Photoabsorbing bioinks for expanding 3D printed human liver in situ

用于原位扩展 3D 打印人类肝脏的光吸收生物墨水

• 批准号: 10490395
• 负责人: Kelly R Stevens
• 金额: $ 72.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490395
• 关键词: 3D Print; Address; Architecture; Artificial Liver; Artificial tissue; Biocompatible Materials; Biological; Biomedical Engineering; Bioreactors; Blood Vessels; Blood capillaries; Caliber; Cellular biology; Cessation of life; Clinical; Collaborations; Data; Disease; Donor person; Engineering; Engraftment; Formulation; Generations; Goals; Growth; Heart Diseases; Hepatic; Hepatocyte; Hepatology; Human; In Situ; Ink; Kidney Diseases; Lead; Libraries; Life; Liver; Liver Failure; Liver diseases; Lobule; Measures; Medical; Methods; Mus; Natural regeneration; Operative Surgical Procedures; Organ; Organ Transplantation; Osteogenesis; Pancreatic Diseases; Patients; Pattern; Physiology; Protein Biosynthesis; Public Health; Research; Resolution; Role; Route; Testing; Therapeutic; Tissue Engineering; Tissues; Transplantation; Work; base; bioink; bioprinting; density; drug metabolism; falls; hepatocyte engraftment; implantation; improved; in vivo; in vivo engraftment; injured; innovation; interstitial; liver injury; liver metabolism; liver transplantation; multidisciplinary; novel strategies; novel therapeutics; regenerative growth; scale up; self assembly; support network; vascular tissue engineering

Project Summary/Abstract Liver disease is a pressing public health challenge, because unlike most other major killers deaths due to liver disease are rapidly rising rather than falling. Although liver transplantation prolongs survival, there is a growing number of patients in need of transplant, but donor supply has remained stagnant. To address this major medical problem, we are working to build artificial liver tissue that could serve as a bridge or alterative to organ transplant. A crucial remaining hurdle for developing artificial liver tissue is building the multiscale vasculature needed to support billions of densely packed hepatocytes. Novel approaches that address this challenge would transform liver research and therapy. Our recent work pushed the field closer to addressing this hurdle by introducing a breakthrough method for 3D printing volumetric vascular networks in artificial tissues. This advance was made possible by addition of photoabsorbers to stereolithography bioinks, which enabled millions of voxels to be patterned over many tissue layers. Yet, tissues produced with stereolithography remain incompletely vascularized and sparsely cellularized, with functional levels that still fall short of those needed for therapy. We have recently gained important clues towards addressing this challenge. First, we identified new photoabsorber formulations that substantively improve print resolution, providing a new route to volumetrically scaling a denser vasculature. Furthermore, we found that adding biological matrices to bioinks allows us “expand” vasculature and hepatocytes within printed tissues after implantation in the body to produce tissues with native density. These data lead us to hypothesize that dual-role bioinks that support both technical and biological modes of scale-up will facilitate generation of human liver tissue with volumetric vasculature that expands in vivo. Further, such tissue will have hepatic functional levels sufficient to therapeutically treat liver disease. To test these hypotheses, we established a team with synergistic expertise in liver and vascular tissue engineering, biomaterials and bioprinting, clinical liver surgery, clinical hepatology, liver cell biology, and liver metabolism. We will employ our expertise to develop vascularized bioprinted liver tissue that grows in the body. We will first formulate a new library of bioinks for projection stereolithography with improved print resolution and bioactivity, to facilitate both 3D printing and in vivo tissue engineering (Aim 1). We will then 3D print scaled vascular topologies that mimic liver vasculature and support hepatocyte engraftment (Aim 2). Finally, we will trigger hepatocyte expansion in the tissues to achieve hepatocyte density and functional levels sufficient to rescue mice with liver injury (Aim 3). The real power of this proposal lies in conflating bioprinting and biological modes of tissue scale-up, which will transform tissue engineering and generate bioprinted liver tissue as a new therapy for liver disease. The new material bioinks and 3D printing innovations developed in proposal would also be broadly useful across diverse fields of translational biomedicine, such as heart and kidney disease.

项目摘要/摘要 肝病是一个紧迫的公共卫生挑战，因为与大多数其他主要杀手不同， 肝病迅速上升而不是下降。尽管肝移植延长了生存，但有一个 需要移植的患者数量越来越多，但供体供应仍然停滞不前。解决这个专业 医疗问题，我们正在努力建立可以用作桥梁或组织的人造肝组织 移植。发展人造肝组织的剩余剩余障碍正在建立多尺度脉管系统 需要支持数十亿个无填充的肝细胞。应对这一挑战的新颖方法将 改变肝脏研究和治疗。 我们最近的工作通过引入突破性方法使该领域更接近解决这一障碍 用于人造组织中的3D打印体积血管网络。通过添加 摄影师到立体光刻生物互联，使数百万的体素能够在许多组织上图案 层。然而，用立体光刻产生的组织仍然不完全进行血管化和稀疏的细胞化， 功能水平仍然没有治疗所需的水平。我们最近获得了重要的俱乐部 面对这一挑战。首先，我们确定了新的光吸光仪公式 改善打印分辨率，提供一条新的途径，以缩放更密集的脉管系统。此外，我们 发现将生物矩阵添加到生物界 在体内植入后的组织以产生天然密度的组织。这些数据导致我们假设 支持扩大技术和生物学模式的双重生物学将有助于生成 人体肝组织具有体内膨胀的体积脉管系统。此外，这种组织将具有肝 功能水平足以治疗治疗肝病。为了检验这些假设，我们建立了一个团队 具有肝脏和血管组织工程，生物材料和生物打印方面的协同专业知识，临床肝 手术，临床肝病学，肝细胞生物学和肝代谢。我们将利用我们的专业知识来发展 血管化生物打印的肝组织在体内生长。我们将首先制定一个新的生物学库 投影立体光刻具有改进的印刷分辨率和生物活性，以促进3D打印和 体内组织工程（AIM 1）。然后，我们将模仿肝脏脉管系统和 支持肝细胞植入（AIM 2）。最后，我们将触发组织中的肝细胞膨胀以实现 肝细胞密度和功能水平足以挽救肝损伤的小鼠（AIM 3）。 该提案的真正力量在于将生物涂印和组织缩放的生物学模式混为一谈， 这将改变组织工程并产生生物打印的肝组织，作为肝病的新疗法。 在提案中开发的新材料生物互联和3D打印创新也将在各个方面广泛使用 转化生物医学的各种领域，例如心脏和肾脏疾病。