A review of bigels for neurotrauma therapeutics: Structural insights for tissue microenvironment alignment

Neural injuries pose a significant clinical challenge due to the brain's limited regenerative capacity and the complexity of developing biomaterials that can provide mechanical support and localized therapeutic delivery. Conventional biomaterials such as hydrogels and electrospun scaffolds exhibit limitations, including suboptimal mechanical integrity and uncontrolled drug diffusion. Bigels, biphasic systems composed of interpenetrating hydrophilic and hydrophobic phases, offer tunable viscoelasticity, enhanced drug loading capacity, and structural adaptability, making them promising candidates for addressing the multifaceted requirements of neurotherapeutics applications. Despite their established applications in the transdermal application, the potential of bigels in neurotherapeutics remains underexplored. This review critically examines bigel formulation strategies, physicochemical characteristics, and neuroregenerative potential. Key analytical techniques, including oscillatory rheology, scanning electron microscopy, and Fourier-transform infrared spectroscopy, are explored to assess pore morphology, viscoelastic behavior, and molecular interactions. The role of bigels in neuronal survival, axonal regeneration, and neuroinflammation modulation is highlighted, alongside considerations for scalability, batch-to-batch reproducibility, and regulatory compliance under Good Manufacturing Practices (GMP). Future research should focus on optimizing biodegradation kinetics, neurotrophic factor release profiles, and preclinical validation in traumatic brain injury and spinal cord injury models. Advancing bigel technology could facilitate their clinical translation as neuroprotective scaffolds in regenerative medicine.