ADDITIVE MANUFACTURING OF PDMS MICROFLUIDICS

PDMS 微流控的增材制造

• 批准号: 10324424
• 负责人: Jeffery Schultz
• 金额: $ 17.36万
• 依托单位: PHASE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324424
• 关键词: 3-Dimensional; 3D Print; Address; Advanced Development; Biological; Blood - brain barrier anatomy; Cells; Characteristics; Clinical; Clinical Trials; Complex; Cultured Cells; Device or Instrument Development; Devices; Disease; Electrical Resistance; Electrodes; Elements; Environment; Face; Foundations; Future; Hour; Human; In Vitro; Laboratory Research; Legal patent; Liquid substance; Malignant neoplasm of brain; Measurement; Measures; Medical; Medicine; Membrane; Microfluidic Microchips; Microfluidics; Modality; Modeling; Needles; Optics; Patients; Performance; Permeability; Pharmacologic Substance; Phase; Phenotype; Physiological; Polyesters; Polymers; Process; Proteins; Quick Test for Liver Function; Research Personnel; Resolution; Shapes; Small Business Innovation Research Grant; Structure; Technology; Testing; Tight Junctions; Time; Transport Process; base; blood-brain barrier disruption; brain endothelial cell; commercialization; design; drug testing; effective therapy; elastomeric; electric field; fluorescein isothiocyanate dextran; in vivo; monolayer; organ on a chip; pressure; shear stress; simulation; success

Properly simulating an in vivo biological environment in vitro generally leads to increased clinical trial success and more rapid access to effective treatments. Microfluidics are a primary means of simulating biological environments in clinical and pharmaceutical laboratory research; however, the current utility of microfluidics is limited by materials and manufacturing challenges. Additive manufacturing (3D printing) has been heralded as the solution to these challenges, but it also faces hurdles, such as a relatively large minimum feature size and difficulty in removing excess build material from internal passages. Additive manufacturing has the potential to build complex, 3D, bio-mimicking structures and solve key challenges in microfluidics such as fabricating efficient mixing elements, incorporating of membranes or electrodes, providing integrated valving, and simplifying the connection between the micro-and macro-scales. However, the most promising and widely used material in microfluidics, PDMS, is currently not available for additive manufacturing. Phase, Inc. has developed a proprietary additive manufacturing technology termed electric field fabrication (EFF) based on liquid dielectrophoresis that shapes uncured PDMS into prescribed cross-sections which can be cured and bonded in succession to build a 3D microfluidic device. As opposed to other 3DP modalities, our patented approach offers unique control over the 3D printing process, opening the door to print new materials such as elastomerics with unprecedented resolution and no post- processing. This technology offers the potential to increase the design space of PDMS microfluidics to more closely match the in vivo environment enabling future advances in technologies such as organ-on-a- chip. Commercialization of an additive manufacturing platform for complex 3D PDMS microfluidic devices will enable broad access to 3D bio-mimicking structures which result in more effective treatments. The microfluidics market is now valued at $14 billion and is expected to grow to $31 billion by 2027. PDMS based products make up approximately 30% of the microfluidics market—the largest share of the market. The proposed Phase I effort will further enhance the fidelity of the EFF process for additively manufacturing PDMS devices through refinement of the overall platform and specifically address two aims which are foundational to the commercial viability of the process. The Phase I effort will 1) demonstrate the functional performance of a representative device and 2) demonstrate the ability to successfully incorporate a membrane into a microfluidic device. The aims of this Phase 1 SBIR proposal are to: Aim 1. Fabricate a representative 3D microfluidic device in PDMS. To demonstrate the broad ranging utility of the EFF process, a representative microfluid device will be fabricated in PDMS with two inlets, a passive mixing element, an observation/measurement channel and an outlet. Successful demonstration of additively manufacturing these basic microfluidic building blocks in a PDMS device will be the launching point for fabrication of specific devices for trial studies and further commercialization. Aim 2. Fabricate a PDMS device with an integrated track-etched membrane for simulation of the blood brain barrier. Incorporation of membranes, electrodes and other elements in PDMS is key to building functionality into microfluidic devices and is a key feature of EFF. Our additively manufactured model will be comprised of brain endothelial cells cultured on a porous membrane (polyester track etch membrane, pores 0.4 µm) sandwiched between two additively manufactured PDMS layers. Human cerebral endothelial cells (hCMEC/D3) will be used, as these cells have been demonstrated to recapitulate key phenotypic characteristics of the BBB such as permeability, expression of junctional proteins and transendothelial electrical resistance. Physiological shear stress will be applied on the cells by flow (~4 Dyn/cm2) to encourage tight junction formation. Demonstration of the blood brain barrier device in Phase I will be followed in Phase II with development of an advanced device. Project summary/abstract

在体外正确模拟体内生物学环境通常会导致临床试验增加 成功并更快地获得有效的治疗方法。微流体是模拟的主要手段 临床和药物实验室研究的生物环境；但是，目前的实用程序 微流体受到材料和制造挑战的限制。增材制造（3D打印）具有 被预示着解决这些挑战的解决方案，但它也面临障碍，例如一个相对较大的障碍 从内部段落中删除多余的构建材料的最小特征大小和难度。添加剂 制造业有可能建立复杂，3D，模仿生物的结构并解决关键挑战 微流体，例如制造有效的混合元件，结合膜或电子， 提供集成的阀门，并简化微型和宏观尺度之间的连接。 但是，PDMS中最有前途和广泛使用的材料，目前尚不可用于 增材制造。阶段，Inc。开发了一种称为专有的添加剂制造技术 电场制造（EFF），基于液体静脉注射，将未固定的PDM塑造成规定的PDM 可以连续治愈和界定以构建3D微流体设备的横截面。而不是反对 对于其他3DP模式，我们的专利方法提供了对3D打印过程的独特控制 打印新材料的门，例如具有前所未有的分辨率的弹性材料，没有后 加工。这项技术提供了将PDMS微流体的设计空间提高到的潜力 更匹配体内环境，从而实现了诸如On-a-的技术的未来进步 芯片。用于复杂3D PDMS微流体设备的上瘾制造平台的商业化 将能够广泛使用3D生物模拟结构，从而导致更有效的治疗方法。这 微流体市场现在的价值为140亿美元，预计到2027年将增长到310亿美元。PDMS。 基于市场最大的市场份额约占微流体市场的30％。 提出的第一阶段努力将进一步增强EFF流程的额外制造的保真度 PDMS设备通过完善整体平台，并特别解决两个目标 该过程商业可行性的基础。第一阶段的努力将1）演示功能 代表性设备的性能和2）证明了成功合并的能力 膜进入微流体设备。 该阶段1 SBIR提案的目的是： AIM 1。在PDMS中制造代表性的3D微流体设备。展示广泛的公用事业 在EFF过程中，将在PDM中制造一个代表性的微流体设备，并用两个入口，一个被动 混合元件，观察/测量通道和出口。成功的演示 在PDMS设备中加上这些基本的微流体构建块将是启动 为试验研究和进一步商业化的特定设备制造的点。 AIM 2。用集成的轨道膜制造PDMS设备，以模拟血液 脑屏障。将膜，电子和其他元素纳入PDMS是建造的关键 微流体设备的功能是EFF的关键特征。我们的其他制造型号将是 完成在多孔膜上培养的脑内皮细胞（聚酯轨道蚀刻膜，孔 0.4 µm）夹在两个额外制造的PDMS层之间。人脑内皮细胞 （HCMEC/D3）将被使用，因为这些细胞已被证明是为了概括关键表型 BBB的特征，例如渗透性，连接蛋白的表达和跨内皮的特征 电阻。生理剪切应力将通过流量（〜4 dyn/cm2）应用于细胞上 鼓励紧密的结。在第一阶段的血脑屏障装置的演示将是 随后在第二阶段开发了高级设备。 项目摘要/摘要