Effective treatments to overcome osteoblast/osteoclast imbalance are the key to achieving desirable bone regeneration for osteoporosis patients. When used for local bone repair, parathyroid hormone (PTH) often leads to either excessive osteoclasts under continuous exposure or insufficient osteoclasts with pulsatile release of PTH. Herein, an injectable multifunctional in situ-generated calcium phosphate nanoparticle (ICPN)-coordinated poly(dimethylaminoethyl methacrylate-co-2-hydroxyethyl methacrylate) (DHCP) hydrogel loaded with PTH for near-infrared (NIR)-stimulated release is developed to achieve bone regeneration in an ovariectomized (OVX) model. Photothermal-responsive poly(N-acryloyl glycinamide-co-acrylamide) PNAmindocyanine green ICG-PTH microspheres (PIP MSs) endow a dual-mode release system with a sustained release at low concentrations, a pulse release of PTH, and in situ pore formation properties. The PIP MS-encapsulated DHCP hydrogel (DHCP-10PIP/d) is injected into the bone defects of OVX rats. Under NIR irradiation, the localized photothermal effects trigger on-demand PTH release and in situ micropores formation through the gel-sol transition of PIP MSs, and the repeated treatment is harmless to the bioactivity of PTH. This platform can enhance osteoblast and osteoclast activity at the same time both in vitro and in vivo and repair the cranial defects of OVX rats successfully. Overall, this work provides a promising strategy for PTH delivery to repair osteoporotic bone defects.

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.