Angiogenesis-osteogenesis coupling lithium-loaded bioglass/GelMA hydrogel for bone regeneration

Glucocorticoids are among the most common causes of nontraumatic osteonecrosis of the femoral head among young people. Bone grafting and core decompression are mainly used to treat glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) clinically. However, the results are usually not as satisfactory as expected. Herein, we report a functional hydrogel used to promote bone repair in GIONFH. Compared with traditional therapy, because of the adipogenic differentiation of mesenchymal stem cells in the ONFH region, the inhibition of fat infiltration better promotes bone remodeling. Given that hydrogels can serve as ideal carriers for continuous drug release to improve the efficiency of treatment and application in vivo, we encapsulated lithium-modified bioglass (M-Li) in a methacryloyl gelatin (GelMA) to construct a lithium-loaded bioglass hydrogel (GM/M-Li).

GM/M-Li hydrogel was synthesized and characterized, and co-cultured with BMSCs, HUVECs, and 3T3-L1 cells, and the lithium concentration was selected after evaluating the biotoxicity and verifying the functions of osteogenesis, angiogenesis, and inhibition of adipogenesis. In addition, New Zealand rabbits were used to establish femoral head necrosis model, and the therapeutic effect was evaluated by establishing bone tunnels through medullary core decompression, and injecting hydrogel into the necrotic bone tissues after removing them. Comparisons between multiple groups were analyzed by one-way or two-way ANOVA.

GM/M-Li hydrogel exhibited a suitable compressive modulus of 4 kPa, and satisfactory biocompatibility, supporting cell proliferation in an adequate microenvironment. Additionally, the synthesized lithium-loaded bioglass, featuring a nanoscale size of 217 ± 3.2 nm, possessed high specific surface area, excellent intracellular effects, and efficient carrier properties. The sustained release of Li⁺ and Si⁴⁺ was observed to last over 35 days, significantly enhanced the proliferation and migration of bone marrow mesenchymal stem cells and human umbilical vein endothelial cells and promoted osteogenesis and angiogenesis both in vitro and in vivo. In vivo, micro-CT analysis at 12 weeks revealed that bone mineral density (BMD) of GM/M-Li group was significantly increased by 50 %, while trabecular separation (Tb.Sp) decreased by 20 %, compared to the model group. Histological and immunofluorescence staining were as well confirmed enhanced osteogenesis and angiogenesis.

Considering the limited therapeutic options for early femoral head necrosis, in order to enhance the efficacy of the treatment and to prevent subchondral osteoradionecrosis collapse of the femoral head, we designed GM/M-Li hydrogels to verify the biocompatibility and the ability of osteogenensis, angiogenesis and fatty infiltration both in vitro and in vivo. In general, GM/M-Li hydrogels provided an appropriate microenvironment for orchestrating ONFH bone regeneration. Therefore, our research presents a promising regenerative platform to improve the ONFH microenvironment and accelerate bone remodeling.

This study presented a novel multi-functional regenerative strategy that simultaneously targeted osteogenesis, angiogenesis, and adipogenesis, using lithium-integrated bioactive hydrogel, offering a comprehensive and promising therapeutic platform beyond conventional bone grafts.