Spatiotemporal Regulation of the Bone Immune Microenvironment via Dam‐Like Biphasic Bionic Periosteum for Bone Regeneration

Abstract

The bone immune microenvironment (BIM) regulates bone regeneration and affects the prognosis of fractures. However, there is currently no effective strategy that can precisely modulate macrophage polarization to improve BIM for bone regeneration. Herein, a hybridized biphasic bionic periosteum, inspired by the BIM and functional structure of the natural periosteum, is presented. The gel phase is composed of genipin-crosslinked carboxymethyl chitosan and collagen self-assembled hybrid hydrogels, which act as the "dam" to intercept IL-4 released during the initial burst from the bionic periosteum fiber phase, thus maintaining the moderate inflammatory response of M1 macrophages for mesenchymal stem cell recruitment and vascular sprouting at the acute fracture. With the degradation of the gel phase, released IL-4 cooperates with collagen to promote the polarization towards M2 macrophages, which reconfigure the local microenvironment by secreting PDGF-BB and BMP-2 to improve vascular maturation and osteogenesis twofold. In rat cranial defect models, the controlled regulation of the BIM is validated with the temporal transition of the inflammatory/anti-inflammatory process to achieve faster and better bone defect repair. This strategy provides a drug delivery system that constructs a coordinated BIM, so as to break through the predicament of the contradiction between immune response and bone tissue regeneration.

Construction of a layer-by-layer self-assembled rosemarinic acid delivery system on the surface of CFRPEEK implants for enhanced anti-inflammatory and osseointegration activities

“…59 Research has shown that implants with excellent immune-inflammatory regulation ability, which creates an advantageous bone immune microenvironment in the early stage of osteogenesis, can enhance osteoanagenesis. 60,61 As the LBL layers gradually degrade, the remaining RA continues to release, and the cumulative release concentration is about 0.06 mg mL À1 during the subsequent release period, which will promote osteoblast differentiation. 6 The entire release process lasts for at least 21 days, and the long-term release of RA can effectively promote osteoanagenesis in the long osteogenic cycle.…”

Electrospun Biomimetic Periosteum Capable of Controlled Release of Multiple Agents for Programmed Promoting Bone Regeneration

“…According to previous reports, calcium salt deposition and bone matrix mineralization are important stages of bone formation. [29] The formation of calcium nodules in the extracellular matrix was analyzed by Alizarin Red S staining. Coaxial-Si and Bilayer-DFO/ASP/Si produced more calcium nodules on days 7 and 14, significantly higher than Coaxial-B (Figures 5C,D).…”

“…A rat skull defect model is commonly employed to validate the reparative efficacy of the artificial periosteum. [29,68] It should be emphasized that combining filler repair with an artificial periosteum can significantly enhance its clinical applicability; However, our study is aimed to investigate the effectiveness of biomimetic periosteum in repairing bone defects without incorporating fillers into the rat skull defect model, thus ensuring unambiguous evaluation of the reparative effect. Therefore, to further validate the osteogenic effect of the biomimetic periosteum in vivo, a rat skull bone defect model was established, and replaced the native periosteum with the biomimetic periosteum (Figures 7A and S10).…”

“…[26][27][28] Several studies have attempted to improve the immune microenvironment, promote angiogenesis, and accelerate bone regeneration through electrospun nanofibers and surface modification to mimic periosteum structures. [29,30] These artificial periosteums have been confirmed to have positive bone defect repair results; However, these studies did not fully mimic the asymmetric structure and functions of each layer of the natural periosteum. Additionally, bone defect repair requires protection against adverse external tissue effects and an internal microenvironment to regulate osteogenesis.…”

Therapeutic Agent-Loaded Fibrous Scaffolds for Biomedical Applications

“…Drug-mixing electrospinning method [246] Wound healing Electrospinning method Vitamin K3 carnosine peptide (agent for antibacterial activity)…”