Traumatic brain injury (TBI) is a leading cause of disability in adults, caused by a physical insult damaging the brain. Growth factor-based therapies have the potential to reduce the effects of secondary injury and improve outcomes by providing neuroprotection against glutamate excitotoxicity, oxidative damage, hypoxia, and ischemia, as well as promoting neurite outgrowth and the formation of new blood vessels. Despite promising evidence in preclinical studies, few neurotrophic factors have been tested in clinical trials for TBI. Translation to the clinic is not trivial and is limited by the short in vivo half-life of the protein, the inability to cross the blood-brain barrier and human delivery systems. Synthetic peptide mimetics have the potential to be used in place of recombinant growth factors, activating the same downstream signalling pathways, with a decrease in size and more favourable pharmacokinetic properties. In this review, we will discuss growth factors with the potential to modulate damage caused by secondary injury mechanisms following a traumatic brain injury that have been trialled in other indications including spinal cord injury, stroke and neurodegenerative diseases. Peptide mimetics of nerve growth factor (NGF), hepatocyte growth factor (HGF), glial cell line-derived growth factor (GDNF), brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) will be highlighted, most of which have not yet been tested in preclinical or clinical models of TBI.

Treatment options for neurodegenerative conditions such as Parkinson's disease have included the delivery of cells which release dopamine or neurotrophic factors to the brain. Here, we report the development of a novel approach for protecting cells after implantation into the central nervous system (CNS), by developing dual-layer alginate beads that encapsulate therapeutic cells and release an immunomodulatory compound in a sustained manner. An optimal alginate formulation was selected with a view to providing a sustained physical barrier between engrafted cells and host tissue, enabling exchange of small molecules while blocking components of the host immune response. In addition, a potent immunosuppressant, FK506, was incorporated into the outer layer of alginate beads using electrosprayed poly-ε-caprolactone core–shell nanoparticles with prolonged release profiles. The stiffness, porosity, stability and ability of the alginate beads to support and protect encapsulated SH-SY5Y cells was demonstrated, and the release profile of FK506 and its effect on T-cell proliferation in vitro was characterized. Collectively, our results indicate this multi-layer encapsulation technology has the potential to be suitable for use in CNS cell delivery, to protect implanted cells from host immune responses whilst providing permeability to nutrients and released therapeutic molecules.

A multi-component immunomodulatory encapsulation system has potential to improve the survival of therapeutic hiPSC-derived dopaminergic neuron progenitors, for the treatment of Parkinson’s disease.

Tissue engineering has the potential to overcome the limitations of using autografts in nerve gap repair, using cellular biomaterials to bridge the gap and support neuronal regeneration. Various types of therapeutic cells could be considered for use in aligned collagen-based engineered neural tissue (EngNT), including Schwann cells and their precursors, which can be derived from human induced pluripotent stem cells (hiPSCs). Using Schwann cell precursors may have practical advantages over mature Schwann cells as they expand readily in vitro and involve a shorter differentiation period. However, the performance of each cell type needs to be tested in EngNT. By adapting established protocols, hiPSCs were differentiated into Schwann cell precursors and Schwann cells, with distinctive molecular profiles confirmed using immunocytochemistry and RT-qPCR. For the first time, both cell types were incorporated into EngNT using gel aspiration–ejection, a technique used to align and simultaneously stabilise the cellular hydrogels. Both types of cellular constructs supported and guided aligned neurite outgrowth from adult rat dorsal root ganglion neurons in vitro. Initial experiments in a rat model of nerve gap injury demonstrated the extent to which the engrafted cells survived after 2 weeks and indicated that both types of hiPSC-derived cells supported the infiltration of host neurons, Schwann cells and endothelial cells. In summary, we show that human Schwann cell precursors promote infiltrating endogenous axons in a model of peripheral nerve injury to a greater degree than their terminally differentiated Schwann cell counterparts.

Glial cell line-derived neurotrophic factor (GDNF) is a neuroprotective protein with widespread applications in regenerative medicine, though its clinical translation has been limited. Peptide mimetics have the potential to overcome the limitations associated with the translation of GDNF. Herein, peptides targeting the GDNF receptor GFRα1 were identified by screening a 12-mer linear peptide phage display library against GFRα1. Peptide hits were rationalized by computational alanine scanning mutagenesis studies to identify residues contributing to GDNF and GFRα1 binding. Four hit peptides were synthesized and tested for GFRα1 binding affinity. All peptides activated the downstream phosphatidylinositol 3 kinase signaling pathway in SH-SY5Y cells and increased cellular proliferation. The biological activity of two peptides matched that of recombinant GDNF, as measured by neurite outgrowth of primary dorsal root ganglion neurons. For the first time, we report monomeric GFRα1-targeting peptides that mimic the biological effects of GDNF, with potential applications in regenerative medicine.