2-N, 6-O sulfated chitosan evokes periosteal stem cells for bone regeneration.

Musculoskeletal injuries and bone defects represent a significant clinical challenge, necessitating innovative approaches for effective bone tissue regeneration. In this study, we investigated the potential of harnessing periosteal stem cells (PSCs) and glycosaminoglycan (GAG)-mimicking materials for in situ bone regeneration. Our findings demonstrated that the introduction of 2-N, 6-O sulfated chitosan (26SCS), a GAG-like polysaccharide, enriched PSCs and promoted robust osteogenesis at the defect area. Mechanistically, 26SCS amplifies the biological effect of endogenous platelet-derived growth factor-BB (PDGF-BB) through enhancing the interaction between PDGF-BB and its receptor PDGFRß abundantly expressed on PSCs, resulting in strengthened PSC proliferation and osteogenic differentiation. As a result, 26SCS effectively improved bone defect repair, even in an osteoporotic mouse model with lowered PDGF-BB level and diminished regenerative potential. Our findings suggested the significant potential of GAG-like biomaterials in regulating PSC behavior, which holds great promise for addressing osteoporotic bone defect repair in future applications.

Matrix stiffness regulates osteoclast fate through integrin-dependent mechanotransduction.

Osteoclasts ubiquitously participate in bone homeostasis, and their aberration leads to bone diseases, such as osteoporosis. Current clinical strategies by biochemical signaling molecules often perturb innate bone metabolism owing to the uncontrolled management of osteoclasts. Thus, an alternative strategy of precise regulation for osteoclast differentiation is urgently needed. To this end, this study proposed an assumption that mechanic stimulation might be a potential strategy. Here, a hydrogel was created to imitate the physiological bone microenvironment, with stiffnesses ranging from 2.43kPa to 68.2kPa. The impact of matrix stiffness on osteoclast behaviors was thoroughly investigated. Results showed that matrix stiffness could be harnessed for directing osteoclast fate in vitro and in vivo. In particular, increased matrix stiffness inhibited the integrin ß3-responsive RhoA-ROCK2-YAP-related mechanotransduction and promoted osteoclastogenesis. Notably, preosteoclast development is facilitated by medium-stiffness hydrogel (M-gel) possessing the same stiffness as vessel ranging from 17.5 kPa to 44.6 kPa by partial suppression of mechanotransduction, which subsequently encouraged revascularization and bone regeneration in mice with bone defects. Our works provide an innovative approach for finely regulating osteoclast differentiation by selecting the optimum matrix stiffness and enable us further to develop a matrix stiffness-based strategy for bone tissue engineering.

Engineering Neutrophil Immunomodulatory Hydrogels Promoted Angiogenesis.

Timely restoration of blood supply following ischemia is critical to rescue damaged tissue. However, clinical efficacy is hampered by the inflammatory response after ischemia. Whether inflammation fine tunes the angiogenesis and the function of blood vessels via the heterogeneity of neutrophils remain poorly understood. Herein, the objective of this work is to incorporate the growth factors secreted by neutrophils into a porous gelatin methacrylate (GelMA) hydrogel, which subsequently is used as a novel regenerative scaffold with defined architecture for ischemia. We demonstrate that anti-inflammatory neutrophils (N2-polarized neutrophils) play an important role in promoting the migration of human umbilical vein endothelial cells (HUVECs) and formation of capillary-like networks in vitro. More importantly, vascular anastomosis can be achieved by modulating the neutrophils to N2 phenotype. In addition, N2-polarized composite hydrogel scaffolds can regulate inflammation, maintain the survival of exogenous cells, and promote angiogenesis in vivo. Notably, the composite hydrogel scaffolds promote neovascularization during exogenous introduction of endothelial cells by anastomosis. Taken together, this study highlights N2-polarized neutrophils composite hydrogels can achieve vascularization rapidly by regulating inflammation and promoting vascular anastomosis. This work lays the foundation for research into the treatment of ischemia and may inspire further research into novel treatment options.

Calcium phosphate-based materials regulate osteoclast-mediated osseointegration.

Calcium phosphate-based materials (CaP) have been widely used as bone graft substitutes with a decent osseointegration. However, the mechanism whereby cells function and repair the bone defect in CaP micro-environment is still elusive. The aim of this study is to find the mechanism how osteoclast behaviors mediate bone healing with CaP scaffolds. Recent reports show that behaviors of osteoclast are closely related with osteogenesis, thus we make a hypothesis that active osteoclast behaviors induced by CaP facilitate bone healing. Here, we found a new mechanism that CaP can regulate osteoclast-mediated osseointegration. Calcium phosphate cement (CPC) is selected as a representative CaP. We demonstrate that the osteoclast-mediated osseointegration can be strongly modulated by the stimulation with CaP. An appropriate Ca/P ratio in CaP can effectively promote the RANKL-RANK binding and evoke more activated NF-κB signaling transduction, which results in vigorous osteoclast differentiation. We observe significant improvement of bone healing in vivo, owing to the active coupling effect of osteoclasts. What is more noteworthy is that the phosphate ions released from CaP can be a pivotal role regulating osteoclast activity by changing Ca/P ratio readily in materials. These studies suggest the potential of harnessing osteoclast-mediated osteogenesis in order to develop a materials-manipulated approach for improving osseointegration.

Nano-needle strontium-substituted apatite coating enhances osteoporotic osseointegration through promoting osteogenesis and inhibiting osteoclastogenesis.

Implant loosening remains a major clinical challenge for osteoporotic patients. This is because osteoclastic bone resorption rate is higher than osteoblastic bone formation rate in the case of osteoporosis, which results in poor bone repair. Strontium (Sr) has been widely accepted as an anti-osteoporosis element. In this study, we fabricated a series of apatite and Sr-substituted apatite coatings via electrochemical deposition under different acidic conditions. The results showed that Ca and Sr exhibited different mineralization behaviors. The main mineralization products for Ca were CaHPO4·2H2O and Ca3(PO4)2 with the structure changed from porous to spherical as the pH values increased. The main mineralization products for Sr were SrHPO4 and Sr5(PO4)3OH with the structure changed from flake to needle as the pH values increased. The in vitro experiment demonstrated that coatings fabricated at high pH condition with the presence of Sr were favorable to MSCs adhesion, spreading, proliferation, and osteogenic differentiation. In addition, Sr-substituted apatite coatings could evidently inhibit osteoclast differentiation and fusion. Moreover, the in vivo study indicated that nano-needle like Sr-substituted apatite coating could suppress osteoclastic activity, improve new bone formation, and enhance bone-implant integration. This study provided a new theoretical guidance for implant coating design and the fabricated Sr-substituted coating might have potential applications for osteoporotic patients.