title: Bioinspired trimodal macro/micro/nano-porous scaffolds loading rhBMP-2 for complete regeneration of critical size bone defect.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China; Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lin
authors.affiliation: The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Yuanman
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Haoyi
authors.initials: H
authors.lastname: Niu
authors.affiliation: Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Guo
authors.affiliation: Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China. Electronic address: yyuan@ecust.edu.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China; Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China. Electronic address: liucs@ecust.edu.cn.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000737:chemistry; D005898:Glass / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D055767:Immobilized Proteins / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010012:Osteogenesis / Q000187:drug effects; D016062:Porosity; D011817:Rabbits; D011884:Radius / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013194:Staining and Labeling; D054457:Tissue Scaffolds / Q000737:chemistry*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D055114:X-Ray Microtomography
chemical_list: D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D005456:Fluorescent Dyes; D055767:Immobilized Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2
keywords: Critical size bone defect; Mesoporous bioactive glass; Recombinant human bone morphogenetic protein-2; Trimodal macro/micro/nano-porous architecture