Development of a thermoresponsive hydrogel as a minimally invasive drug delivery platform for bone regeneration
Osteoporosis, a disease affecting an estimated 200 million people worldwide, silently degrades bone mass and architecture, making it fragile and prone to fractures. In clinically severe scenarios effective management becomes challenging due their recurrence and potential loosening of surgical fixation. These issues are underpinned by an actively weakening tissue that poorly adapts to structural changes from fractures or fixation. Prevention strategies aim to conserve bone structure, but this often comes too late as the tissue is already compromised.
Osteoporotic bone therefore presents a clinical need for local regeneration strategies that accelerate bone restoration processes at key intervention sites. While many biomaterial and tissue engineering approaches exist for bone tissue restoration, they primarily target non-union fractures or critical-sized defects, which are less relevant in osteoporotic fragility fractures. These challenges are further compounded by dysregulated metabolic processes, marked by overactive osteoclast catabolism and diminished osteoblast activity, hindering natural bone regeneration.
Thermoresponsive hydrogels meet these challenges by having capacity to access delicate and intricate tissue sites. Additionally, they have also been shown to be promising therapeutic reservoirs capable of carrying and releasing appropriate therapeutic regimens at the site of action.
This thesis explores the development of a minimally invasive, in situ-fixing hydrogel-based therapeutic delivery platform for local bone structure and function restoration. The hydrogel formulation consists of methylcellulose as a thermoresponsive polymer, optimised with collagen and hydroxyapatite for improved cell infiltration, biocompatibility, and rheological performance, crucial for injectable application and sol-gel transition at body temperature. Simultaneously, simvastatin is investigated to address impaired bone remodeling, enhancing mesenchymal stem cell osteogenic differentiation while attenuating osteoclastogenesis.
Combining these elements yielded a biocompatible material with extended simvastatin release capabilities, offering a potential multifaceted approach to restoring bone health. This research concludes further optimisation of simvastatin release is needed; however, this platform holds promise for delivery of other therapeutics for bone or other delicate tissue regeneration.
History
First Supervisor
Dr. Ciara M. MurphySecond Supervisor
Prof. Helena M. KellyComments
Submitted for the Award of Doctor of Philosophy to RCSI University of Medicine and Health Sciences, 2024Published Citation
Simpson CR,. Development of a thermoresponsive hydrogel as a minimally invasive drug delivery platform for bone regeneration. [PhD Thesis] Dublin: RCSI University of Medicine and Health Sciences; 2024Degree Name
- Doctor of Philosophy (PhD)
Date of award
2024-05-31Programme
- Doctor of Philosophy (PhD)
Research Area
- Biomaterials and Regenerative Medicine