TRPV4 Activator-Containing CMT-Hy Hydrogel Enhances Bone Tissue Regeneration In Vivo by Enhancing Mitochondrial Health

Treating different types of bone defects is difficult, complicated, time-consuming, and expensive. Here, we demonstrate that transient receptor potential cation channel subfamily V member 4 (TRPV4), a mechanosensitive, thermogated, and nonselective cation channel, is endogenously present in the mesenchymal stem cells (MSCs). TRPV4 regulates both cytosolic Ca²⁺ levels and mitochondrial health. Accordingly, the hydrogel made from a natural modified biopolymer carboxymethyl tamarind CMT-Hy and encapsulated with TRPV4-modulatory agents affects different parameters of MSCs, such as cell morphology, focal adhesion points, intracellular Ca²⁺, and reactive oxygen species- and NO-levels. TRPV4 also regulates cell differentiation and biomineralization in vitro. We demonstrate that 4α-10-CMT-Hy and 4α-50-CMT-Hy (the hydrogel encapsulated with 4αPDD, 10 and 50 nM, TRPV4 activator) surfaces upregulate mitochondrial health, i.e., an increase in ATP- and cardiolipin-levels, and improve the mitochondrial membrane potential. The same scaffold turned out to be nontoxic in vivo. 4α-50-CMT-Hy enhances the repair of the bone-drill hole in rat femur, both qualitatively and quantitatively in vivo. We conclude that 4α-50-CMT-Hy as a scaffold is suitable for treating large-scale bone defects at low cost and can be tested for clinical trials.