Injectable thermoresponsive hydrogels as drug delivery system for the treatment of central nervous system disorders: A review.

The central nervous system (CNS), consisting of the brain, spinal cord, and retina, superintends to the acquisition, integration and processing of peripheral information to properly coordinate the activities of the whole body. Neurodegenerative and neurodevelopmental disorders, trauma, stroke, and brain tumors can dramatically affect CNS functions resulting in serious and life-long disabilities. Globally, the societal and economic burden associated with CNS disorders continues to grow with the ageing of the population thus demanding for more effective and definitive treatments. Despite the variety of clinically available therapeutic molecules, medical interventions on CNS disorders are mostly limited to treat symptoms rather than halting or reversing disease progression. This is attributed to the complexity of the underlying disease mechanisms as well as to the unique biological microenvironment. Given its central importance, multiple barriers, including the blood brain barrier and the blood cerebrospinal fluid barrier, protect the CNS from external agents. This limits the access of drug molecules to the CNS thus contributing to the modest therapeutic successes. Loco-regional therapies based on the deposition of thermoresponsive hydrogels loaded with therapeutic agents and cells are receiving much attention as an alternative and potentially more effective approach to manage CNS disorders. In this work, the current understanding and challenges in the design of thermoresponsive hydrogels for CNS therapy are reviewed. First, the biological barriers that hinder mass and drug transport to the CNS are described, highlighting the distinct features of each barrier. Then, the realization, characterization and biomedical application of natural and synthetic thermoresponsive hydrogels are critically presented. Advantages and limitations of each design and application are discussed with the objective of identifying general rules that could enhance the effective translation of thermoresponsive hydrogel-based therapies for the treatment of CNS disorders.