Next generation 3D-printed auricular implants involving degradable materials and cells for ultimate implant integration and tissue regeneration

矫正先天性出生缺陷所需的耳廓重建仍然是整形外科的主要挑战1。目前，铸造的不可降解聚合物支架，如多孔聚乙烯（PE）仍被广泛使用。植入物整合仍然是不可降解支架的一个问题，炎症和感染仍然经常发生，并且通常观察到植入物断裂和暴露（从皮肤）。生物相容性不足和力学不匹配可能是导致这些临床复杂性的原因。这需要重新考虑材料和新的支架设计和制造方法。本项目计划采用两种方法：首先，我们将改进我们合作者（中国南方医学院）开发的3D打印HDPE支架，并专注于两个方面的开发：1）修改植入物表面以增加生物相容性。通过新型纤维纺丝，将一层可生物降解的纳米纤维（例如聚己内酯（PCL））沉积在HDPE支架上; 2）探索在支架中建立药物递送系统的可行性，目的是递送抗菌剂或促进血管生成和组织向内生长。银离子和VEGF（血管内皮生长因子）将在纤维纺丝后通过预纺丝共混或浸渍来掺入。为了评估改良植入物的性能及其释放药物的功效，将用支架培养成纤维细胞、内皮细胞和软骨细胞，并评估细胞粘附、增殖和分化。将收集药物释放曲线，并监测组织沉积和向内生长，特别是关于血管化和纤维组织生长以及与支架的整合。第二，将采用组织工程方法来评估天然软骨是否可以在缺损部位再生。作为基础支架材料的生物惰性和不可降解的HDPE将被天然多糖可打印材料取代。在打印之前将软骨细胞或间充质干细胞混合到多糖溶液中，并调整打印参数以按照耳廓形状制造，保持最终的解剖结构，同时保留细胞活力和表型。本研究将评估含细胞支架内天然纤维软骨的形成，并测量初始支架材料的降解情况，希望新开发的耳廓支架能够为下一代耳廓植入物提供更好的临床性能，最终实现植入物整合或天然组织再生.埃卜拉希米·A.等人，耳廓缺损的重建手术：综述，创伤Mon. 20（4），e28202（2015）。

Auricular reconstruction which is required to correct congenital birth defects remains a major challenge in plastic surgery1. Currently, casted non-degradable polymeric scaffolds, such as porous polyethylene (PE) are still widely used. Implant integration remains a problem with non-degradable scaffolds, with inflammation and infection still frequently occurring, and implant fracture and exposure (from skin) commonly observed. Inadequate biocompatibility and un-matching mechanics are likely reasons leading to those clinical complexities. This calls for re-consideration of materials and novel approaches for scaffold design and fabrication.A 2-fold approach is planned in this project: Firstly, we will improve 3D-printed HDPE scaffold developed at our collaborator's (Southern Medical School, China), and focus on two aspects of development: 1) modify the implant surface to add biocompatibility. With novel fibre spinning, a layer of biodegradable nanofibers (e.g. polycaprolactone (PCL)) will be deposited on the HDPE scaffold; 2) explore the feasibility to set up a drug delivery system in the scaffold, with the aim of delivering anti-bacterials or promoting angiogenesis and tissue ingrowth. Silver ions and VEGF (vascular endothelial growth factor) will be incorporated by pre-spinning blending or impregnation after fibre spinning. To assess the performance of the modified implant and its efficacy releasing the drugs, fibroblasts, endothelial cells, and chondrocytes will be cultured with the scaffolds and cell adhesion, proliferation, and differentiation assessed. Drug release profiles will be collected, and tissue deposition and ingrowth monitored particularly concerning vascularization and fibrous tissue growth and integration with the scaffold.Secondly, a tissue engineering approach will be adopted to assess whether native cartilage can be regenerated at the defect site. The bio-inert and non-degradable HDPE as the base scaffold material will be replaced by a natural polysaccharide printable material. Chondrocytes or mesenchymal stem cells will be mixed into the polysaccharide solution prior to printing, and printing parameters adjusted to fabricate following the auricular shape, maintain ultimate anatomical structure while retaining cell viability and phenotype. Formation of natural fibrous cartilage within the cell-containing scaffold will be assessed with the degradation of the initial scaffolding material measured.It is hoped that the newly developed auricular scaffolds can offer next generation auricular implants with improved clinical performances, with ultimate implant integration or native tissue regeneration.1. Ebrahimi A. et al, Reconstructive surgery of auricular defects: an overview, Trauma Mon. 20 (4), e28202 (2015).