Fractured foundations: moving a step closer to understanding and treating traumatic bone injuries

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Chipara, Miruna ORCID: https://orcid.org/0000-0002-4742-5183 (2025). Fractured foundations: moving a step closer to understanding and treating traumatic bone injuries. University of Birmingham. Eng.D.

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Abstract

Traumatic bone injuries caused by ballistic or blast trauma represent a significant clinical challenge due to the complex biological processes triggered as a response, including progressive tissue necrosis, dysregulated inflammation, and impaired bone healing. These injuries often result in delayed healing, nonunion, or amputation, highlighting the urgent need for a deeper understanding of the mechanisms underlying bone damage and repair.

Current treatment strategies focus on surgical debridement and the management of necrotic tissue without addressing the underlying causes of necrosis. Therefore, this often requires multiple interventions and leads to suboptimal outcomes. Despite advancements in trauma care, key knowledge gaps remain, particularly in relation to cellular and molecular mechanisms involved in progressive necrosis, as well as the limited ability to study bone trauma repair in large animal models and within three-dimensional (3D) environments. Therefore, this thesis aims to address these gaps through a multifaceted approach.

Firstly, in-vivo bone traumatic injury models cannot be studied for a prolonged period due to associated ethical considerations, ex-vivo bone trauma injury-like model was developed using murine bone chips cultured in fibrin and collagen type I. Comparative analyses of cell migration, differentiation, matrix deposition, and gene expression revealed that fibrin matrices significantly enhanced cellular infiltration, supported intercellular connectivity, and upregulated key osteogenic and matrix-associated genes compared to collagen type I, thereby offering a more physiologically relevant scaffold for modelling early bone repair responses after trauma.

Secondly, using this model, bioactive agents targeting key pathways involved in necroptosis, inflammation, and bone healing were tested, revealing promising candidates to improve healing outcomes. To allow for localised and sustained delivery of these therapeutics, a self-adhesive gel was formulated and evaluated to determine its potential to act as an active bandage for direct application at the injury site.

Lastly, a 3D visualisation method was optimised for both small (rat) and large (sheep) bone samples to further advance the understanding of bone architecture and cellular networks. This technique combined advanced optical tissue clearing with high-resolution imaging, enabling the visualisation of the lacunocanalicular network in the cortical bone.

This work provides novel insights into the cellular and molecular mechanisms underlying bone repair and necrosis in traumatic injuries. By bridging the gap between experimental models, therapeutic development, and advanced imaging techniques, this thesis contributes to the foundation of knowledge on bone traumatic fractures and to innovative treatment strategies that aim to improve bone healing after trauma.

Type of Work:

Thesis (Doctorates > Eng.D.)

Award Type:

Doctorates > Eng.D.

Supervisor(s):