UCLA researchers develop new p-microscope

Photo: Left: Euglena gracilis growth within PicoShells over the course of two days. Right: Close-up of a picoshell with algae, through bright field imaging and lipid dye.
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Credit: Mark Van Zee/UCLA

Production of high-energy lipids by microalgae may provide a sustainable source of renewable energy that could help tackle climate change. However, microalgae engineered to produce lipids quickly usually grow slowly themselves, making it difficult to increase overall yield.

Bioengineers at UCLA have created a new type of petri dish in the form of permeable microparticles that can dramatically accelerate research and development (R&D) schedules for biological products, such as fatty acids for biofuels. Porous particles and hydrogels termed as PicoShells (trillionths of a liter) can enable the fractionation and culture of more than one million individual cells in production-relevant environments and their selection based on growth traits and biomass accumulation using standard cell processing equipment.

Proceedings of the National Academy of Sciences recently published Study detailing how PicoShells work and their potential applications.

PicoShells consist of a hollow inner cavity in which cells are encapsulated and a porous outer shell that allows continuous solution exchange with the external environment so that nutrients, cell communication molecules and cytotoxic cellular byproducts can freely move in and out of the inner lumen. The cortex also maintains small groups of developing cells, allowing researchers to study and compare their behaviors — what they do, how quickly they grow, and what they produce — with those of other groups within the various PicoShells.

This new class of laboratory tools allows researchers to grow single-celled microorganisms — including algae, fungi and bacteria — under the same conditions as industrial production, such as in a sewage-filled bioreactor or an outdoor culture pond.

PicoShells are like very small mesh balloons. “The cells growing inside are effectively fenced off but not sealed off,” said study leader Dino DiCarlo and Dr. With this new tool, we can now study the individual behaviors of millions of living cells in the relevant environment. This can shorten commercial production timelines for research and development of vital products from a few years to a few months. PicoShells can also be a valuable tool for basic biology studies.”

The permeability of PicoShells can move the laboratory into the industrial environment, allowing testing to be conducted in a divided area of ​​a work facility. Growth can occur more quickly and the strains of cells that function well can be identified and selected for further examination.

According to the researchers, another advantage of this new tool is that the analysis of millions of PicoShells is done automatically since it is also compatible with standard laboratory equipment used to process high-volume cells.

Huge groups of cells, up to 10 million in a single day, can be sorted and organized by certain characteristics. Continuous analysis can produce ideal populations of cells – those that actually perform well in the environment with the right temperature, nutrient composition and other properties that can be used for mass production – in just a few days rather than the many months it would take to use current technologies.

The shells can be designed to explode when the cells inside divide and grow beyond their peak size. These free cells are still viable and can be recovered for further research or further selection. Researchers can also create shells with chemical groups that disintegrate when exposed to a biocompatible reagent, enabling a multifaceted approach to releasing select cells.

“If we want to focus on algae that are better at producing biofuels, we can use PicoShells to organize, grow and process millions of single algae cells,” said lead author Mark Van Zee, a graduate student in bioengineering at the University of California, Samueli. “And we can do this in machines that sort them with fluorescent markers that light up to indicate fuel levels.”

Currently, such microorganisms are often cultured and compared using traditional lab instruments, such as microwell plates – cans containing dozens of tiny test tube-like sizes. However, these methods are slow and their effectiveness difficult to determine because it can take weeks or months for large colonies to grow for study. Other methods, such as emulsions of water-in-oil droplets, can be used to decompose cells at smaller volumes, but surrounding oils prevent the free exchange of the medium in the water droplets. Even cells or microorganisms that function well in laboratory conditions may not perform well once placed in industrial environments, such as bioreactors or outdoor culture farms. As a result, cell strains developed in the laboratory often do not display the same characteristic beneficial behavior when transferred to industrial production.

Microwell plates are also limited in the number of experiments that can be performed, which has resulted in a great deal of trial and error finding cell strains that perform well enough for mass production.

The researchers demonstrated the new tool by culturing algae and yeast colonies, comparing their growth and viability with other colonies grown in water-in-oil emulsions. For the algae, the team found that PicoShell colonies rapidly accumulated biomass while the algae did not grow at all in water-in-oil emulsions. Similar results were found in yeast experiments. By choosing the most algae grown in PicoShells, researchers can increase chlorophyll biomass production by 8% after just one cycle.

The authors said PicoShells could offer a faster alternative to developing new strains of algae and yeast, leading to improved biofuels, plastics, carbon capture materials and even food products and alcoholic beverages. Further improvements in technology, such as coating the shells with antibodies, could lead to the development of new types of protein-based drugs.

Di Carlo and Van Zee and study co-author Joseph de Root Ph.D. ’20, a former member of by Carlo Research Group, the inventors on a patent application filed by UCLA Technology Development Group.

Other UCLA authors on the paper are Rose Roman, Cayden Williamson, Trevor Burns, Andrew Soniko Eugenio, Sarah Badeh, Dong Hyun Lee and Manny Archang. Randor Radakowitz of San Diego Synthetic Genomes is also an author.

The study was supported by the Presidential Prize for Early Career Scientists and Engineers and the Planning Award from california nano systems institute (CNSI) at the University of California.

by Carlo Holds faculty appointments in Bioengineering and Mechanical and Aerospace Engineering at University of California, Los Angeles Samueli. He is a member of CNSI and the Johnson Comprehensive Cancer Center at the University of California.

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