Stevens, Andrew Robert 
ORCID: 0000-0002-3222-133X
(2024).
Development of an optical device for therapeutics and diagnostics in neurotrauma.
University of Birmingham.
Ph.D.
![[img]](http://etheses.bham.ac.uk//style/images/fileicons/text.png) |
Stevens2024PhD.pdf
Text - Accepted Version Restricted to Repository staff only until 1 January 2026. Available under License All rights reserved. Download (617MB) |
Abstract
Neurotrauma (traumatic injury to the brain or spinal cord) is a global health challenge and major cause of death and disability. Pharmacological therapies, typically targeting single receptors or pathways, have thus far proven unable to significantly affect the multitude of pathophysiological mechanisms required to promote effective repair. Photobiomodulation (PBM) is a therapeutic approach using red/near-infrared light to promote recovery after injury by mitigating neuroinflammation and preventing neuronal apoptosis. Whilst there is growing evidence for the efficacy of PBM in neurotrauma, two key translational barriers exist: (1) the ability to deliver effective doses transcutaneously to injured tissue within the CNS of humans is severely limited; and (2) there is no currently available means to monitor the therapeutic response to PBM in order to optimise dose delivery. As such, this thesis seeks to develop a medical device which can address these barriers: an implant, composed of optical fibres, which is capable of both delivering PBM directly to injured tissue; and monitor the response to therapy using Raman spectroscopy (RS).
A systematic review of the literature identified key components of effective PBM in traumatic brain injury (TBI): use of 660 nm or 810 nm wavelengths; short duration of treatment; and early implementation post-injury. Using an experimental rat model of spinal cord injury (SCI), 660 nm PBM (24.4 mW/cm\(^2\), 60 s, daily for 7 days) was shown to improve functional recovery, lesion size and axonal regeneration after SCI, and delivery of PBM using an implantable device improved early expression of regeneration-associated proteins. Raman spectral differences were identified between injury conditions. Using a rat model of mild TBI, 810 nm transcranial PBM was superior to 660 nm PBM, alone and in combination (20.0 mW/cm\(^2\), 120 s, daily for 3 days), and resulted in improvements in functional recovery. PBM reduced astrocyte and microglial activation after TBI, and treatment was identifiable by spectral biomarkers monitored using RS. Investigation of the mechanisms of PBM demonstrated that 660 nm PBM reduces neuroinflammation in microglia in vitro. Transcriptomics and pathway analysis of 660 nm PBM vs no treatment in the injured spinal cord demonstrated significant upregulation of regeneration associated pathways, and downregulation of key apoptotic genes. This was accompanied by reduced transcription of mitochondrial components and ribosomal transcription, supporting a metabolic mechanism for PBM which leads to neuroprotective and restorative effects. Development of prototype devices demonstrated that effective doses of PBM can be delivered to the brain and spinal cord, using optical fibres integrated into clinically-feasible implantation methods. Lensing and spatial distribution of fibres improved PBM distribution to maximise the volume of injured tissue exposed to treatment.
The work presented here demonstrates proof-of-concept for implantable PBM delivery, with monitoring of effect using RS. Beneficial effects have been demonstrated in both TBI and SCI, and the doses to achieve these effects are deliverable using the developed prototype. RS has been demonstrated as a suitable tool to identify biomarkers associated with successful and effective PBM therapy. This supports the subsequent development of a full device prototype, suitable for use in first-in-human study, toward the translation of this device for clinical trials.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Award Type: | Doctorates > Ph.D. | |||||||||
| Supervisor(s): |
|
|||||||||
| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges > College of Medicine and Health | |||||||||
| School or Department: | Institute of Inflammation and Ageing | |||||||||
| Funders: | Medical Research Council, National Institute for Health Research, Other, Wellcome Trust | |||||||||
| Other Funders: | National Institute for Health Research (Surgical Reconstruction and Microbiology Research Centre), Royal College of Surgeons of England (Roberta Swan Surgical Research Fellowship), The Wellcome Trust (Translational Development Fund), Medical Research Council (Impact Accelerator Account), Midland Neuroscience Teaching and Research Fund, University of Birmingham Research Development Fund | |||||||||
| Subjects: | R Medicine > RD Surgery R Medicine > RM Therapeutics. Pharmacology T Technology > T Technology (General) |
|||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/15226 |
Actions
 |
Request a Correction |
 |
View Item |
Downloads
Downloads per month over past year