Localization and promotion of recombinant human bone morphogenetic protein-2 bioactivity on extracellular matrix mimetic chondroitin sulfate-functionalized calcium phosphate cement scaffolds

[Display omitted] Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium p...

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Bibliographic Details
Published in:Acta biomaterialia 2018-04, Vol.71, p.184-199
Main Authors: Huang, Baolin, Wu, Zihan, Ding, Sai, Yuan, Yuan, Liu, Changsheng
Format: Article
Language:English
Subjects:
Animals
Biocompatibility
Bioinspired interactions
Biological activity
Biomedical materials
Biomimetics
Bone Cements - chemistry
Bone growth
Bone matrix
Bone morphogenetic protein 2
Bone Morphogenetic Protein 2 - chemistry
Bone Morphogenetic Protein 2 - pharmacokinetics
Bone morphogenetic protein receptor type I
Bone morphogenetic protein receptors
Bone regeneration
Calcium
Calcium phosphates
Calcium Phosphates - chemistry
Calcium sulfate
Cement
Cements
Chondroitin sulfate
Chondroitin Sulfates - chemistry
Controlled release
Decapentaplegic protein
Delayed-Action Preparations - chemistry
Delayed-Action Preparations - pharmacokinetics
Extracellular matrix
Extracellular Matrix - chemistry
Extracellular signal-regulated kinase
Fruit flies
Glycosaminoglycans
Growth factors
Humans
In vivo methods and tests
Kinases
Kinetics
Localization
Male
Mimicry
Ossification (ectopic)
Osteogenesis
Protein transport
Proteins
Rats
Rats, Sprague-Dawley
Receptors
Recombinant Proteins - chemistry
Recombinant Proteins - pharmacokinetics
Regeneration
Regeneration (physiology)
rhBMP-2 bioactivity
Scaffolds
Stimulation
Sulfates
Sustained release
Tissue engineering
Translocation
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Summary:[Display omitted] Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) scaffolds through specific noncovalent interactions. CS, one of the core glycosaminoglycans, was covalently conjugated onto CPC scaffolds with the assistance of polydopamine (PDA) and further immobilized rhBMP-2 in a biomimetic form. The CPC-PDA-CS scaffolds not only controlled the release kinetics and presentation state of rhBMP-2 but also effectively increased the expression levels of bone morphogenetic protein receptors (BMPRs) and enhanced the recognitions of the remaining rhBMP-2 to BMPRs. Strikingly, the rhBMP-2-loaded CPC-PDA-CS significantly promoted the cellular surface translocation of BMPRs (especially BMPR-IA). In vivo studies demonstrated that, compared with the rhBMP-2 upon CPC and CPC-PDA, the rhBMP-2 upon CPC-PDA-CS exhibited sustained release and induced high quality and more ectopic bone formation. Collectively, these results suggest that rhBMP-2 can be localized within CS-functionalized CPC scaffolds and exert continuous, long-term, and effective osteogenic stimulation. Thus, this work could provide new avenues in mimicking bone extracellular matrix microenvironment and localizing growth factor activity for enhanced bone regeneration. A bioinspired chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) platform was developed to tether recombinant human bone morphogenetic protein-2 (rhBMP-2), which could exhibit continuous, long-term, and effective osteogenic stimulation in bone tissue engineering. Compared with rhBMP-2-loaded CPC, the rhBMP-2-loaded CPC-polydopamine-CS scaffolds induced higher expression of bone morphogenetic protein receptors (BMPRs), greater cellular surface translocation of bone morphogenetic protein receptor-IA, higher binding affinity of BMPRs/rhBMP-2, and thus higher activation of the drosophila gene mothers against decapentaplegic protein-1/5/8 (Smad1/5/8) and extracellular-regulated protein kinases-1/2 (ERK1/2) signaling. This work can provide new guidelines for the design of BMP-2-based bioactive materials for bone regeneration.
ISSN:1742-7061
1878-7568
DOI:10.1016/j.actbio.2018.01.004