Towards clinical translation of ‘second-generation’ regenerative stroke therapies: hydrogels as game changers?

The stroke cavity is an ideal site for administration, being closest to a zone of neuroplasticity and able to accommodate hydrogels without compressing surrounding tissue. However, it is prohibitive to first-generation regenerative stroke therapies as it lacks an extracellular matrix; is surrounded by a glial scar; and is filled with extracellular fluid, debris, and inflammatory mediators. Hydrogels can remodel the hostile stroke cavity to be more receptive to repair due to their innate anti-inflammatory properties, good space conformity, ability to deliver a playload, and interface with the glial scar. Hydrogel 3D structure and tuneable mechanics provide physical support for endogenous and exogenous repair processes. Hydrogels are used extensively in the clinic, yet no clinical trials have been successfully commissioned to explore the potential of regenerative hydrogels in the treatment of chronic stroke. Stroke is an unmet clinical need with a paucity of treatments, at least in part because chronic stroke pathologies are prohibitive to ‘first-generation’ stem cell-based therapies. Hydrogels can remodel the hostile stroke microenvironment to aid endogenous and exogenous regenerative repair processes. However, no clinical trials have yet been successfully commissioned for these ‘second-generation’ hydrogel-based therapies for chronic ischaemic stroke regeneration. This review recommends a path forward to improve hydrogel technology for future clinical translation for stroke. Specifically, we suggest that a better understanding of human host stroke tissue–hydrogel interactions in addition to the effects of scaling up hydrogel volume to human-sized cavities would help guide translation of these second-generation regenerative stroke therapies. Stroke is an unmet clinical need with a paucity of treatments, at least in part because chronic stroke pathologies are prohibitive to ‘first-generation’ stem cell-based therapies. Hydrogels can remodel the hostile stroke microenvironment to aid endogenous and exogenous regenerative repair processes. However, no clinical trials have yet been successfully commissioned for these ‘second-generation’ hydrogel-based therapies for chronic ischaemic stroke regeneration. This review recommends a path forward to improve hydrogel technology for future clinical translation for stroke. Specifically, we suggest that a better understanding of human host stroke tissue–hydrogel interactions in addition to the effects of scaling up hydrogel volume to human-sized cavities would help guide translation of these second-generation regenerative stroke therapies. up to 48 hours. properties that help the formation of new vasculature. programmed cell death. provide blood–brain barrier and synaptic support and control of blood flow. abnormal increase in the number of astrocytes due to the destruction of nearby neurons. can be introduced into body tissue to replace an organ or bodily function. a barrier between blood and brain tissue made of endothelial cells, pericytes, and smooth muscle cells amongst other cells. helps produce newborn cells in the brain. involved in cell–cell interactions, cell adhesion, and migration recruits cells to sites of inflammation. 30 days or more. suppress the body's immune mechanisms. molecules released from damaged or dying cells that are a component of the innate immune response. measures electric activity in neurons. originating from within an organism. line blood vessels. increases the rate of production of red blood cells due to reduced oxygen. massive release of the excitatory amino acid l-glutamate into the extracellular space that causes cell death. external origin. tissue that surrounds cells that provide biomechanical and biochemical cues. a protein which is the chief constituent of silk. expressed by astrocytes. dense, cell-loaded fibrous network. involved in oxidation-reduction reactions. found in the peripheral blood and the bone marrow. escape of blood from a ruptured vessel. highly water saturated 3D matrix within which cells or other payloads can be encapsulate. from skin or blood, reprogrammed back into pluripotent state. in a living organism. a cell reprogrammed to become a neural stem cell. blockage in blood flow due to a clot. removes dead cells and stimulates the action of other immune system cells. present in tissues like umbilical cord, bone marrow, and fat tissue. act as the primary line of immune system defense in central nervous system. most commonly occluded artery in human stroke. death of cells due to disease, injury, or failure of the blood supply. found in brain tissue. properties that help the growth of new neurons from neural stem cells. the ability of the brain to form and reorganise synaptic connections. associated with pathogen infection and serve as ligands for host pattern recognition molecules. a substance made from a large number of similar units bonded together. descendants of stem cells that then further differentiate to create specialised cell types. interact with the glial scar to lessen the density of the glial scar without disrupting its integrity so that it is less of a prohibitive barrier to regeneration. engineered to cause desirable cellular interactions that contribute to the formation of new functional tissues for medical purposes. have the same shape and outline. has the ability to self-renew and develop into specialised cell types. lack of cerebral blood flow to part of the brain with lasting neurological deficits. 3–9 days. clot buster used in ischaemic stroke. mechanical method of removing a clot.