Driving endogenous bone regeneration by cell‐ and factor‐free biomaterials is the most ideal repair strategy. Herein, hybrid interleaved scaffold (HDSH) with nanosized interfacial integration is assembled by organic/inorganic interactive bonding at the nanoscale. With the help of transcriptome and proteome analysis, the regenerative mechanism of this scaffold is elaborated at the molecular level, which confirms that this strategy recreates a suitable immune microenvironment (anti‐inflammatory and M2‐polarizing) and drives functional cell and cytokine adhesion, as well as inchoate vascularization. It greatly enhances endogenous stem cell recruitment, and subsequently initiates robust vasculogenesis and osteogenesis. Significant bony reconstitution in the rabbit cranial defect model (Φ = 10 mm) is observed after 12 weeks, which realizes completely new bone coverage and 79% breaking load strength relative to the natural cranium. By enhancing nano‐sized functional interfacial integration, this strategy can provide effective guidance for developing highly bioactive bone‐regenerative implants.

Seeking high biological activity and osteoinductive ability has always been an urgent problem for three-dimensional-printed (3DP) bony implants. Here, a 3DP methacrylic anhydride-modified gelatin (GelMA)/ hydroxyapatite (HAp) scaffold with a high solid content of 82.5% was prepared and anchored by a functionalized polyphenol hydrogel. The scaffold and hydrogel were organically integrated into a bioinspired bony implant (HGH) by phenolic hydroxyl of hyaluronan derivatives conjugating amino groups of collagen I and GelMA and further chelating calcium ions of HAp. Compared with a simplex 3DP scaffold, this freeze-dried HGH presented better water retention, delayed degradation, and mechanical stability. It could promote migration, proliferation, and osteogenic differentiation of bone marrow stem cells in vitro. One week of implantation showed that it promoted directional migration of endogenous stem cells and early osteogenesis and angiogenesis. After 15 week surgery of rabbit skull defects, the BV/TV value of HGH returned to 73% of the normal group level. This strategy provided a new research idea for bone regeneration.

Integrating a biomimetic extracellular matrix to improve the microenvironment of 3D printing scaffolds is an emerging strategy for bone substitute design. Here, a “soft–hard” bone implant (BM‐g‐DPCL) consisting of a bioactive matrix chemically integrated on a polydopamine (PDA)‐coated porous gradient scaffold by polyphenol groups is constructed. The PDA‐coated “hard” scaffolds promoted Ca2+ chelation and mineral deposition; the “soft” bioactive matrix is beneficial to the migration, proliferation, and osteogenic differentiation of stem cells in vitro, accelerated endogenous stem cell recruitment, and initiated rapid angiogenesis in vivo. The results of the rabbit cranial defect model (Φ = 10 mm) confirmed that BM‐g‐DPCL promoted the integration between bone tissue and implant and induced the deposition of bone matrix. Proteomics confirmed that cytokine adhesion, biomineralization, rapid vascularization, and extracellular matrix formation are major factors that accelerate bone defect healing. This strategy of highly chemically bonded soft–hard components guided the construction of the bioactive regenerative scaffold.

Bone Regeneration In article number 2212738, Yong Sun and co‐workers construct a hybrid interwoven scaffold by nano‐sized interfacial integration between fibrillar matrix and hydrophilic nanohydroxyapatite, which recreated a suitable immune microenvironment and drove functional cell/cytokine adhesion to initiate robust vasculogenesis and osteogenesis.

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