Self-Assembled Injectable Nanocomposite Hydrogels Coordinated by in Situ Generated CaP Nanoparticles for Bone...

Due to the great similarity to the natural extracellular matrix and minimally invasive surgeries, injectable hydrogels are appealing biomaterials in cartilage and bone tissue engineering. Nevertheless, undesirable mechanical properties and bioactivity greatly hamper their availability in clinic applications. Here, we developed an injectable nanocomposite hydrogel by in situ growth of CaP nanoparticles (ICPNs) during the free-radical polymerization of dimethylaminoethyl methacrylate (DMAEMA) and 2-hydroxyethyl methacrylate (HEMA) matrix (PDH) for bone regeneration. The ICPNs are self-assembled by incorporation of poly-l-glutamic acid (PGA) with abundant carboxyl functional groups during the formation of carboxyl-Ca²⁺ coordination and further CaP precipitation. Furthermore, the carboxyl groups of PGA could interact with the tertiary amines of DMAEMA fragments and thus improve the mechanical strength of hydrogels. Upon mixing solutions of DMAEMA and HEMA bearing PGA, Ca²⁺, and PO₄^3-, this effective and dynamic coordination led to the rapid self-assembly of CaP NPs and PDH nanocomposite hydrogels (PDH/mICPN). The obtained optimal nanocomposite hydrogels exhibited suitable injectable time, an enhanced tensile strength of 321.1 kPa, and a fracture energy of 29.0 kJ/m² and dramatically facilitated cell adhesion and upregulated osteodifferentiation compared to hydrogels prepared by blending ex situ prefabricated CaP NPs. In vivo experiments confirmed the promoted osteogenesis, which shows a striking contrast to pure PDH hydrogels. Additionally, the methacrylate groups on the monomers could easily be functionalized with aptamers and thereby facilitate recognition and capturing of bone marrow stromal cells both in vitro and in vivo and strengthen the bone regeneration. We believe that our conducted research about in situ self-assembled CaP nanoparticle-coordinated hydrogels will open a new avenue for bone regeneration in the future endeavors.