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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

基本信息

批准号：
10669960
负责人：
Kelly R Stevens
金额：
$ 2.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2023-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669960
关键词：
3D Print Acceleration Address Architecture Artificial Liver Artificial tissue Biocompatible Materials Biological Biomedical Engineering Bioreactors Blood Vessels Blood capillaries Cellular biology Cessation of life Clinical Collaborations Data Diameter Disease Engineering Engraftment Formulation Generations Goals Growth Heart Diseases Hepatic Hepatocyte Hepatology Human In Situ Ink Kidney Diseases 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 Printing Protein Biosynthesis Public Health Research Resolution Role Route Technology Testing Therapeutic Tissue Engineering Tissues Transplantation Vascularization Work bioink bioprinting density drug metabolism falls hepatocyte engraftment implantation improved in vivo in vivo engraftment injured innovation interstitial liver injury liver metabolism liver transplantation meter multidisciplinary novel strategies novel therapeutics regenerative growth scale up self assembly support network vascular tissue engineering

项目摘要

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.

项目概要/摘要肝脏疾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，肝脏疾病导致的死亡肝脏疾病的发病率正在迅速上升而不是下降。虽然肝移植可以延长生存期，但需要移植的患者数量不断增加，但供体供应却停滞不前。为了解决这个重大问题医学问题，我们正在努力构建人造肝组织，可以作为器官的桥梁或替代品移植。开发人工肝组织的一个关键障碍是构建多尺度脉管系统需要支持数十亿个密集的肝细胞。应对这一挑战的新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推动该领域更接近解决这一障碍用于在人造组织中 3D 打印体积血管网络。这一进步是通过添加光吸收剂到立体光刻生物墨水，使数百万个体素能够在许多组织上形成图案层。然而，用立体光刻技术生产的组织仍然不完全血管化且细胞化稀疏，功能水平仍然达不到治疗所需的水平。我们最近获得了重要线索来应对这一挑战。首先，我们确定了新的光吸收剂配方，其实质上提高打印分辨率，提供了一种在体积上缩放更致密的脉管系统的新途径。此外，我们发现将生物基质添加到生物墨水中可以让我们在打印的内容中“扩展”脉管系统和肝细胞植入体内后产生具有天然密度的组织。这些数据使我们做出假设支持技术和生物放大模式的双作用生物墨水将促进产生具有在体内扩张的体积脉管系统的人类肝脏组织。此外，此类组织将具有肝功能水平足以治疗肝病。为了检验这些假设，我们成立了一个团队拥有肝脏和血管组织工程、生物材料和生物打印、临床肝脏方面的协同专业知识外科、临床肝病学、肝细胞生物学和肝脏代谢。我们将利用我们的专业知识来开发在体内生长的血管化生物打印肝组织。我们将首先制定一个新的生物墨水库投影立体光刻技术具有改进的打印分辨率和生物活性，以促进 3D 打印和体内组织工程（目标 1）。然后，我们将 3D 打印模拟肝脏脉管系统的按比例缩放的血管拓扑，支持肝细胞植入（目标 2）。最后，我们将触发组织中的肝细胞扩张以实现肝细胞密度和功能水平足以拯救肝损伤小鼠（目标 3）。该提案的真正力量在于将生物打印和组织放大的生物模式混为一谈，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。提案中开发的新材料生物墨水和 3D 打印创新也将广泛用于各个领域转化生物医学的各个领域，例如心脏和肾脏疾病。