Type I collagen decorated nanoporous network on titanium implant surface promotes osseointegration through mediating immunomodulation, angiogenesis, and osteogenesis

Abstract

Osseointegration of implants is a complex physiological process that requires temporal and spatial regulation of immune responses, angiogenesis, and osteogenesis. To achieve efficient and long-term osseointegration, type I collagen (COL1) decorated nanoporous network was developed on titanium substrates via alkali treatment, polydopamine coating, and layer-by-layer (LBL) self-assembly. It was noted that the simple physisorbed COL1 could be easily desorbed from the nanostructured surface, however, multilayer COL1 constructed by polydopamine and LBL self-assembly obscured the nanoporous network of the alkali-treated titanium surfaces. Interestingly, the nanostructured surface covalently immobilized with COL1 (T-ADC) could timely convert macrophages (MΦs) from pro-inflammatory M1 to pro-healing M2 phenotype, generating a beneficial osteoimmune microenvironment and promoting angio/osteo-genesis. RNA sequencing revealed that the nanostructure and COL1 could synergistically activate RhoA/ROCK, PI3K-AKT, and classical MAPK signaling pathways in MΦs to sustain the cell cycle, and trigger autocrine feedback-mediated JAK-STAT and FoxO signaling pathways, which in turn motivated autophagy and oxidative stress resistance and attenuated lipopolysaccharide-induced Toll-like receptor signaling pathway and its downstream NF-κB and JNK/p38 MAPK signaling cascades, leading to the inhibition of inflammation and osteoclastic-related gene expression of MΦs. Simultaneously, T-ADC prominently facilitated angiogenesis of endothelial cells and osteogenesis of osteoblasts as well as their cross-talks, further highlighting synergistically positive effects of the nanostructure and COL1 on osseointegration. In vivo experiments revealed that T-ADC could induce abundant new bone mass and ameliorative osseointegration, corroborating the in vitro results. The study elucidated that the COL1 decorated nanoporous network on titanium surfaces could significantly regulate early inflammatory reaction and subsequent angio/osteo-genesis processes, resulting in favorable osseointegration.

Keywords: Angiogenesis; Implant; Osseointegration; Osteogenesis; Osteoimmunomodulation; Titanium.