A roadmap for promoting endogenous in situ tissue restoration using inductive bioscaffolds after acute brain injury.

The regeneration of brain tissue remains one of the greatest unsolved challenges in medicine and by many is considered unfeasible. Indeed, the adult mammalian brain does not regenerate tissue, but there is ongoing endogenous neurogenesis, which is upregulated after injury and contributes to tissue repair. This endogenous repair response is a conditio sine que non for tissue regeneration. However, scarring around the lesion core and cavitation provide unfavorable conditions for tissue regeneration in the brain. Based on the success of using extracellular matrix (ECM)-based bioscaffolds in peripheral soft tissue regeneration, it is plausible that the provision of an inductive ECM-based hydrogel inside the volumetric tissue loss can attract neural cells and create a de novo viable tissue. Following perturbation theory of these successes in peripheral tissues, we here propose 9 perturbation parts (i.e. requirements) that can be solved independently to create an integrated series to build a functional and integrated de novo neural tissue. Necessities for tissue formation, anatomical and functional connectivity are further discussed to provide a new substrate to support the improvement of behavioral impairments after acute brain injury. We also consider potential parallel developments of this tissue engineering effort that can support therapeutic benefits in the absence of de novo tissue formation (e.g. structural support to veterate brain tissue). It is envisaged that eventually top-down inductive "natural" bioscaffolds composed of decellularized tissues (i.e. ECM) will be replaced by bottom-up synthetic designer hydrogels that will provide very defined structural and signaling properties, potentially even opening up opportunities we currently do not envisage using natural materials.