Hierarchical Therapeutic Ion‐Based Microspheres with Precise Ratio‐Controlled Delivery as Microscaffolds for In Situ Vascularized Bone Regeneration

Abstract

Therapeutic ions, such as Si and Mg, play vital roles in regulating metabolism and promoting tissue repair, hence providing an efficient strategy in tissue engineering. The regenerative outcome is strongly dependent on the targeted delivery and controlled release of therapeutic ions. Nevertheless, it remains challenging to deliver multiple ions at controlled manners and ratios. Herein, hierarchical therapeutic ion‐based microspheres are fabricated. The coordinated release of Mg and Si ions at pre‐set ratios is achieved, based on which, Mg favors osteogenesis by inducing highly efficient cell recruitment and angiogenesis, and Si promotes massive collagen secretion and biomineralization to accelerate the bone maturation process. These therapeutic ion‐based microspheres (namely PNM2) can steadily release Mg and Si ions at an optimized ratio of 2:1, which shows the most significant synergistic effect on angiogenesis and osteogenesis. Furthermore, in a rat calvarial defects model, the volume and maturity of the vascularized neo‐bone tissue regenerated with PNM2 microspheres are comparable with or even surpassing those defects regenerated with growth factors and/or cell‐laden scaffolds. Overall, this platform provides a controllable strategy for the coordinated delivery of Mg/Si ions, opening a new avenue for developing therapeutic ion‐based microscaffold for tissue engineering.

Biomaterials to promote vascularization in tissue engineering organs and ischemic fibrotic diseases

“…In a rat skull defect model, PNM2 microspheres can significantly increase the volume of regenerating vascularized new bone tissue (Figure 4D). 68 [SrCuSi 4 O 10 ] nanosheets can continuously release bioactive ions (Sr, Cu, Si), which promote the cell proliferation of HUVECs in vitro and improve vascularized bone regeneration in vivo 73 …”

“…In a rat skull defect model, PNM2 microspheres can significantly increase the volume of regenerating vascularized new bone tissue (Figure 4D). 68 69 (F) The engineered exosomes encapsulate a vascular endothelial growth factor (VEGF) plasmid. Copyright permission from Zha et al 70 Angiogenic cytokines, peptides, and nucleic acids loaded on tissue-engineered scaffolds can promote the reconstruction of vascularized bone tissue.…”

“…Copyright permission from Wang et al 67 (D) The angiogenic peptide (AP)‐delivered tricalcium phosphate (TCP)/Poly(lactic‐co‐glycolic acid) (PLGA) composite scaffolds can be implanted in bone defects to induce improve bone regeneration with required vascularization. Copyright permission from Wan et al 68 (E) The role of basic fibroblast growth factor (bFGF) released from in situ tissue engineering scaffold (iTE‐scaffold) on periodontal bone repair. Copyright permission from Ding et al 69 (F) The engineered exosomes encapsulate a vascular endothelial growth factor (VEGF) plasmid.…”

A SiO2 layer on PEO-treated Mg for enhanced corrosion resistance and bone regeneration

“…Overall, these findings indicated that the PEO@SiO coating effectively promoted angiogenesis attributed to the release of Si ions. It is well established that Si has a positive effect on angiogenesis in vitro and in vivo (Mao et al, 2017;Wan et al, 2022). For example, Si doping of biomaterials is beneficial for the proliferation of HUVEC and upregulates the expression of angiogenesis-related genes (Wang et al, 2018b).…”

Strategy of a cell-derived extracellular matrix for the construction of an osteochondral interlayer

“…The electrospun fibers (PLLA/Gel) are composed of poly(L-lactide) (PLLA) and gelatin (Gel), which showed excellent cell affinity and good mechanical support for cell sheets and D-ECMs as displayed in our previous research studies. [32][33][34] BMSCs are the main cells involved in the osteochondral repair via microfracture treatment in clinical therapy, 35,36 as illustrated in Scheme 1, we herein investigated the capacity of the D-ECMs secreted by BMSCs, MC3T3, Cho, and HCho to modulate the biological responses of BMSCs, followed by in vivo evaluations using a subcutaneous implantation model in rats. Promisingly, the findings of this study may lay a foundation to construct a gradient osteochondral scaffold with a D-ECMbased intermediate layer for enhanced cartilage-to-bone transition remodelling, which decides the subsequent osteochondral regeneration.…”