3D Bioprinting of Complex Tissue Structures Using Nanoengineered Ionic-Covalent Entanglement (NICE) Bioinks

1705852可以模拟、增强或取代天然组织功能的复杂工程组织在治疗因损伤、衰老和疾病而导致的器官衰竭方面具有巨大的潜力。3D生物打印是一种使用细胞加载的水凝胶(称为生物墨水)快速制造复杂组织结构的新兴方法。然而，由于缺乏合适的可打印并能指导细胞功能的生物墨水，3D生物打印遇到了进展中的瓶颈。本项目致力于设计一种用于3D打印的新型纳米工程离子-共价纠缠(NICE)生物墨水。NICE生物墨水结合了两种方法--使用2D纳米硅酸盐的纳米复合材料，以及由明胶甲基丙烯酸酯(一种经常用于生物印刷的胶原基生物墨水)和k-卡拉胶(一种经常用于增稠和稳定的多糖凝胶)形成的ICE网络--以获得比单独使用这两种方法都要好的机械性能。这项工作将导致一种新的平台技术，以选择性地控制和模式细胞行为，这将对人类健康产生广泛的科学影响；具体地说，再生工程和治疗输送。新的生物墨水家族的开发也将刺激生物制造的增长，对社会和国民经济产生积极影响。综合多学科研究平台将提供一个独特的环境来吸引、激励和留住学生，特别是在科学和工程教育中代表不足的群体。该项目将通过一系列不同的K-12活动提供教育和外展机会，包括：开发教育截屏；培训教师；让当地学校参与课后计划；以及接待高中生进行研究。具体地说，将开发一系列教育和研究截屏，以参与和提高对纳米材料和生物打印的认识。该项目将通过流行的社交媒体网站(包括博客、Facebook、Flickr、Pinterest、SlideShare、Twitter、Vimeo和YouTube)共享和分发截屏视频，并通过与可汗学院等在线K-12视频门户网站互动来扩展范围。该项目解决了生物医学工程中的一个关键挑战-如何设计由生物分子、细胞和支架组成的三维复杂结构-通过设计一种新型的纳米工程离子共价缠结(NICE)生物墨水用于3D打印来控制和图案细胞行为。所采用的方法将阐明负载了独特的二维(2D)纳米硅酸盐的离子共价纠缠(ICE)网络的关键基本性质。这项研究将揭示纳米材料、生长因子和人类细胞之间的相互作用，为利用和增强这些相互作用的新型纳米工程方法铺平道路。智能贡献包括：1)引入一种新的材料设计(NICE)来形成剪切变稀生物墨水，使用2D纳米材料和离子共价缠结(ICE)，将使细胞能够以复杂的3D结构沉积，从而提高对复杂微环境中细胞与生物材料相互作用的理解和知识；2)阐明2D纳米硅酸盐与ICE网络之间的相互作用将加深对利用非共价相互作用以机械地增强水凝胶网络的基础理解；3)通过消除不稳定治疗药物的复杂化学修饰，将有助于建立2D纳米硅酸盐作为即插即用型治疗药物输送的模块化方法。了解2D纳米材料与生物分子之间的相互作用将有助于更长时间地保持不稳定疗法的生物活性，并将导致新现象的发现；以及4)建立持续有效的疗法以调节细胞功能的新范式将最终导致更有效的输送系统的开发。

PI: Gaharwar, Akhilesh K.Proposal: 1705852Engineering complex tissues that can mimic, augment, or replace native tissue functions holds enormous potential for treating organ failures resulting from injuries, aging, and diseases. 3D bioprinting is an emerging approach for rapid fabrication of complex tissue structures using cell-loaded hydrogels, called bioinks. However, 3D bioprinting has hit a bottleneck in progress due to the lack of suitable bioinks that are printable and can guide cell functions. This project focuses on designing a novel family of nanoengineered ionic-covalent entanglement (NICE) bioinks for 3D-printing. The NICE bioink combines two approaches - nanocomposites using 2D nanosilicates and ICE networks formed from gelatin methacrylate (a collagen based bioink often used in bioprinting) and k-carrageenan (a polysaccharide based gel often used for thickening and stabiliazation) - to achieve mechanical properties superior to either approach alone. This work will lead to a novel platform technology to selectively control and pattern cell behavior that will have broad scientific impact on human health; specifically, regenerative engineering and therapeutic delivery. The development of a new family of bioinks will also spur growth in biofabrication, leading to positive impacts on society and the national economy. The integrated multidisciplinary research platform will provide a unique environment to attract, motivate, and retain students, particularly underrepresented groups, in science and engineering education. The project will provide educational and outreach opportunities through a diverse array of K-12 activities, including: development of educational screencasts; training teachers; engaging local schools in after-school programs; and hosting high school students for research. Specifically, a range of educational and research screencasts will be developed to engage and promote awareness about nanomaterials, and bioprinting. Outreach will be extended by sharing and distributing the screencasts via popular social media sites (including blogs, Facebook, Flickr, Pinterest, SlideShare, Twitter, Vimeo, and YouTube) and by interacting with online K-12 video portals such as Khan Academy.This project addresses a key challenge in biomedical engineering - how to engineering three-dimensional complex structures consisting of biomolecules, cells, and scaffolds - by designing a novel family of nanoengineered ionic-covalent entanglement (NICE) bioinks for 3D-printing to control and pattern cell behavior. The approach taken will elucidate key fundamental properties of ionic covalent entanglement (ICE) networks loaded with unique, two-dimensional (2D) nanosilicates. The research will reveal the interactions among nanomaterials, growth factors, and human cells, paving the way for novel nanoengineered approaches to harness and augment these interactions. Intellectual contributions include: 1) introducing a novel material design (NICE) to form shear-thinning bioinks, using 2D nanomaterials and ionic-covalent entanglement (ICE), will enable deposition of cells in complex 3D structures which in turn will advance understanding and knowledge of cell-biomaterial interactions in complex microenvironments; 2) Elucidating interactions between 2D nanosilicates and the ICE network will advance fundamental understanding for leveraging non-covalent interactions to mechanically reinforce hydrogel networks; 3) establishing 2D nanosilicates as a modular approach for plug-and-play types of therapeutics delivery will be facilitated by eliminating complex chemical modification of labile therapeutics. Understanding the interactions between 2D nanomaterials and biomolecules will provide insight into retaining bioactivity of labile therapeutics for prolonged durations and will lead to discovery of new phenomena; and 4) establishing a new paradigm for sustained and effective delivery of therapeutics to modulate the cellular function will ultimately lead to development of more effective delivery systems.