Igniting Life with Sparks of Light: 3D Spatiotemporal Photoactivation of Angiogenesis via Radiational Kinesis (3D SPARK)

用光的火花点燃生命：通过辐射运动进行血管生成的 3D 时空光激活 (3D SPARK)

• 批准号: MR/X034976/1
• 负责人: Hossein Heidari
• 金额: $ 175.02万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX034976%2F1
• 关键词: Igniting; Life; Sparks; Light; 3D

Replicating a human organ is a highly complex challenge both structurally and functionally. At the core of this grand challenge lies the critical need for vascularisation and more broadly the need for cellularisation. Cellular systems in our bodies are naturally programmed in a bottom-up fashion where structure is an evolutionary consequence of function. For instance, the need for optimal exchange and transport drives morphogenesis, manifesting itself via dynamic signalling and secretion patterns during vascularisation, alveolarization and the formation of all self-organised tissue compartments. Tissue engineers have attempted the inverse hoping function will also follow form, with a laser focus on the structure problem: the ability to produce acellular architectures such as perfusable networks for transport and microporous scaffolds for cellular aggregation. These top-down engineered matrices are intricate yet static and non-responsive, leaving us with rudimental means of bulk seeding, cellularisation and stimulation, and limiting cell-mediated bottom-up growth and remodelling. Organotypic growth patterns are a dynamic response to physiological needs, driven by the spatiotemporally controlled release of biochemical factors and stimuli, and require extremely soft and degradable cell encapsulated extracellular microenvironments capable of bottom-up remodelling, both of which are currently only afforded at small microfluidic footprints.The 3D SPARK project offers a game-changing solution to large-scale volumetric tissue production via computed axial lithography (CAL) and computed axial stimulation (CAS) - the optical inverses of computed axial tomography (CAT). Volumetric processing challenges conventional wisdom in tissue engineering showing that complex and delicate 3D cellular architectures can be produced all-at-once without relying on slow, sequential processing of biological matter, and that large volumes of manufactured tissue can be accessible at a single cell level without a need for physical manipulation or slow optical scanning. At its core, this revolutionary CAT-inspired method utilises a superposition of 2D angular light projections to construct a 3D spatial distribution of exposure dose, and volumetrically trigger photopolymerization (bioprinting), photorelease (biomodulation) and photoexcitation (imaging) to regulate and monitor key cellular events during tissue development in a photoactive cell-encapsulated hydrogel matrix.With light-mediated volumetric processing and the ability to pattern light intensity in 3D at multiple wavelengths, we introduce a scalable solution to: (1) trigger photopolymerization and manufacture intact vascular structures in such soft (<10 kPa) cell-encapsulated photoactive gels; (2) control the light-induced depletion of chemical species such as oxygen (via radical quenching), and secretion of biochemical factors such as growth factors (via uncaging) directing tissue development across the entire volume; and (3) rapidly image the entire volume to monitor 3D cellularisation concurrent with photomodulation and tissue growth. In our tissue models, larger features such as macrovascular networks are designed and volumetrically printed in a top-down fashion and are internally coated with endothelial cells (ECs). Finer features such as microvascular capillaries are then stimulated with light to emerge and develop from sparsely encapsulated ECs within the printed gel to bridge the macrovascular gaps in a bottom-up fashion. This all-in-one platform goes beyond patterning the physical and chemical properties of the matrix, to enable dynamic manipulation of cellular processes allowing us to accommodate for top-down engineering and bottom-up development simultaneously. Hence, the proposed technology will be the dream tool of tissue engineers giving them spatiotemporal access to large volumes of printed tissue at a single cell level with light in a way never achievable before.

在结构和功能上，复制人体器官是一个高度复杂的挑战。这一大挑战的核心在于对血管化的关键需求，并且更广泛地需要细胞化。我们体内的细胞系统自然而然地以自下而上的方式编程，其中结构是功能的进化后果。例如，对最佳交换和运输的需求驱动形态发生，通过动态信号传导和分泌模式在血管化，肺泡化以及所有自组织组织室的形成过程中表现出来。组织工程师尝试了反向希望功能也将遵循形式，激光侧重于结构问题：产生细胞结构的能力，例如用于运输的灌注网络和用于细胞聚集的微孔支架。这些自上而下的工程矩阵既复杂又静态且无反应，这使我们拥有批量播种，细胞化和刺激的批判性手段，并限制了细胞介导的自下而上的生长和重塑。器官型生长模式是对生理需求的动态反应，这是由空间控制的生物化学因素和刺激的释放驱动的，并且需要极其柔软且可降解的细胞细胞外包裹的细胞外微环境，能够自下而上的重塑，目前仅在小型微型脚步上提供了一个较小的脚步投影。通过计算的轴向光刻（CAL）和计算的轴向刺激（CAS）的组织生产 - 计算的轴向断层扫描（CAT）的光学逆。体积处理挑战组织工程中的常规智慧表明，可以全面生产复杂而细腻的3D细胞体系结构，而无需依赖生物学的缓慢，顺序处理，并且可以在单个单元格的水平上访问大量的生产组织，而无需进行物理操纵或放慢光学扫描。在其核心上，这种革命性的猫启发的方法利用2D角光投影的叠加来构建3D暴露剂量的3D空间分布，并在体积上触发光聚糖化（生物启动），光启动酶（生物调节）（生物调节）（生物调节）和光陈述（成像），以调节和监测键孔的键盘，并在图片中进行键入的键盘，并在键盘上进行凝聚的凝胶型在整个过程中，并在键盘上进行凝聚的凝聚力，并在键盘上进行凝聚的凝聚力，并在形成型细胞，并在键盘上进行启用。体积处理和在多个波长下在3D中模拟光强度的能力，我们将可扩展的解决方案引入：（1）在这种软（<10 kPa）细胞包裹的光活性凝胶中触发光聚合和制造完整的血管结构； （2）控制化学物种的光诱导的耗竭，例如氧（通过根本淬灭），并分泌生长因子（通过脱离）引导整个体积组织发展的生长因子（通过）； （3）迅速对整个体积进行迅速对3D细胞化的量与光调节和组织生长的同时进行。在我们的组织模型中，设计和体积以自上而下的方式设计和体积印刷较大的特征，并在内部涂有内皮细胞（ECS）。然后用光刺激微血管毛细血管等更精细的特征，以从印刷凝胶中稀疏的ecs发育，以自下而上的方式弥合大血管间隙。这个多合一平台不仅超越了矩阵的物理和化学特性，还可以动态操纵细胞过程，使我们能够同时适应自上而下的工程和自下而上的开发。因此，拟议的技术将是组织工程师的梦想工具，使他们的时空访问大量的印刷组织在单个细胞水平上以光线从未实现的方式进行。