Traditional microfabrication techniques suffer from several disadvantages, including the inability to create truly three-dimensional (3D) architectures, expensive and time-consuming processes when changing device designs, and difficulty in transitioning from prototyping fabrication to bulk manufacturing. 3D printing is an emerging technique that could overcome these disadvantages. While most 3D printed fluidic devices and features to date have been on the millifluidic size scale, some truly microfluidic devices have been shown. Currently, stereolithography is the most promising approach for routine creation of microfluidic structures, but several approaches under development also have potential. Microfluidic 3D printing is still in an early stage, similar to where polydimethylsiloxane was two decades ago. With additional work to advance printer hardware and software control, expand and improve resin and printing material selections, and realize additional applications for 3D printed devices, we foresee 3D printing becoming the dominant microfluidic fabrication method.
This work demonstrates for the first time the creation of microchip electrophoresis devices with ~50 µm cross sectional dimensions by stereolithographic 3D printing and their application in the analysis of medically significant biomarkers related to risk for preterm birth (PTB). We determined that device current was linear with applied potential up to 800 V (620 V/cm). We optimized device and separation conditions using fluorescently labeled amino acids as a model system and compared the performance in our 3D printed microfluidic devices to that in other device materials commonly used for microchip electrophoresis analysis. We demonstrated for the first time microchip electrophoresis in a 3D printed device of three PTB biomarkers, including peptides and a protein, with suitable separation characteristics. Limits of detection for microchip electrophoresis in 3D printed microfluidic devices were also determined for PTB biomarkers to be in the high picomolar to low nanomolar range.
We have developed multichannel integrated microfluidic devices for automated preconcentration, labeling, purification, and separation of preterm birth (PTB) biomarkers. We fabricated multilayer poly(dimethylsiloxane)-cyclic olefin copolymer (PDMS-COC) devices that perform solid-phase extraction (SPE) and microchip electrophoresis (μCE) for automated PTB biomarker analysis. The PDMS control layer had a peristaltic pump and pneumatic valves for flow control, while the PDMS fluidic layer had five input reservoirs connected to microchannels and a μCE system. The COC layers had a reversed-phase octyl methacrylate porous polymer monolith for SPE and fluorescent labeling of PTB biomarkers. We determined μCE conditions for two PTB biomarkers, ferritin (Fer) and corticotropin-releasing factor (CRF). We used these integrated microfluidic devices to preconcentrate and purify off-chip-labeled Fer and CRF in an automated fashion. Finally, we performed a fully automated on-chip analysis of unlabeled PTB biomarkers, involving SPE, labeling, and μCE separation with 1 h total analysis time. These integrated systems have strong potential to be combined with upstream immunoaffinity extraction, offering a compact sample-to-answer biomarker analysis platform. Graphical abstract Pressure-actuated integrated microfluidic devices have been developed for automated solid-phase extraction, fluorescent labeling, and microchip electrophoresis of preterm birth biomarkers.
Preterm birth (PTB) is responsible for over one million infant deaths annually worldwide. Often, the first and only indication of PTB risk is the onset of early labor. Thus, there is an urgent need for an early PTB risk diagnostic that is inexpensive, reliable, and robust. Here, we describe the development of a microchip electrophoresis (μCE) method for separating a mixture of six PTB protein and peptide biomarkers present in maternal blood serum. μCE devices were photografted with a poly(ethylene glycol) diacrylate surface coating to regulate EOF and reduce nonspecific analyte adsorption. Separation conditions including buffer pH, buffer concentration, and applied electric field were varied to improve biomarker peak resolution while minimizing deleterious effects like Joule heating. In this way, it was possible to separate six PTB biomarkers, the first μCE separation of this biomarker panel. LODs were also measured for each of the six PTB biomarkers. In the future, this μCE separation can be integrated with upstream maternal blood serum sample preparation steps to yield a complete PTB risk diagnosis microdevice.
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