Advanced biomanufacturing of scalable, perfusable, pre-vascularized adipose tissues

脂肪组织是一种动态的内分泌器官，是能量储存、减震的主要部位，也是代谢、葡萄糖、温度和激素过程的重要调节者。因此，工程脂肪组织对于理解生理和病理（如肥胖和糖尿病）以及修复由创伤性损伤和侵入性外科手术引起的体表缺陷至关重要。虽然组织工程已经为此目的进行了探索，但由于扩散限制，以及与天然组织相比脂肪细胞密度和稳定性不足，方法取得的成功有限。该项目旨在通过提供一种创新技术来解决这些工程挑战，该技术可以制造高密度、大型的人体脂肪组织，并具有集成的、可灌注的血管系统。该项目的教育影响将通过将与研究有关的示范与现有的生物医学工程课程相结合，并提供机会，以提高代表性不足的少数民族在研究中的代表性来实现。该项目的目标是利用脱细胞肺基质（DLM）整合脂肪和血管组织工程，并为可灌注、血管化、高密度脂肪组织模型的工程提供革命性的解决方案。肺是血管化程度最高的器官之一，具有高流量、低阻力和由非常薄的基底膜（1µm）分隔的大血-肺泡界面。DLM为脂肪组织工程提供了以下独特的优势：(1)其大容量的肺泡室可以容纳高密度的脂肪细胞填充；(2)它提供了一个保存的、无细胞的维管床，允许有效的组织灌注和维管细胞播种；(3)肺泡隔室通过将高流速限制到血管床来保护浮力和脆弱的脂肪细胞免受有害的高剪切应力，而血管床是内皮细胞正常功能所必需的；(4)它是可扩展的，可以使用从大型供体来源（例如：猪）获得的支架材料来适应临界尺寸的缺陷。具体的项目任务将包括：(1)构建可扩展的、预血管化的脂肪组织；(2)模拟高血糖期间脂肪-血管-细胞外基质的相互作用。该模型将有助于脂肪生理学基础知识的获取，并为修复临界尺寸（200ml）皮下组织缺损提供组织工程平台。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Adipose/fat tissue is a dynamic endocrine organ that acts as a major site of energy storage, shock absorption, and a crucial regulator of metabolism, glucose, temperature, and hormonal processes. Accordingly, engineering adipose tissues is of critical importance for understanding physiology and pathology (such as obesity and diabetes), and for repairing body surface defects that can result from traumatic injury and invasive surgical procedures. While tissue engineering has been explored for these purposes, approaches have met limited success due to diffusion constraints, and insufficient adipose cell density and stability compared to the native tissue. This project aims to address these engineering challenges by delivering an innovative technology for manufacturing high-density, large human adipose tissues with integrated, perfusable vascular systems. The educational impact of this project will be achieved through integrating research-related demonstrations with existing biomedical engineering courses and facilitating opportunities to enhance the representation of underrepresented minorities in research. The goal of this project is to integrate adipose and vascular tissue engineering using a decellularized lung matrix (DLM) and offer a transformative solution for engineering perfusable, vascularized, high-density adipose tissue models. The lung is one of the most highly vascularized organs with high flow, low resistance, and a large blood-alveolar interface separated by a very thin basement membrane (1 µm). The DLM offers the following unique advantages for adipose tissue engineering: (1) its large volume alveolar compartment can accommodate high-density adipose cell filling; (2) it offers a preserved, acellular vascular bed allowing efficient tissue perfusion and vascular cell seeding; (3) the alveolar compartment shields buoyant and fragile adipocytes from harmful high shear stresses by confining high flow rates to the vascular bed where they are required for proper endothelial functionality; and (4) it is scalable and can be adapted for critically sized defects using scaffold materials derived from large donor sources (example: pigs). Specific project tasks will: (1) engineer scalable, pre-vascularized adipose tissues; and (2) model adipose-vascular-extracellular matrix interactions during hyperglycemia. This model will facilitate the acquisition of basic knowledge on adipose physiology as well as provide a tissue-engineering platform for repairing critically sized (200 mL) subcutaneous tissue defects.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.