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

在体外适当地模拟体内生物环境通常会增加临床试验 成功和更快地获得有效的治疗。微流体是一种主要的模拟手段 临床和药物实验室研究中的生物环境；然而，目前 微流控技术受到材料和制造挑战的限制。添加制造(3D打印)具有 被誉为这些挑战的解决方案，但它也面临着障碍，如比较大的 最小特征尺寸和从内部通道中移除多余建筑材料的难度。添加剂 制造业有可能建立复杂的3D生物模拟结构，并解决关键挑战 微流体，例如制造有效的混合元件，结合膜或电极， 提供集成式阀门，并简化微观和宏观尺度之间的连接。 然而，在微流体中最有希望和最广泛使用的材料PDMS目前还不能用于 加法制造。Phase，Inc.开发了一种名为 基于液体介质电泳法的电场加工(EFF)将未固化的PDMS成形成规定的形状 可以连续固化和粘接的横截面，建立了三维微流控装置。与之相反 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，打开 以前所未有的分辨率打印弹性体等新材料，无需开机自检- 正在处理。这项技术提供了将PDMS微流体的设计空间增加到 更紧密地匹配体内环境，使未来的技术进步，如器官上的一个-a- 奇普。复杂三维PDMS微流控器件添加剂制造平台的商业化 这将使人们能够广泛获得3D生物模拟结构，从而产生更有效的治疗方法。这个 微流控药物市场目前价值140亿美元，预计到2027年将增长到310亿美元。PDMS 基于此的产品约占微流控产品市场的30%，是该市场的最大份额。 拟议的第一阶段工作将进一步提高用于附加制造的EFF工艺的保真度 通过对PDMS设备整体平台的细化，具体解决了以下两个目标 这对该过程的商业可行性具有基础性意义。第一阶段工作将1)演示功能 代表性设备的性能和2)展示成功整合 将膜制成微流控装置。 这项第一阶段SBIR提案的目的是： 目的1.制作具有代表性的PDMS三维微流控器件。演示广泛的实用程序 在EFF工艺中，将在PDMS中制造具有代表性的微流体器件，该器件具有两个入口，一个无源入口 混合元件、观察/测量通道和出口。成功演示 此外，在PDMS设备中制造这些基本的微流控构建块将是启动 为试验研究和进一步商业化制造特定设备的点。 目的2.制作一种用于模拟血液的集成径迹刻蚀膜的PDMS器件 大脑屏障。膜、电极和其他元素在PDMS中的结合是构建 这些功能被集成到微流控设备中，是EFF的一个主要特点。我们额外制造的型号将是 由培养在多孔膜(聚酯膜，孔道)上的脑内皮细胞组成 0.4微米)，夹在两个额外制造的PDMS层之间。人脑内皮细胞 将使用(hCMEC/D3)，因为这些细胞已被证明概括了关键表型 血脑屏障的通透性、结合蛋白和跨内皮细胞的表达 电阻。生理剪应力将通过流动(~4dyn/cm2)施加到细胞上 鼓励形成紧密连接。将在第一阶段演示血脑屏障设备 随后是第二阶段，开发了一种先进的设备。 项目摘要/摘要