Humidity-Controlled Micro-Additive Manufacturing with Polymeric Bioinks

生物墨水是生物相容性水凝胶和水溶性聚合物，用于增材制造下一代医疗和制药产品。这些材料被合成为与活细胞、它们的营养物或药物一起携带大量的水沿着，同时支持它们的活性或在人体内可控地释放它们。通过增材制造，精确装载生物材料的生物墨水可以被挤出并逐层组装，以制造个性化的人工组织和药物递送载体。 这些突破性技术的成功在很大程度上取决于它们如何精确地模仿它们所使用的天然组织。这一要求带来了重大的制造挑战，因为人体组织非常复杂，关键特征尺寸约为数十微米。当前的生物打印技术具有大于100微米的打印分辨率，不能打印足够精细的特征。由于缺乏对打印较小特征时的生物油墨行为的完整理解以及其他实际问题（诸如导致打印不均匀性的较小打印几何形状的快速干燥）而出现挑战。该项目将解决这些科学挑战，并大幅提高生物打印组件的分辨率。 如果成功，这种新方法将通过实现有效的个性化医疗来提高美国的生物打印制造能力和国家福利。在这方面的直接影响将包括提高用于治疗退行性疾病的人工组织植入物的成功率，以及在治疗慢性皮肤病（影响30%以上的人口）中通过皮肤递送药物的更高有效性。该项目的研究活动将与教育和推广活动密切结合。教育部分将培养下一代工程师从事生物医学相关的增材制造技术，而计划中的推广活动将提高公众对这些令人兴奋的技术的认识和理解。本研究旨在通过打印头喷嘴处的局部湿度和温度控制来实现生物墨水的可控微增材制造。据信，这些参数的局部控制将防止与较小的印刷几何形状相关联的较高的生物油墨干燥速率，该较高的生物油墨干燥速率目前阻碍后续构建层之间的高分辨率印刷均匀性和粘附。湿度控制印刷过程的基本方面将通过实验和计算建模相结合的方法进行研究。任务包括：1）表征各种水凝胶和水溶性聚合物的湿度和温度依赖性粘弹性毛细管行为，2）产生基于多物理的计算模型，结合粘弹性毛细管作用，以捕获在特定湿度和温度条件下的油墨沉积和层与层融合机制，和3）通过检查高分辨率生物打印结构的机械完整性和特性来实验验证模型。这项工作的发现将推进水凝胶和水溶性聚合物的科学，同时也为产品和生物打印工艺设计提供信息。该奖项反映了NSF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。

Bio-inks are biocompatible hydrogels and water-soluble polymers that are used to additively manufacture next-generation medical and pharmaceutical products. These materials are synthesized to carry substantial amounts of water along with living cells, their nutrients or drugs, while supporting their activity or controllably releasing them in the human body. Through additive manufacturing, bio-inks precisely loaded with bio-materials can be extruded and assembled layer-by-layer to fabricate personalized artificial tissues and drug delivery vehicles. Success of such groundbreaking technologies relies heavily on how precisely they mimic the native tissues they are working with. This requirement poses a significant manufacturing challenge since human tissues are highly complex with critical feature sizes in the order of tens of microns. Current bio-printing technologies, having a print resolution of greater than 100 microns, are incapable of printing sufficiently fine features. Challenges arise because of a lack of a complete understanding of the bio-ink behavior when printing smaller features, and other practical issues such as rapid drying of the smaller printed geometries leading to print non-uniformity. This project will address these scientific challenges and substantially increase the resolution of bio-printed components. If successful, this novel approach will advance U.S. bioprinting manufacturing capabilities and National Welfare by enabling the realization of effective personalized medicine. Immediate impacts in this regard will include increased success rate in artificial tissue implants for treatment of degenerative diseases, and higher effectiveness of drug delivery through the skin in the treatment of chronic skin diseases, which affect more than 30% of the population. The research activities of this project will be closely integrated with educational and outreach activities. Educational components will prepare the next generation of engineers to work in biomedical related additive manufacturing technologies, while the planned outreach will increase the public's awareness and understanding of these exciting technologies. This research seeks to achieve controllable micro-additive manufacturing of bio-inks via localized humidity and temperature control at the printhead nozzle. It is believed that local control of these parameters will prevent the higher bio-ink drying rates, associated with smaller printed geometries, that currently hinder high-resolution print uniformity and adhesion between subsequent build layers. The fundamental aspects of the humidity-controlled printing process will be studied through a combined experimental and computational modelling approach. Tasks include; 1) characterization of the humidity and temperature dependent visco-elasto-capillary behavior of various hydrogels and water-soluble polymers, 2) generation a multi-physics-based computational model, incorporating visco-elasto-capillary action, to capture ink deposition and layer-to-layer fusion mechanisms under specified humidity and temperature conditions, and 3) experimental validation of the model by examining the mechanical integrity and properties of high resolution, bio-printed structures. The findings of this work will advance the science of hydrogels and water-soluble polymers, while also informing product and bio-printing process design.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.