Acta Biomaterialia ( IF 9.4 ) Pub Date : 2020-08-11 , DOI: 10.1016/j.actbio.2020.07.054 Yamin Li 1 , Ximeng Guo 2 , Shikui Dong 1 , Tonghe Zhu 1 , Yunsu Chen 3 , Song Zhao 1 , Guoming Xie 1 , Jia Jiang 1 , Hongyan He 2 , Changsheng Liu 2 , Jinzhong Zhao 1
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Absence of ligament-bone healing due to poor bioactivity and hyperplasia of fibrous tissue caused by immune response severely impairs ligament grafts’ functional duration in anterior cruciate ligament (ACL) reconstruction. While osteogenic modification is a popular technique for promoting ligament-bone integration, inadequate osseointegration remains a common experience, due to occupying fibrous hyperplasia and impaired osteogenesis potential. In the present study, a triple-nano-coating polyethylene terephthalate (PET) graft was developed by polydopamine self-assembly, chondroitin sulfate (CS) chemical-grafting and BMP-2 physical-immobilization to facilitate robust ligament-bone healing, The CS/polydopamine-modified PET (C-pPET) graft was demonstrated to inhibit fibrogenesis by regulating polarization of macrophages and promoting the secretion of anti-inflammatory factors. Moreover, the immunoregulatory function of CS cooperated with BMP-2 to facilitate osteogenic differentiation of stem cells, promoting the expression of ALP, Runx2, OCN and COL I. Bone regeneration was significantly enhanced at early-middle stage in the BMP-loaded pPET (B/pPET) group, while occurring at middle-late stage in the C-pPET group. Continuous new bone formation and optimal ligament-bone healing were observed in the B/C-pPET group via sequential and synergistic immune osteogenesis by CS and cytokine osteogenesis by BMP-2. Thus, the present study revealed a practical avenue for the promotion of ligament-bone healing through the development of a triple-nano-coating engineered ligament combining immunoregulatory anti-fibrogenesis and sequential-synergistic osteogenesis, which holds a great potential for improving the clinical efficacy of ligament graft in ACL reconstruction.
Statement of Significance
A triple-nano-coating polyethylene terephthalate (PET) graft was developed by polydopamine self-assembly, chondroitin sulfate (CS) chemical-grafting and BMP-2 physical-immobilization to facilitate robust ligament-bone healing. This study demonstrated that the multifunctional ligament grafts could reshape the local immune microenvironment by regulating macrophage phenotype and immune cytokine secretion to inhibit the fibrous hyperplasia and regulate stem cell towards osteogenic differentiation to promote bone regeneration. The present study demonstrates that efficient ligament-bone healing is achieved via the combination of immunoregulatory anti-fibrogenesis and dual osteogenesis of immunoregulation and cytokine induction.
中文翻译：
三层韧带移植物，通过抑制纤维发生和促进成骨作用，促进韧带骨愈合。
由生物活性差和免疫反应引起的纤维组织增生引起的韧带骨愈合严重损害了韧带移植物在前交叉韧带（ACL）重建中的功能持续时间。尽管成骨修饰是促进韧带-骨整合的流行技术，但由于骨纤维增生和成骨能力受损，骨整合不足仍然是一种普遍的经验。在本研究中，通过聚多巴胺自组装，硫酸软骨素（CS）化学嫁接和BMP-2物理固定开发了三纳米涂层聚对苯二甲酸乙二醇酯（PET）接枝物，以促进韧带-骨的牢固愈合，CS /聚多巴胺改性的PET（C-pPET）移植物通过调节巨噬细胞的极化和促进抗炎因子的分泌来抑制纤维发生。此外，CS的免疫调节功能与BMP-2协同作用，促进干细胞的成骨分化，促进ALP，Runx2，OCN和COL I的表达。在载有BMP的pPET的中早期阶段，骨再生显着增强（ B / pPET）组，而发生在C-pPET组的中晚期。B / C-pPET组通过CS的顺序和协同免疫成骨作用以及BMP-2的细胞因子成骨作用，观察到连续的新骨形成和最佳的韧带骨愈合。从而，
重要声明
通过聚多巴胺自组装，硫酸软骨素（CS）化学接枝和BMP-2物理固定开发了三纳米涂层聚对苯二甲酸乙二醇酯（PET）接枝物，以促进韧带韧带的愈合。这项研究表明，多功能韧带移植物可以通过调节巨噬细胞表型和免疫细胞因子的分泌来重塑局部免疫微环境，从而抑制纤维增生，并调节干细胞向成骨细胞分化，从而促进骨再生。本研究表明，通过免疫调节抗纤维化和免疫调节与细胞因子诱导的双重成骨作用的结合，可以实现有效的韧带骨愈合。
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