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Synchronization of material resorption and new bone formation is vital to achieve harmonious bone regeneration in the treatment of large bone defects. To exposit the resorption/osteogenesis properties in the guided bone repairing, rhBMP-2-loaded trimodal macro/micro/nano-porous bioactive glass scaffolds (TMS-rhBMP-2) were set as substrate model. We penetratingly investigated the particular function of hierarchical structure and incorporated rhBMP-2 in the resorption/osteogenesis, and dissected the cellular interplay throughout the regenerative procedure. The results suggested that rhBMP-2 significantly facilitated osteoclastogenesis-mediated scaffold degradation and strikingly up-regulated mesenchymal stem cells (MSCs)-involved osteogenesis in vitro. Further gene microarray and related proteins expression indicated that in the presence of rhBMP-2, MSCs rather than differentiated MSCs could exert synergistic effects on osteoclastogenesis, osteoclasts maturation and resorptive function; meanwhile, rhBMP-2-induced MSCs osteogenesis was also strengthened by the osteoclasts. In vivo micro-CT, X-ray, kinetic and histological analyses qualitatively and quantitively demonstrated the optimized coupling of bioresorption/osteogenesis and the most rapid regeneration in TMS-rhBMP-2. Consequently, with rhBMP-2 acted as ignitor and MSCs/osteoclasts interaction as booster, a harmonious bone regeneration was obtained. Besides, long-term magnetic resonance imaging (MRI) in virtue of Gd 3+ suggested that the degradation products mainly distributed in liver and spleen, verifying the accumulation/discharge profiles and safety application of TMS-rhBMP-2 system in vivo. This study will not merely provide guidance for the design of clinical bone repairing materials, but shed substantial light on the multicell-mediated tissue regeneration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Critical size bone defects raise great demands for efficient bone substitutes. Mimicking the hierarchical porous architecture and specific biological cues of natural bone has been considered as an effective strategy to facilitate bone regeneration. Herein, a trimodal macro/micro/nano-porous scaffold loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) was developed. With mesoporous bioactive glass (MBG) as matrix, a trimodal MBG scaffold (TMS) with enhanced compressive strength (4.28 MPa, porosity of 80%) was prepared by a "viscosity controlling" and "homogeneous particle reinforcing" multi-template process. A 7.5 nm, 3D cubic (Im3m) mesoporous structure was tailored for a "size-matched entrapment" of rhBMP-2 to achieve sustained release and preserved bioactivity. RhBMP-2-loaded TMS (TMS/rhBMP-2) induced excellent cell attachment, ingrowth and osteogenesis in vitro. Further in vivo ectopic bone formation and orthotopic rabbit radius critical size defect results indicated that compared to the rhBMP-2-loaded bimodal macro/micro- and macro/nano-porous scaffolds, TMS/rhBMP-2 exhibited appealing bone regeneration capacity. Particularly, in critical size defect, complete bone reconstruction with rapid medullary cavity reunion and sclerotin maturity was observed on TMS/rhBMP-2. On the basis of these results, TMS/rhBMP-2 developed here represents a promising bone substitute for clinical application and the concepts proposed in this study might provide new thoughts on development of future orthopedic biomaterials., Statement of Significance: Limited self-regenerating capacity of human body makes the reconstruction of critical size bone defect a significant challenge. Current bone substitutes often exhibit undesirable therapeutic efficacy due to poor osteoconductivity or low osteoinductivity. Herein, TMS/rhBMP-2, an advanced mesoporous bioactive glass (MBG) scaffold with osteoconductive trimodal macro/micro/nano-porosity and osteoinductive rhBMP-2 delivery was developed. The preparative and mechanical problems of hierarchical MBG scaffold were solved without affecting its excellent biocompatibilities, and rhBMP-2 immobilization in sizematched mesopores was first explored. Combining structural and biological cues, TMS/rhBMP-2 achieved a complete regeneration with rapid medullary cavity reunion and sclerotin maturity in rabbit radius critical size defects. The design conceptions proposed in this study might provide new thoughts on development of future orthopedic biomaterials., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)‐co‐poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia‐mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion‐chelating after injection, giving rise to the activation of HIF‐1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF‐1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial‐based iron ion‐chelating and ensuing hypoxia‐mimicking, representing a novel and promising concept for future application in bone regeneration. [ABSTRACT FROM AUTHOR]

The reconstruction of the vascular network is crucial step in bone regeneration. Therefore, effectively modulating angiogenesis-osteogenesis coupling in bone tissue engineering scaffolds is currently an urgent need. In this study, we employed silane coupling agents containing double bonds to modify tetrahedral silicate, resulting in the preparation of a photocurable precursor of 45S5 bioactive glass (PG). PG was utilized as a binding agent for tricalcium phosphate (TCP) powder, and we employed a one-step photocuring 3D printing approach to fabricate PG/TCP (PT) scaffolds. Furthermore, the endothelial progenitor cell-derived exosomes (EPC-exos) was encapsulated by GelMA and anchored onto the PT scaffolds to create exosome-functionalized PT/G@Exos composite scaffolds. In summary, the PT/G@Exos composite scaffold effectively orchestrates the creation of a vascularized bone regeneration microenvironment by releasing EPC-exos, as well as calcium, silicon (Si), and phosphorus (P) elements. This enables an efficient modulation of the angiogenesis-osteogenesis coupling of bioactive scaffolds and accelerates bone regeneration. [ABSTRACT FROM AUTHOR]