State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No. 14 Section 3, Renmin South Road, Chengdu, Sichuan 610041, PR China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No. 14 Section 3, Renmin South Road, Chengdu, Sichuan 610041, PR China; Department of Oral and Maxillofacial Surgery, Sichuan Hospital of Stomatology, Chengdu 610031, PR China.
Acta Biomater. 2021 Nov;135:274-288. doi: 10.1016/j.actbio.2021.08.050. Epub 2021 Sep 4.
The biology of immediate post-extraction implant osseointegration is mediated by a coordinated cascade of osteoblast-osteoclast interactions. The aim of this study was to develop a dual-delivery system that allowed sequential release of substance P (SP) to promote bone regeneration and alendronate (ALN) to reduce bone resorption, which will improve the implant osseointegration. We used coaxial electrospinning to fabricate the core-shell poly lactic-co-glycolic acid (PLGA)/gelatin nanofibers, which consists of SP in the shell and ALN in the core. This programmed delivery system was shown to release SP and ALN sequentially to match the spatio-temporal specificity of bone healing. The migration assay demonstrated that the SP-ALN dual-delivery system increased bone marrow mesenchymal stem cells (BMSCs) transmigration. Besides, the expression of osteogenic/osteoclastic markers, Alizarin Red staining, tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and bone resorption experiment showed that the dual-delivery system can render a microenvironment favorable for osteogenic differentiation and adverse to osteoclastogenesis. Using a rat immediate implant model, we validated the promoted osteogenic property and osseointegration around the implants of SP-ALN dual-delivery system by micro-computed tomography (micro-CT) and histological analysis. These findings suggest that the dual-delivery system with time-controlled release of SP and ALN by core-shell nanofibers provides a promising strategy to facilitate immediate implant osseointegration through favorable osteogenesis. STATEMENT OF SIGNIFICANCE: Immediate implant placement is potentially challenged by the difficulties in achieving primary implant stability and early osteogenesis. Initial period of osteointegration is regulated by osteoblastic/osteoclastic cells resulting in a coordinated healing process. To have an efficient bone regeneration, the coaxial electrospinning was used to fabricate a programmed dual-delivery system. The SP released rapidly and favored for BMSCs migration and osteogenic differentiation, while the sustained release of ALN can reduce the bone resorption. The rat immediate implant model indicated that the SP-ALN dual-delivery system could present the promoted peri‑implant osteogenic property and osseointegration through modulating the osteogenesis-osteoclastogenesis balance. This work highlights the sequential dual delivery of SP and ALN has a promising potential of achieving enhanced osseointegration for immediate implant placement.
即刻种植体植入后骨整合的生物学机制是由成骨细胞-破骨细胞相互作用的协调级联反应介导的。本研究旨在开发一种双重递药系统，使神经肽 P（SP）的顺序释放来促进骨再生，同时使阿仑膦酸钠（ALN）持续释放来减少骨吸收，从而改善种植体的骨整合。我们采用同轴静电纺丝技术制备了具有核壳结构的聚乳酸-羟基乙酸共聚物（PLGA）/明胶纳米纤维，其中壳层中含有 SP，核中含有 ALN。该程控递药系统可实现 SP 和 ALN 的顺序释放，以匹配骨愈合的时空特异性。迁移实验表明，SP-ALN 双重递药系统可促进骨髓间充质干细胞（BMSCs）的迁移。此外，成骨/破骨标志物的表达、茜素红染色、抗酒石酸酸性磷酸酶（TRAP）染色、F-肌动蛋白染色和骨吸收实验表明，该双重递药系统可营造有利于成骨分化和抑制破骨细胞形成的微环境。通过大鼠即刻种植模型，我们通过微计算机断层扫描（micro-CT）和组织学分析验证了 SP-ALN 双重递药系统在促进种植体周围成骨和骨整合方面的作用。这些发现表明，通过核壳纳米纤维控制释放 SP 和 ALN 的双重递药系统为通过促进成骨来实现即刻种植体骨整合提供了一种有前途的策略。
即刻种植体的植入可能会受到难以实现种植体初期稳定性和早期成骨的挑战。骨整合的初始阶段受成骨细胞/破骨细胞的调节，从而导致协调一致的愈合过程。为了实现有效的骨再生，我们采用同轴静电纺丝技术制备了程控双重递药系统。快速释放的 SP 有利于 BMSCs 的迁移和成骨分化，而持续释放的 ALN 可减少骨吸收。大鼠即刻种植模型表明，SP-ALN 双重递药系统可通过调节成骨-破骨平衡来改善种植体周围的成骨特性和骨整合。这项工作强调了 SP 和 ALN 的顺序双重递药具有增强即刻种植体骨整合的潜力。
