Regenerative Engineering Laboratory, Columbia University Medical Center, 630 W. 168 St.-VC12-230, New York, NY 10032, USA.
Biofabrication. 2016 Apr 25;8(2):025003. doi: 10.1088/1758-5090/8/2/025003.
Three dimensional (3D) printing has emerged as an efficient tool for tissue engineering and regenerative medicine, given its advantages for constructing custom-designed scaffolds with tunable microstructure/physical properties. Here we developed a micro-precise spatiotemporal delivery system embedded in 3D printed scaffolds. PLGA microspheres (μS) were encapsulated with growth factors (GFs) and then embedded inside PCL microfibers that constitute custom-designed 3D scaffolds. Given the substantial difference in the melting points between PLGA and PCL and their low heat conductivity, μS were able to maintain its original structure while protecting GF's bioactivities. Micro-precise spatial control of multiple GFs was achieved by interchanging dispensing cartridges during a single printing process. Spatially controlled delivery of GFs, with a prolonged release, guided formation of multi-tissue interfaces from bone marrow derived mesenchymal stem/progenitor cells (MSCs). To investigate efficacy of the micro-precise delivery system embedded in 3D printed scaffold, temporomandibular joint (TMJ) disc scaffolds were fabricated with micro-precise spatiotemporal delivery of CTGF and TGFβ3, mimicking native-like multiphase fibrocartilage. In vitro, TMJ disc scaffolds spatially embedded with CTGF/TGFβ3-μS resulted in formation of multiphase fibrocartilaginous tissues from MSCs. In vivo, TMJ disc perforation was performed in rabbits, followed by implantation of CTGF/TGFβ3-μS-embedded scaffolds. After 4 wks, CTGF/TGFβ3-μS embedded scaffolds significantly improved healing of the perforated TMJ disc as compared to the degenerated TMJ disc in the control group with scaffold embedded with empty μS. In addition, CTGF/TGFβ3-μS embedded scaffolds significantly prevented arthritic changes on TMJ condyles. In conclusion, our micro-precise spatiotemporal delivery system embedded in 3D printing may serve as an efficient tool to regenerate complex and inhomogeneous tissues.
三维（3D）打印已成为组织工程和再生医学的有效工具，因为它具有构建具有可调节微观结构/物理特性的定制设计支架的优势。在这里，我们开发了一种嵌入 3D 打印支架中的微精确时空递药系统。PLGA 微球（μS）被包裹在生长因子（GFs）中，然后嵌入构成定制设计 3D 支架的 PCL 微纤维中。鉴于 PLGA 和 PCL 的熔点差异很大，且热导率低，μS 能够在保持其原始结构的同时保护 GF 的生物活性。通过在单个打印过程中交换分配筒，实现了多种 GF 的微精确空间控制。GF 的空间控制释放，具有延长的释放时间，指导骨髓间充质干细胞/祖细胞（MSCs）形成多组织界面。为了研究嵌入 3D 打印支架中的微精确递药系统的功效，采用微精确时空递药的方法构建了颞下颌关节（TMJ）盘支架，模拟了类似天然的多相纤维软骨。在体外，MSCs 形成了多相纤维软骨组织，TMJ 盘支架空间嵌入了 CTGF/TGFβ3-μS。在体内，在兔中进行 TMJ 盘穿孔，然后植入 CTGF/TGFβ3-μS 嵌入支架。4 周后，与对照组（支架中嵌入空 μS）相比，CTGF/TGFβ3-μS 嵌入支架显著改善了穿孔 TMJ 盘的愈合。此外，CTGF/TGFβ3-μS 嵌入支架显著防止了 TMJ 髁突的关节炎变化。总之，我们嵌入 3D 打印的微精确时空递药系统可以作为一种有效的工具来再生复杂和不均匀的组织。
