Sorting cells by their type is an important capability in biological research and medical diagnostics. However, most cell sorting techniques rely on labels or tags, which may have limited availability and specificity. Sorting different cell types by their different physical properties is an attractive alternative to labels because all cells intrinsically have these physical properties. But some physical properties, like cell size, vary significantly from cell to cell within a cell type; this makes it difficult to identify and sort cells based on their sizes alone. In this work we continuously sort different cells types by their density, a physical property with much lower cell-to-cell variation within a cell type (and therefore greater potential to discriminate different cell types) than other physical properties. We accomplish this using a 3D-printed microfluidic chip containing a horizontal flowing micron-scale density gradient. As cells flow through the chip, Earth’s gravity makes each cell move vertically to the point where the cell’s density matches the surrounding fluid’s density. When the horizontal channel then splits, cells with different densities are routed to different outlets. As a proof of concept, we use our density sorter chip to sort polymer microbeads by their material (polyethylene and polystyrene) and blood cells by their type (white blood cells and red blood cells). The chip enriches the fraction of white blood cells in a blood sample from 0.1% (in whole blood) to nearly 98% (in the output of the chip), a 1000x enrichment. Any researcher with access to a 3D printer can easily replicate our density sorter chip and use it in their own research using the design files provided as online Supporting Information. Additionally, researchers can simulate the performance of a density sorter chip in their own applications using the Python-based simulation software that accompanies this work. The simplicity, resolution, and throughput of this technique make it suitable for isolating even rare cell types in complex biological samples, in a wide variety of different research and clinical applications.
Measurements of an object’s fundamental physical properties like mass, volume, and density can offer valuable insights into the composition and state of the object. However, many important biological samples reside in a liquid environment where it is difficult to accurately measure their physical properties. We show that by using a simple piece of glass tubing and some inexpensive off-the-shelf electronics, we can create a sensor that can measure the mass, volume, and density of microgram-sized biological samples in their native liquid environment. As a proof-of-concept, we use this sensor to measure mass changes in zebrafish embryos reacting to toxicant exposure, density changes in seeds undergoing rehydration and germination, and degradation rates of biomaterials used in medical implants. Since all objects have these physical properties, this sensor has immediate applications in a wide variety of different fields including developmental biology, toxicology, materials science, plant science, and many others.
Most microfluidic chips utilize off-chip hardware (syringe pumps, computer-controlled solenoid valves, pressure regulators, etc.) to control fluid flow on-chip. This expensive, bulky, and power-consuming hardware severely limits the utility of microfluidic instruments in resource-limited or point-of-care contexts, where the cost, size, and power consumption of the instrument must be limited. In this work, we present a technique for on-chip fluid control that requires no off-chip hardware. We accomplish this by using inert compounds to change the density of one fluid in the chip. If one fluid is made 2% more dense than a second fluid, when the fluids flow together under laminar flow the interface between the fluids quickly reorients to be orthogonal to Earth’s gravitational force. If the channel containing the fluids then splits into two channels, the amount of each fluid flowing into each channel is precisely determined by the angle of the channels relative to gravity. Thus, any fluid can be routed in any direction and mixed in any desired ratio on-chip simply by holding the chip at a certain angle. This approach allows for sophisticated control of on-chip fluids with no off-chip control hardware, significantly reducing the cost of microfluidic instruments in point-of-care or resource-limited settings.
The frequencies of notes made by a musical instrument are determined by the physical properties of the instrument. Consequently, by measuring the frequency of a note, one can infer information about the instrument’s physical properties. In this work, we show that by modifying a musical instrument to contain a sample and analyzing the instrument’s pitch, we can make precision measurements of the physical properties of the sample. We used the mbira, a 3000-year-old African musical instrument that consists of metal tines attached to a wooden board; these tines are plucked to play musical notes. By replacing the mbira’s tines with bent steel tubing, filling the tubing with a sample, using a smartphone to record the sound while plucking the tubing, and measuring the frequency of the sound using a free software tool on our website, we can measure the density of the sample with a resolution of about 0.012 g/mL. Unlike existing tools for measuring density, the mbira sensor can be made and used by virtually anyone in the world. To demonstrate the mbira sensor’s capabilities, we used it to successfully distinguish diethylene glycol and glycerol, two similar chemicals that are sometimes mistaken for each other in pharmaceutical manufacturing (leading to hundreds of deaths). We also show that consumers could use mbira sensors to detect counterfeit and adulterated medications (which represent around 10% of all medications in low- and middle-income countries). We expect that many other musical instruments can function as sensors and find important and lifesaving applications.
Osmotic transport devices (OTDs) are forward osmosis membrane devices that we recently developed to remove accumulated fluid from swollen tissue, in-vivo, under severe conditions. As such, the relative volume of the fluid required to be removed and the volumetric flowrate may be two orders of magnitude less than the operating volume and tangential flowrate of the device. This makes it challenging to measure the rate of fluid flow from the swollen tissue. Here, we introduce a differential densimetry method for determining ultra-low volumetric flux through tissue samples. This technique uses two vibrating tube density sensors, one placed upstream of the membrane in contact with the tissue sample, and one placed downstream. Any flow of biological fluid withdrawn through the tissue will combine with the OTD operating fluid resulting in an observed density shift in the second density sensor. By measuring the difference in density between the upstream and downstream fluids, one can calculate the amount of fluid flowing across the tissue with a relatively high level of sensitivity. This method is also relatively insensitive to drift from temperature fluctuations and capable of continuously monitoring tissue permeability in real time. As a proof of concept, we used this technique to measure fluid flow across ex-vivo rat spinal tissue for an appropriately scaled OTD. The repeatability error had a maximum of only 12%. This implies that this method can provide highly acceptable flux measurements with reasonable reproducibility in real-time applications of fluid removal in-vivo.
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