Bioactive cell niche mediating uniform thermal stimulus for BMSC neural differentiation through TRPV1 channel activation

As one of the physical stimulus tools to target neuromodulation-related biological entities, mild thermal stimulus has attracted increasing attention in unraveling neural differentiation processing. However, thermal stimulus for neural behavior regulation has been relatively unexplored due to the challenge in finding a good method of exerting thermal stimulus. Considering the distance-dependent temperature preservation efficiency and the native importance of a bioactive matrix, we herein put forward the design of a photothermal hydrogel by immobilizing photothermal dopamine (DA) in hyaluronic acid (HA) chains. Benefitting from the minuscule disaccharide repeat unit size (≈1 nm) of HA used for the DA grafting, and the additional adhesion capacity of the DA for recruiting cells, a uniformly close distance from heating source to cells is realized. Therefore, we successfully established a near-infrared light initiated photothermal stimulus platform, with full bioactivity and high thermal manipulation efficiency. After extensive characterization, we proved that the thermal activation, from matrix to cells, triggered TRPV1 ion channel opening and Ca²⁺ influx, which finally promoted neural differentiation of bone marrow mesenchymal stem cells (BMSCs). This work broadens the possibilities of polymeric photothermal materials, and is of great significance for remotely manipulating neural and other cellular machinery for stem cell therapeutics in tissue engineering.