期刊
BIOMATERIALS
卷 277, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2021.121117
关键词
Bone morphogenetic protein-2 (BMP-2); Protein engineering; Site-specific coupling; Covalent immobilization; Bone-tissue engineering
资金
- National Natural Science Foundation of China [81902199]
- Shenzhen Municipal Science and Technology Innovation Committee Project [JCYJ20190806160407178, SGLH201 80625141602256, JSGG20180504170427135, JCYJ20180305164659 637, JCYJ20180305164544288, JCYJ2017041362104773]
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration [ZDSYS20200811143752005]
The modification strategy using His6-T4L enhances the stability and solubility of BMP-2, allowing for controlled release and maximizing its activity to enhance bone regeneration. Additionally, the gelatin-based hydrogel incorporated with MPs-His6-T4L-BMP2 displays favorable properties for bone defect repair.
Scaffolds functionalized with bone morphogenetic protein-2 (BMP-2) have shown great potential for bone regeneration. However, structural instability and the necessity for supra-physiological dose have thus far limited practical applications for BMP-2. Protein modification and site-specific covalent immobilization of BMP-2 to carrier materials might be optimal strategies to overcome these problems. Here, we report a broadly applicable strategy where the polyhistidine tag-T4 Lysozyme (His6-T4L) was genetically fused at the N-terminus of BMP-2 and used as a protein spacer, which on one hand enhanced protein solubility and stability, and on the other hand mediated site-specific covalent anchoring of BMP-2 upon binding to nickel-chelated nitrilotriacetic acid (Ni-NTA) microparticles (denoted as MPs-His6-T4L-BMP2) to further maximize its rescued activity. We also constructed a novel gelatin-based hydrogel that was crosslinked by transglutaminase (TG) and tannic acid (TA). This hydrogel, when incorporated with MPs-His6-T4L-BMP2, displayed excellent in-situ injectability, thermosensitivity, adhesiveness and improved mechanical properties. The effective loading mode led to a controlled and long-term sustained release of His6-T4L-BMP2, thereby resulting in enhancement of bone regeneration in a critical-sized bone defect. We believe that the protein modification strategy proposed here opens up new route not only for BMP-2 applications, but can be used to inform novel uses for other macromolecules.
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