Human T cell responses to bone regenerating biomaterials

Roberts, Jessica (2025) Human T cell responses to bone regenerating biomaterials. PhD thesis, University of Glasgow.

Abstract

Enhanced bone healing and bone provision are fundamental therapeutic orthoplastic strategies for complex fracture management, and for post-oncological or traumatic composite wounds with critical bone loss. Such surgery remains highly challenging and potentially morbid, such that synthetic bone provision would have particular appeal. It could also be indicated to enhance prosthetic fitment after blast injury, and for restoration after digit or limb loss or congenital absence.

Regenerative medicine aims to improve the body’s inherent regenerative capacity after injury, or to replace damaged or lost tissues with fully functional, engineered ones, to address unmet clinical need. Bone requires both scaffold and cellular therapy options. Bioengineered tissues come in many forms, with allogenic mesenchymal stem cell (MSC) based biomaterials achieving successful osteogenesis in vitro, and in animal models in vivo.

Despite these advances, the T cell immune reactivity of a human host towards bone biomaterials remains unknown yet may present a critical barrier to the clinical translation of these promising therapies. Ethical investigation has been precluded through lack of a human in vitro model. Here, a novel, human, multicellular, in vitro, T cell response model was established. Host responses to osseoreconstructive fibronectin and laminin MSC biomaterials were defined across their differentiation into osteoblasts, for the first time. Subsequent, T cell responses to engineered immunomodulation of the allogenic biomaterial were examined.

These data demonstrate successful in vitro T cell modelling. MSC biomaterials triggered human T cell activation responses that increased with osteogenic differentiation. These responses were mixed encompassing regulatory, Thelper (Th) 1 and Th17 associated responses that were detectable by 5 days in vitro. Furthermore, manipulation of the biomaterial glycoprotein did not change the surface activation marker expression of T cells but revealed differences in the cytokine response. Less osteogenic differentiation of MSCs occurred on laminin biomaterials, highlighting the importance of fibronectin for functional presentation of bone morphogenic protein 2 (BMP-2) to guide successful osteogenesis. Finally, manipulation of the immune microenvironment, towards pro-inflammation, appeared to reduce the viability of the allogenic MSCs within the biomaterial, which may have consequences for biomaterial engraftment, longevity and function in vivo.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Funder's Name: Engineering and Physical Sciences Research Council (EPSRC)
• Supervisor's Name: Macleod, Dr. Megan, Salmeron-Sanchez, Professor Manuel and Hart, Professor Andrew
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-84907
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Feb 2025 13:56
• Last Modified: 17 Feb 2025 13:56
• Thesis DOI: 10.5525/gla.thesis.84907
• URI: https://theses.gla.ac.uk/id/eprint/84907