Developing High-Fidelity In Vitro Models of Traumatic Brain Injury to Test Therapeutic Biomaterials

Introduction: Traumatic brain injury (TBI)Traumatic Brain Injury (TBI) can cause significant disability and is a leading cause of death amongst under 40s. There is a clinical need to develop new and effective therapies for TBI but this represents a significant challenge given the complexity of the injury and pathological barriers to regenerationRegeneration. Development of combinatorial therapeutic biomaterialsBiomaterials, capable of achieving multiple clinical goals such as promoting nerve growth, disrupting scarring tissue and modulating neuroinflammation holds promise to augment repair. Fine tuning material properties during developmental screening to optimise efficacy requires complex and pathology mimetic models of TBI. Animal models are not appropriate for initial optimisation given their expense, requirement for infrastructure and expertise and associated ethical hurdles, requiring appropriate alternatives to simulate TBI. Our goal in this chapter is to review the current state of the art in modelling TBI using in vitro modelIn vitro model systems which replicate complex pathological processes of TBI, can be interfaced with biomaterialsBiomaterials, provide detailed histological and functional readouts, whilst offering ease of use in the laboratory. Methods: Searches of literature in PubMed and Web of Science were conducted using combinations of “traumatic brain injury”Traumatic Brain Injury (TBI), “neurological injuryNeurological injury”, “in vitro modelIn vitro model”, “3D model”3D model, “stem cellsStem cell”, “organoidsOrganoids”, “organotypicOrganotypic”, “biomaterialsBiomaterials”, “nanomaterialsNanomaterials” and “tissue engineeringTissue engineering”. Primary research articles, literature reviews and book chapters were used to inform the writing of the article. Results: Many in vitro modelsIn vitro model of TBI exist, ranging in complexity from monocellular cultures to 3D self-assembling organoidsOrganoids and 3D organotypicOrganotypic slices. Each system has advantages and disadvantages for testing therapeutic biomaterialsBiomaterials in TBI. The primary drawbacks of the most common models are lack of complex modelling of pathology (especially the neuroimmune component), limited capacity for biomaterialBiomaterials interfacing and limited functional readouts. However, we identify promising in vitro modelsIn vitro model and new strategies to address these challenges. Conclusions: Novel advances in in vitro TBI modelling can allow for a translational pipeline of therapeutic biomaterialBiomaterials development in pathology simulating, yet facile benchtop systems.