Biomaterials to Neuroprotect the Stroke Brain: A Large Opportunity for Narrow Time Windows

Abstract

Ischemic stroke represents one of the most prevalent pathologies in humans and is a leading cause of death and disability. Anti-thrombolytic therapy with tissue plasminogen activator (t-PA) and surgical thrombectomy are the primary treatments to recanalize occluded vessels and normalize the blood flow in ischemic and peri-ischemic regions. A large majority of stroke patients are refractory to treatment or are not eligible due to the narrow time window of therapeutic efficacy. In recent decades, we have significantly increased our knowledge of the molecular and cellular mechanisms that inexorably lead to progressive damage in infarcted and peri-lesional brain areas. As a result, promising neuroprotective targets have been identified and exploited in several stroke models. However, these considerable advances have been unsuccessful in clinical contexts. This lack of clinical translatability and the emerging use of biomaterials in different biomedical disciplines have contributed to developing a new class of biomaterial-based systems for the better control of drug delivery in cerebral disorders. These systems are based on specific polymer formulations structured in nanoparticles and hydrogels that can be administered through different routes and, in general, bring the concentrations of drugs to therapeutic levels for prolonged times. In this review, we first provide the general context of the molecular and cellular mechanisms impaired by cerebral ischemia, highlighting the role of excitotoxicity, inflammation, oxidative stress, and depolarization waves as the main pathways and targets to promote neuroprotection avoiding neuronal dysfunction. In the second part, we discuss the versatile role played by distinct biomaterials and formats to support the sustained administration of particular compounds to neuroprotect the cerebral tissue at risk of damage.

Silk Fibroin: An Ancient Material for Repairing the Injured Nervous System

“…The delivery of drugs to the brain becomes even further challenging in injured brains, e.g., due to a traumatic injury or brain edema, as the result of damage limits the drug diffusion significantly [ 177 ]. Although a breach in the BBB permeability occurs after injury [ 178 ], systemically administered molecules might not necessarily have open access to the brain.…”

Tat-Endophilin A1 Fusion Protein Protects Neurons from Ischemic Damage in the Gerbil Hippocampus: A Possible Mechanism of Lipid Peroxidation and Neuroinflammation Mitigation as Well as Synaptic Plasticity

“…In addition, transient forebrain ischemia increases pro-inflammatory cytokine release from astrocytes and microglia to enhance neuronal damage in the hippocampus [ 8 , 9 ]. Several mechanisms have been proposed for the execution of neuronal damage upon ischemic insult [ 10 , 11 , 12 ]; however, there is a dearth of therapeutic agents owing to their limited ability to cross the blood–brain barrier as well as the cell membrane. To overcome these difficulties, cell-penetrating peptides (CPPs) have been introduced [ 13 ], and one of these CPPs consists of the trans -acting activator of transcription (Tat), originating from the human immunodeficiency virus.…”

Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery

“…The development of drug delivery systems may be a key element to achieve successful therapy [ 26 , 27 , 28 ]. The particular advantages of drug delivery systems in brain injury include that (i) blood-brain barrier permeability for a specific drug is substantially increased, (ii) drug delivery can be targeted selectively to sites at risk of injury, (iii) these systems carry the potential of gradual drug release to elongate drug exposure, and (iv) local drug concentration may become high enough to exert therapeutic effect, without the risk of drug accumulation in non-target tissues, which carries the risk of undesirable side effects or off-target toxicity.…”