Osteochondral tissue engineering using novel 3D printed scaffolds and multi-layered cell sheet technology

使用新型 3D 打印支架和多层细胞片技术的骨软骨组织工程

• 批准号: 2111178
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2111178
• 关键词: Osteochondral; tissue; engineering; using; novel

Osteochondral tissue damage or loss is one of the most common diseases due to traumatic injuries, natural degradation of cartilaginous tissue with aging, arthritis or surgery. These clinical situations encompass serious damage to not only articular cartilage but also the underlying calcified subchondral bone. The conventional therapeutic approaches include autografts, allografts, stimulation of bone marrow and debridement. Autografts have limited stock and allografts are associated with the risk of immune rejection or disease transmission, while bone marrow stimulation treatments are only palliative and not completely curative. Therefore, the ability to treat osteochondral defects is a major clinical need. Over the last decades, tissue engineering approaches have been utilised for regenerating articular cartilage. However the output of these is still not satisfactory. Part of the reason may be due to the unique and complex structure of articular cartilage (e.g. it does not have blood vessels, lymphatics and nerves, but it is under a biomechanical environment). Over the last a few years, researchers have suggested that a healthy subchondral bed plays a key role for the success of cartilage tissue regeneration. In this project, a multidisciplinary approach will be utilised to combine material science, mechanical engineering (Dr Xiaodong Jia) with stem cell biology (Dr Jiang) for osteochondral tissue engineering (Dr Yang). The multi-layered cell sheet (MLCS) technology, in close collaboration with Tokyo Women's Medical University under a formal collaborative agreement, allows us to harvest intact cell sheet with minimum damage to the cells and maximum retention of cell-cell junctions, extracellular matrix and growth factors embedded in the matrix. This technology could be useful for stem cell handling and the development of novel collagen scaffolds to mimic natural structure of articular cartilage. Previously we have showed the potential of using epigenetic approaches to control stem cell function without change the genome. A novel histone deacetylase inhibitors (HDACi), MI192 will be used for the pre-treatment of human MSCs to enhance their osteogenic differentiation potential for new bone formation. The combination of the bone phase and cartilage phase will provide a novel solution for repair/restoration of osteochondral defect in clinical relevant animal models.The aim of this project is to develop a novel natural collagen scaffold and combine these scaffolds with 3D printed scaffolds, epigenetic modified stem cells as well as multi-layered cell sheet technology for osteochondral tissue engineering in vitro and in vivo.The project fits very well within EPSRC's Healthcare and Technologies Theme - Developing Future Therapies. The objectives include:A) Development of novel collagen scaffolds using MLCS technology.B) Fabricate cartilage phase in vitro using epigenetic modified stem cell, MLCS technology, novel collagen scaffolds.C) Fabricate bone phase in vitro using epigenetic modified stem cell, MLCS technology and PepGEN P-15 enhanced 3D printed porous polymer scaffold (in collaboration Otago University, UCL and University of Manchester).D) Osteochondral tissue engineering in vivo using the bone and cartilage constructs formed above.MLCS technology is a novel engineering method.A novel natural collagen scaffolds will be developed with unique architecture similar to natural articular cartilage, which could be patentable.A combination of MLCS technology, novel collagen scaffolds and 3D printed polymer scaffolds will provide a novel approach for complex tissue engineering.

骨软骨组织损伤或丢失是由于创伤性损伤、软骨组织随年龄增长的自然降解、关节炎或手术引起的最常见疾病之一。这些临床情况不仅包括关节软骨的严重损伤，还包括潜在的钙化软骨下骨。传统的治疗方法包括自体移植、同种异体移植、骨髓刺激和清创术。自体移植物的存量有限，同种异体移植物与免疫排斥或疾病传播的风险相关，而骨髓刺激治疗仅是姑息性的，并不完全治愈。因此，治疗骨软骨缺损的能力是主要的临床需求。在过去的几十年中，组织工程方法已被用于再生关节软骨。然而，这些项目的产出仍不令人满意。部分原因可能是由于关节软骨独特而复杂的结构（例如，它没有血管，神经和神经，但它处于生物力学环境下）。在过去的几年里，研究人员认为，健康的软骨下床对软骨组织再生的成功起着关键作用。在这个项目中，将采用多学科方法，将联合收割机材料科学、机械工程（贾晓东博士）与干细胞生物学（蒋博士）结合起来，用于骨软骨组织工程（杨博士）。多层细胞片（MLCS）技术，与东京女子医科大学密切合作，根据正式的合作协议，使我们能够收获完整的细胞片，对细胞的损伤最小，最大限度地保留细胞-细胞连接，细胞外基质和嵌入基质中的生长因子。该技术可用于干细胞处理和新型胶原支架的开发，以模拟关节软骨的天然结构。以前，我们已经展示了使用表观遗传方法在不改变基因组的情况下控制干细胞功能的潜力。一种新的组蛋白去乙酰化酶抑制剂（HDACi），MI 192将用于预处理人MSC，以提高其成骨分化的新骨形成的潜力。骨相和软骨相的结合将为临床相关动物模型中骨软骨缺损的修复/恢复提供新的解决方案。本项目的目的是开发一种新型天然胶原支架，并将这些支架与3D打印支架相结合，表观遗传修饰的干细胞以及多-体外和体内骨软骨组织工程的分层细胞片技术。该项目非常符合EPSRC的医疗保健和技术主题-开发未来疗法。这些目标包括：A）使用MLCS技术开发新型胶原支架。B）使用表观遗传修饰的干细胞、MLCS技术、新型胶原支架体外制造软骨相。C）使用表观遗传修饰的干细胞、MLCS技术和PepGEN P-15增强的3D打印多孔聚合物支架体外制造骨相。（合作单位：OtagoUniversity，UCL和UniversityofManchester）.D）利用上述形成的骨和软骨构建体进行体内骨软骨组织工程。MLCS技术是一种新的工程方法。将开发一种具有类似于天然关节软骨的独特结构的新型天然胶原支架，该支架可能获得专利。MLCS技术的组合，新型胶原支架和3D打印聚合物支架将为复杂的组织工程提供新的方法。