From heterotopic ossification to fracture healing: identifying and delivering adjuvants to modulate bone formation
File(s)
Author(s)
Broda, Krysia
Type
Thesis
Abstract
Perturbation of bone remodelling after trauma can result in over-repair or under-repair mechanisms. Over-repair mechanisms result in trauma-acquired Heterotopic Ossification (HO) characterised by the excessive formation of bone in soft tissue, whilst under-repair mechanisms result in non-unions, where fractures do not heal appropriately. Previous research into HO has predominantly been conducted by clinicians and has focused on whole-body patterns of injury, however in comparison, at the cellular level, the field is still in its infancy resulting in a lack of successful prophylactics. Here, the first objective was to improve our understanding of the cellular responses to injury that lead to HO through a systematic review of current literature which identified 6 biomarkers that were conserved over multiple species (CCL2, COL1A1, COL2A1, IL6, OCN and RUNX2). The second objective was to conduct my own analysis of initial transcriptomic changes leading to HO using our in-house HO model which identified 6 genes of interest (ADH1B, NEAT1, NEGR1, NT5DC3, SDC1 and SLC6A9) that were used to develop a Trauma-Response indEX (T-REX) that can predict and test the efficacy of therapeutics for HO in vitro. From this, a potential therapeutic for HO (siNT5DC3) was identified and altered (encapsulated in nanoparticles and loaded into hydrogels) for clinical translation. Additionally, previous research into use of Bone-Marrow Aspirate Concentrate (BMAC) and Platelet-Rich Plasma (PrP) as biological adjuvants to promote bone repair (preventing non-unions) has yielded inconsistent results. My final objective was to characterise the osteo-inductive properties of BMAC and PrP. This work elucidates the paracrine mechanisms elicited from BMAC and PrP that promote mineralisation in vitro. Overall, this thesis has added to the understanding of HO formation and developed a potential therapeutic for HO, as well as added to the understanding of BMAC and PrP as biological adjuvants for the treatment of non-unions.
Version
Open Access
Date Issued
2023-07-17
Date Awarded
01/01/2024
License URL
Advisor
Higgins, Claire
Sponsor
Royal British Legion (Centre for Blast Injury Studies)
NTL Biologica (Firm)
Grant Number
BMPF_PS3015
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)