Design Optimisation of Tissue Scaffolds Using Patient-specific and In Vivo Criteria

背景：由于预期寿命的增加，骨骼和各种软组织疾病已经成为一个主要的健康问题。例如，在英国，肌肉骨骼疾病是NHS支出的一个主要领域，仅2009-2010年就消耗了47.6亿GB。目前，在我们的有生之年，三分之一的人患有癌症，2010年，全英国的癌症诊断和治疗费用估计为94亿英镑。治疗过程可能需要移除或销毁大量的组织，由此造成的损害需要患者或捐赠者提供适当的可存活组织，而这可能是有限的。组织工程学作为一个迅速崛起的交叉学科领域，为解决这一公共卫生和社会经济中的关键问题提供了巨大的潜力。该支架不仅创建了一个结构基质，以生成所需的空间组织解剖结构，而且还提供了一种载体，用于从细胞增殖和组织生长所需的周围环境中摄取营养物质和清除废物。然而，仍然存在关键的挑战，包括缺乏支架结构的定量设计优化方法，以及如何在支架选择中融入体内环境和患者特定的因素，这在一定程度上阻止了组织工程转化为临床可采用的技术。计划和方法这项第一笔赠款建议解决以上确定的挑战，更重要的是，通过赋予组织特异性和患者特异性的额外维度，在弥合体外组织工程进展与其最终目标--体内组织再生--之间的差距方面迈出关键的一步，即支架的设计优化受组织特异性和患者特异性的影响。这里采取的方法是建立一个设计优化框架，考虑不同的组织环境，体内支架的潜在工程挑战，以及涉及的流体和固体力学问题，使用最先进的计算工具，包括结构优化和反均质。本项目旨在解决支架微结构设计过程中的以下关键方面：i)支架微结构的渗透性将根据支架-宿主界面附近局部微流体环境中的各向异性程度进行优化；ii)为了提高大型支架的运输能力，将通过施加梯度测试场(宏观均匀但微观梯度)来获得跨支架的梯度输送特性；Iii)将引入关于最小化界面应力的额外优化目标，该目标不仅要求支架在几何上适合于组织腔，而且还确保支架与宿主组织之间可能的相对运动引起的界面应力可保持在最小；iv)考虑宿主组织微环境受组织特定因素和患者特定因素影响的多目标优化方案；v)支架微结构中氧扩散和营养供应的有效能力随后将通过硅质量扩散模型进行评估。项目成果这一第一批赠款的最终成果是一种用于组织支架的新型设计优化工具。这一工具将首次使支架微结构能够针对个体和在体内的个性化使用而设计。临床关系该项目还受益于一名临床顾问，他不仅可以为该计划提供额外的可持续性，并带来来自NHS的新的合作和临床联系，而且还可以确保任何简化的影响可以在未来的工作中得到解决。

Background:As a result of increasing life expectancy diseases in bone and various types of soft tissue have become a major health concern. For example, in the UK, musculoskeletal conditions are a major area of NHS expenditure, consuming £4.76 billion in 2009-2010 alone. Currently cancer affects one in three of us during our lifetime and, in 2010, the costs of cancer diagnosis and treatment across the UK was estimated at £9.4 billion. The treatment process can require significant amounts of tissue to be removed or destroyed, with the resulting damage requiring a supply of appropriate viable tissues from the patient or from donors which may be of limited availability. Tissue engineering, as a fast emerging interdisciplinary area, offers enormous potential to solve such a critical problem in public health and socio-economy. Not only does the scaffold create a structural matrix to generate the required spatial tissue anatomy, but also provides a vehicle for the nutrient intake and waste product removal from/to the surrounding environment necessary for cell proliferation and tissue growth. However, there remain critical challenges, including a 'lack of quantitative design optimisation approach for scaffold architecture' and 'how to incorporate in vivo environment and patient-specific factors in scaffold selection', which to some extent prevent tissue engineering from being translated to a clinically-adoptable technology.Programme and MethodologyThis First Grant proposes to address the challenges identified above and, more importantly, to make critical steps forward in bridging the gap between the advances in in vitro tissue engineering and its ultimate goal of 'in vivo tissue regeneration' by giving it an additional dimension of vitality, i.e. design optimisation of scaffolds subject to tissue-specificity and patient-specificity. The approach taken here is to establish a design optimisation framework that considers different tissue environment, the underlying engineering challenges of scaffolding in vivo, and the fluid and solid mechanics problems involved, using state-of-the-art computational tools including structural optimisation and inverse homogenisation. This project aims to address the following critical aspects in the design process of scaffold microstructure: i) Permeability of scaffold microstructure will be optimised towards the degree of anisotropy in the local microfluidic environment near the scaffold-host interface; ii) To improve the transport capacity of large scaffolds, a gradient transport property across the scaffold will be obtained by applying a gradient test field (macroscopically uniform but microscopically gradient); iii) An additional optimisation objective with respect to the minimisation of interfacial stress will be introduced, which not only dictates that the scaffold geometrically fits into the tissue cavity but also ensures that the interfacial stress caused by the possible relative movement between scaffold and the host tissue can be kept to a minimum; iv) A multi-objective optimisation scheme that takes into account the microenvironment of host tissue affected by both tissue-specific and patient-specific factors; v) The effective capacity of oxygen diffusion and nutrient supply in the scaffold microstructure will then be evaluated by an in silico mass diffusion model. Project OutcomeThe ultimate deliverable from this First Grant is a novel design optimisation tool for tissue scaffold. This tool will, for the first time, enable the scaffold microstructures to be designed towards individual and personalised use in vivo. Clinical RelevanceThe project also benefits from a clinical advisor who can provide not only additional sustainability to the programme and bring a new collaboration and clinical contacts from the NHS, but also the biomedical context to ensure that the implications of any simplifications can be addressed in future work.