating thermosensitive moieties grafted by click chemistry and named HA-L-PNIPAM. Specific characterization workflows allowed to experimentally confirm the spontaneous and reversible microgel-structure thermoformation above 27°C. HA-L-PNIPAM showed unique temperature-dependent properties leading to facile injection and high viscoelastic values at body temperature, along with enhanced resistance to enzymatic (hyaluronidase challenge) and oxidative (hydrogen peroxide challenge) degradation as shown by comparative rheological studies using commercial viscosupplement and dermal filler products as references. Cytocompatiblity was established using fibroblast and synovial cells. In a rat model of osteoarthritis (anterior cruciate ligament transection), the nano-hydrogel shown beneficial effects against the development of chondral defects. The applicability and safety of this new thermoresponsive polymer was also evaluated in combination with lyophilized human chondroprogenitors. Finally, we characterized lyophilized cell-free progenitor tenocytes extracts and investigated fractionation and sterilization methods for inclusion in cytotherapy-inspired injectable preparations. The numerous promising and original data obtained during this thesis justify further preclinical work for various musculoskeletal applications of the easy-to-use formulation of filtered lyophilized cell extracts in combination with HA-L-PNIPAM and in vivo studies with GMP-grade formulations of HA-L-PNIPAM toward the management knee osteoarthritis.

eng
Keywords
  • Cartilage
  • Cell therapy
  • Hyaluronic acid
  • Hydrogels
  • Osteoarthritis
  • PNIPAM
  • Preclinical safety
  • Rodent model
  • Thermo-responsive
  • Viscosupplementation
Citation (ISO format)
PORCELLO, Alexandre. Hyaluronan-Based Hydrogel Formulations for Therapeutic Applications. 2022. doi: 10.13097/archive-ouverte/unige:166064
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Creation01/09/2023 7:05:00 PM
First validation01/09/2023 7:05:00 PM
Update time03/16/2023 10:24:14 AM
Status update03/16/2023 10:24:11 AM
Last indexation02/01/2024 9:24:34 AM
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