Tissue engineering of the human thymus: developing the optimal scaffold through integrating biological protocols with advanced imaging

胸腺在免疫系统的发育中起着重要的作用。先天性无胸腺症是一种胸腺缺失的疾病，具有危及生命的意义。胸腺组织工程（即，在实验室中制造人造器官）可能会导致这种情况的新治疗方法。此外，人工胸腺可用于离体产生功能性T细胞，用于获得性先天性缺陷、癌症治疗和自身免疫中的免疫耐受。我们以前表明，去细胞胸腺细胞外基质（ECM）可以重建一个功能性的人胸腺与培养的胸腺基质细胞。脱细胞ECM具有几个优点，例如临床相关性，生物相容性和促进细胞间组织以进行适当的区室化。然而，该ECM显示批次间的可变性，并且对于需要定制应用的可扩展性的离体系统来说并不理想。在这个项目中，学生将测试原代基质细胞在定制生物材料中重组的能力，以重新创建一个促进功能性T细胞发育的3D可扩展和可再现的微环境。成像技术有助于这种方法的发展，本项目的目标是利用先进成像技术的最新发展，生成有关支架和再细胞化过程的详细信息，从而改进胸腺工程方法。由于通常用于此目的的成像技术（SEM，组织学）本质上是破坏性的，因此它们不符合全组织3D成像的要求，我们将应用X射线显微CT。后者的优势在于其高穿透深度、微米空间分辨率和非破坏性地生成3D图像。该学生将与UCL医学物理学的高级X射线成像组合作，在那里开发尖端的X射线技术，并首次将这些方法应用于工程胸腺。图像数据将为应用的生物学方案提供反馈，使其能够迭代改进。

The thymus plays an important role in the development of the immune system.Congenital athymia is a condition whereby the thymus is absent, with life-threateningimplications. Thymic tissue engineering (i.e., creation of artificial organs in the lab)could lead to new treatments for this condition. Moreover, an artificial thymus may beutilised for ex vivo production of functional T cells for acquired congenital deficiencies,cancer therapies and immune tolerance in autoimmunity. We previously showed that adecellularised thymic extracellular matrix (ECM) allows rebuilding a functional humanthymus with cultured thymic stromal cells. Decellularised ECM has several advantagessuch being clinically relevant, biocompatible, and promoting cell-to-cell organisationfor proper compartmentalisation. However, this ECM shows batch-to-batch variabilityand is not ideal for ex vivo systems that shall require scalability for tailoredapplications. In this project the student will test the ability of primary stromal cells toreorganise within customised biomaterials to re-create a 3D scalable and reproduciblemicroenvironment that promotes functional T-cell development. Imaging isinstrumental to the development of such approaches and the goal of this project is toexploit the latest developments in advanced imaging technology to generate detailedinformation on scaffolds and recellularization processes that will allow refiningmethods for engineering the thymus. Since imaging techniques commonly used forthis purpose (SEM, histology) are essentially destructive, hence they do not qualify forwhole-tissue 3D imaging, we will apply x-ray micro-CT. The strength of the latter is itshigh penetration depth, micrometric spatial resolution and the generation of 3Dimages non-destructively. The student will collaborate with the Advanced X-RayImaging group at UCL Medical Physics, where cutting-edge x-ray technology is beingdeveloped, and apply those methods to engineered thymi for the first time. The imagedata will provide feedback on the biological protocols applied, enabling their iterativerefinement.