The development of a hydrogel-based regenerative therapy for brain tissue repair and functional recovery following ischaemic stroke

  • Oana-Roxana Sava

Student thesis: Phd

Abstract

The limited therapeutic options for stroke have supported the exploration of novel regenerative medicine approaches to enhance the functional recovery for most patients in later stages. Angiogenic therapies hold great promise for tissue recovery after stroke, when administered in the sub-acute stages. Vascular endothelial growth factor (VEGF) is the most utilised factor in preclinical studies to promote long-term angiogenesis and recovery. Delivery from a hydrogel increases the temporal availability of VEGF, improving its therapeutic effects. However, no hydrogel meets the requirements for translation into clinical use yet. Self-assembling peptide hydrogels (SAPHs) are excellent off the shelf options and have been proven as feasible for stroke applications. Nevertheless, no commercial SAPHs for longer term VEGF release have been reported. In addition, evidence has shown that immunomodulation is a key process for tissue recovery by promoting a more permissive environment for repair. Tumour necrosis factor-alpha stimulated gene 6 (TSG-6) is a great immunomodulatory candidate, having previously been shown to exert anti-inflammatory effects and to switch the microglial phenotype towards a pro-reparative state in brain injuries. The aim of this PhD project was to investigate the potential beneficial effect of a VEGF, TSG-6 and SAPH combination after ischaemic stroke. We compared three new commercial SAPHs based on their applicability in stroke. All hydrogels showed brain compliant physicochemical properties, good compatibility with brain cells and tissue in vitro and in vivo and enhanced sustained VEGF release compared to a hydrogel control. For future use we selected RGD/IKVAV-PeptiGel-Alpha2. We next evaluated the effect of TSG-6 on post-stroke recovery in a small-scale study in mice, which showed promising trends towards improved sickness behaviour and tissue repair after sub-acute intracerebral administration. Finally, we investigated the effect of VEGF, TSG-6 and RGD/IKVAV-PeptiGel-Alpha2 hydrogel combination at 28 days post-stroke. We observed a modest improvement in motor function for VEGF and TSG-6 in aqueous solution and a promising trend towards decreased inflammation in the stroke lesion for the hydrogel-delivered proteins. Further assessment of tissue repair in the penumbral region is required before future optimised studies, to fully evaluate the beneficial effect of this combination.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorStuart Allan (Supervisor), Emmanuel Pinteaux (Supervisor), Jeffrey Penny (Supervisor) & Kostas Kostarelos (Supervisor)

Keywords

  • brain regeneration
  • immunomodulation
  • TSG-6
  • brain repair
  • ischaemic stroke
  • hydrogel
  • VEGF

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