Thesis

Engineered silk hydrogels for the delivery of mesenchymal stem cells to the stroked brain

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Awarding institution
  • University of Strathclyde
Date of award
  • 2022
Thesis identifier
  • T16151
Person Identifier (Local)
  • 201868230
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Bombyx mori silk has the potential to be deployed as a delivery matrix in advanced cell-based therapies (Chapter 1). My principle hypothesis is that silk can be engineered into hydrogels to mimic the structure and function of the native extracellular matrix [ECM], ultimately influencing cellular biology. The aim of this thesis was to assess self-assembling silk hydrogels that serve as ECM mimetics to support mesenchymal stem cell [MSCs] function, and to assess silk hydrogel performance in the context of strokes. Viscoelasticity is a key mechanical property of the ECM. Therefore, the mechanics of silk hydrogels were engineered, and the impact in two-dimensional MSC cultures was assessed (Chapter 2; Phuagkhaopong et al. 2021). Elastic and viscoelastic silk hydrogels with identical stiffness (~1 kPa) were generated from equal silk concentrations by chemical and physical crosslinking, respectively. Physically crosslinked silk hydrogels showed stress relaxation (τ1/2 = 250 s) when exposed to 15% compressive stress, covering the stress relaxation range observed in soft tissues (60–3,600 s). The viscoelastic and elastic silk hydrogels induced differential patterns of gene expression, protein secretion, and extracellular metabolome that were linked to substrate mechanics. For example, strong activation of IL-1β signaling was observed in MSCs grown on elastic silk hydrogels. In Chapter 3, viscoelastic silk hydrogels were tuned to match native brain tissue. These self-assembling silk hydrogels were stereotactically injected into the stroke epicenter to assess their 6- and 12-month performance in rats. Histological assessment showed excellent host-tissue integration, cell ingrowth, and M2-like phenotype macrophages. Also, neuronal progenitor cells remodeled the chronic stroke. This thesis drew on both in vitro and in vivo studies to assess the potential of tissue-mimetic silk hydrogels intended for cell therapy. The reported findings will expand the use of silk hydrogels as an engineered ECM mimetic in advanced therapy products (Chapter 4).
Advisor / supervisor
  • Carswell, Hilary
  • Seib, Philipp
Resource Type
Note
  • This thesis was previously held under moratorium from 5th June 2022 until 5th June 2026.
DOI
Date Created
  • 2021

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