Fateh, Shirin
(2024)
Screening, Discovery, and Development of Immune-Instructive Biomaterials for Modulation of Dendritic Cells.
PhD thesis, University of Nottingham.
Abstract
Biomaterials are increasingly important in healthcare for their potential applications in medical implants, immunotherapies, vaccine development, tissue engineering, organ transplantation, and personalised medicine. However, challenges such as infection and complications at implantation sites necessitate the development of biomaterials that induce appropriate immune responses. While polymer microarrays are effective in biomaterial discovery, they often overlook non-adherent immune cells, secretome profiles, and paracrine signalling, which are critical for comprehensive understanding.
Dendritic cells (DCs), as central regulators of the immune system, serve as a relevant model for studying the modulation of immune responses by biomaterials. Various studies have demonstrated that natural and synthetic polymers can influence DC maturation and phenotype, indicating the potential to design biomaterials that modulate adaptive immune responses. Nonetheless, achieving specific biological functions, like anti-inflammatory properties, remains challenging due to an incomplete understanding of material-biological interactions.
This project hypothesises that synthetic acrylate-based polymers can modulate monocyte-derived DC (moDC) secretome and phenotypes to induce either pro-inflammatory or anti-inflammatory responses, thereby influencing the adaptive immune system. Such polymers could serve as a foundation for developing immune-instructive biomaterials applicable to a range of medical contexts. These immune-instructive biomaterials are essential for addressing the growing prevalence of autoimmune diseases, cancer, and inflammatory conditions, as well as for supporting an aging population with enhanced medical devices.
To test this hypothesis, a polymer contact printing methodology was optimised to create 7 mm × 7 mm thin homopolymer areas of 98 homopolymers from acrylate, methacrylate, and acrylamide functional groups. Polymer-printed slides were fitted onto 16-well ProPlates® to assess secretome profiles of moDCs exposed to different polymers for the anti- and pro-inflammatory cytokines, chemokine and immunomodulatory enzyme activity.
As a result, a group of polymers with anti- and pro-inflammatory properties were identified such as pro-inflammatory polymer decyl methacrylate (DMA) and anti-inflammatory polymer N-Dodecylmethacrylamide (NDMAm). These polymers were further assessed based on their impact on the expression of maturation, migratory, stimulatory and inhibitory surface molecules. The impact of polymer-primed moDCs on pan naïve T cell polarisation was also investigated. This showed that DMA induced proliferation and production of proinflammatory cytokine interferon-gamma (IFN-γ) while NDMAm conditioned moDCs polarised T cells towards the production of anti-inflammatory cytokines Transforming growth factor-beta 1 (TGF-β1) and interleukin-4 (IL-4).
To elucidate the mechanisms of the observed polymer-induced modulation in behaviour and phenotype of moDCs and T cells, the thickness of adsorbed proteins from serum-supplemented culture medium on scaled-up polymers as well as their stiffness and wettability was investigated. Quantitative analysis revealed that the moDC phenotype was modulated by the adsorption of selective proteins and the change of surface oxygen as opposed to the thickness of the adsorbed protein layer. Lastly, the applicability of identified anti-inflammatory chemistries was pursued by fabricating these into free-standing polymer films, for application as localised delivery into the dermal layer of skin by using ready-needling instruments.
In summary, the findings from this study demonstrate that (meth)acrylate/acrylamide polymer surfaces can directly modulate moDC phenotypes, leading to downstream effects on adaptive immunity, including T cell activity. The observations discussed provide a framework for developing immune-instructive therapeutics applicable to medical implants, vaccine adjuvants, cancer therapies, and autoimmune diseases.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Alexander, Morgan
Ghaemmaghami, Amir |
| Keywords: |
Immune-instruction, Immuno-bioengineering, Biomaterials, Inkjet Printing, Contact Printing, (Meth)acrylates, (Meth)acrylamides, Dendritic Cells, T cells, Immunomodulation |
| Subjects: |
Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General) > R855 Medical technology. Biomedical engineering. Electronics |
| Faculties/Schools: |
UK Campuses > Faculty of Science > School of Pharmacy |
| Item ID: |
79801 |
| Depositing User: |
Fateh, Shirin
|
| Date Deposited: |
13 Dec 2024 04:40 |
| Last Modified: |
13 Dec 2024 04:40 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/79801 |
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