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Volta Labs, Miroculus Independently Harness Electrowetting for Automated NGS Sample Prep


BALTIMORE – Aiming to make next-generation sequencing sample prep easier, faster, and more user-friendly, Volta Labs and Miroculus are both pursuing electrowetting technology, independently developing commercial platforms. While Miroculus' Miro Canvas instrument hit the market this week, Volta Labs is close behind, aiming for a launch early next year.

With a recent $20 million cash injection from a Series A financing and the financial backing from high-profile investors such as Illumina Cofounder John Stuelpnagel, 23andMe CEO Anne Wojcicki, and Kapa Biosystems Cofounder Paul McEwan, lab automation startup Volta Labs is poised to break the so-called next-generation sequencing sample prep bottleneck with its automated, "dramatically simplified" microfluidics platform.

The Cambridge, Massachusetts-based company, currently with ​​22 employees, said it has already deployed "technology demonstration prototypes" to a handful of customers across the country for testing. It plans to unveil the platform, said to integrate "electronics, automation, and materials industries with a modern software stack," at the Advances in Genome Biology and Technology conference in June.

However, with publicly available data lacking at this time, it remains to be seen whether the company's "sequencer-agnostic front-end platform" will outperform existing manual or automated NGS sample prep schemes in terms of speed, throughput, and quality control.

Founded in 2018 as a Massachusetts Institute of Technology spinout, Volta Labs was born out of CEO Udayan Umapathi's graduate work at the MIT Media Lab, where he explored applying fluidic technologies to biological workflows. Umapathi, who has a background in electrical engineering, said it was "pretty clear" to him early on that "there is a need to build automation from the ground up" when it comes to carrying out biological experimentation.

Especially for next-generation sequencing, Umapathi said, after walking into labs and talking to scientists, it was "kind of crazy" to find out that researchers can have "a push-button experience" for sequencing, yet the sample preparation steps upstream can still be cumbersome and often require extensive manual labor.

An array of automated platforms performing various steps for NGS sample prep already exist, such as Thermo Fisher Scientific's KingFisher Flex, Hamilton's Nimbus Presto liquid handling platform for DNA extraction, or Eppendorf's epMotion series for library preparation. However, Umapathi said, such liquid handling robots are "all sort of large," "meant to do very simple things," and are not specifically built for next-generation sequencing.

Also, because these systems can be "​​very complex, both physically and digitally," he said, many labs end up needing to hire a dedicated automation engineer to oversee automation protocols. Furthermore, Umapathi claimed that the protocol setup for these instruments can be complicated, resulting in labs dedicating one machine for just one particular workflow. "Picture a future lab performing genomic, proteomic, and metabolomic [experiments], how many machines do you think a single lab can actually house?" he asked.

To change that, Umapathi said Volta Labs sought to build "something much simpler," a single sample prep system that can "process many samples, many chemistries, and provide a push-button experience." With this initiative, the startup raised seed funding in early 2019, he said, collecting millions of dollars of financial support from "a range of amazing investors," including Maverick Ventures, Y Combinator, Village Global, and E14 Funds.

The base technology for the Volta platform is electrowetting, which involves manipulating fluids using an electric field, he said, adding that for the past two and a half years, the team has focused on inventing "completely novel methods for fluidic manipulation," a technology he referred to as "digital fluidics."

Touting the Volta platform as "a sophisticated conveyor belt without robotics," Umapathi said the system is equipped with "an array of electrodes" that are roughly a few millimeters in size and can have different shapes. On top of the electrode array, there is an insulator or dielectric, processed with surface coating. By charging or discharging the electrodes via an electronic circuit underneath, the platform is able to manipulate fluids in droplet form to move, merge, or split. Additionally, Umapathi said the instrument can accommodate other components, such as a magnetic field or thermal control to achieve further droplet manipulations.

Volta is not the first or the only company to take a crack at electrowetting for NGS sample prep. In 2015, Illumina launched Neoprep, a sample prep instrument that also used electrowetting, but the platform was discontinued just two years later, reportedly because of poor performance. Illumina originally obtained the electrowetting technology through its acquisition of Advanced Liquid Logic in 2013. Before that, ALL had deployed the technology in another NGS sample prep device, called Mondrian SP+.

Not long after Illumina's failed attempt, San Francisco-based Miroculus unveiled its digital microfluidics system in February 2020, although the company did not commercially launch the platform until this week. The system, called Miro Canvas, also taps electrowetting technology to manipulate droplets in a cartridge, allowing researchers to achieve a series of procedures, such as NGS library prep, in an automated and miniaturized way.

"Compared to any other digital microfluidic approaches, we have dramatically simplified our approach to digitally controlling fluids and samples," said Umapathi, while pointing out that Volta's approach does not rely on "massive plastic usage such as with a microfluidic approach" and "scales to much larger throughputs and allows for many applications on a single platform."

Specifically, Volta's platform is capable of handling different types of reagents and samples on the same surface without the issue of biofouling, meaning having materials left behind on the surface, he said. The system is also able to work with different volumes, ranging from a few to hundreds of microliters, thus enabling users to conduct various sample prep workflows — such as DNA extractions, library prep, and enrichment — all on a single platform.

In terms of throughput, Umapathi said the first instrument will be able to process "at least eight samples," while the company envisions to achieve "very high throughputs in the long run."

Despite these differentiators, there are still hurdles Volta will likely have to overcome in order to drive the platform's adoption across NGS workflows.

For one, Umapathi acknowledged that the starting material for Volta's platform is, at this point, limited to liquid-type samples, such as cell suspensions, blood, or saliva for DNA extraction, or DNA or RNA solutions for library prep.

It is also unclear how well Volta's system can prevent contamination, a key pitfall for NGS research. Umapathi said Volta scientists "haven't explicitly done any benchmarking" in terms of environmental contamination of samples, but he noted that out of the "hundreds of samples" that the company has processed so far, they have not seen external contamination in the sequencing data. In addition, he said, the topmost surface of the platform consists of disposable "peelable layers," ensuring a fresh sterile layer before each preparation. As for cross-contamination between samples, he said he is confident that "it is not a problem" for Volta since the platform can "isolate the samples well enough," though he declined to disclose the specific mechanisms for now.

Another open question is how the end-to-end, "push-button experience" proposed by Volta will ensure quality control. Many existing sample prep workflows require multiple stopping points to conduct quality control along the way, which Volta's platform seemingly won't be able to do. Umapathi said the firm is "thinking about it" but declined to comment further at this time.

As for speed, he said the instrument has a turnaround time "equivalent to or faster than manual preparation," but he acknowledged that "right now, we have not optimized for speed." And even with enhanced throughput, Umapathi said the platform is "not competing with high-throughput or ultra-high-throughput [platforms] at a first attempt." He added that the firm considers labs with an eight- or 16-sample sequencing throughput as sweet-spot customers at this point.

According to Umapathi, Volta's first benchtop product will be compact enough to be "one of the smallest instruments in the industry," though he said the team has not zeroed in on the exact dimensions quite yet. He is also fairly confident that the product will be user-friendly, judging by the experience from the early customers. "We installed the instrument, we trained them for 30 minutes, and we walked away," he said. These customers were able to "robustly run multiple workflows on the instrument" without any "hand-holding." While he did not reveal the customers by name, he shared that they are from "different segments of the market," including a genome center, a biotech company, a clinical translational lab, and a core facility.

Volta has also not yet provided a price tag for the platform. Umapathi said while the company considers the instrument "a premium product," it is also "keeping an eye toward the budget."

Miroculus Miro Canvas

Meanwhile, with the full commercial launch of its Miro Canvas this week, Volta Lab's competitor Miroculus has set the price for its digital microfluidics-based NGS library prep system at around $32,000, according to the company's cofounder and CEO Alejandro Tocigl.

Since the debut of the platform in February 2020, Miroculus scientists have been "working really hard on expanding the menu of applications that can be run on the system," Tocigl said. As a result, the Miro Canvas now hosts "a whole set of applications" ranging from whole-genome sequencing on long-read sequencers such as PacBio and Oxford Nanopore to rapid whole-genome sequencing on Illumina, he said. Before the commercial launch, the company shipped over 25 instruments to be tested by scientists, many at high-profile biomedical institutions such as Rady Children's Hospital, the Broad Institute, and the Earlham Institute in the UK.

The size of a laptop computer, Miro Canvas is a fully automated system that also uses electrowetting technology to carry out various NGS library prep steps, including dispensing, mixing, dilution, PCR, and beat cleanup, according to Tocigl. Mirroring Volta's claims, he said Miro Canvas can handle "a very wide range of volumes" while achieving "comparable" turnaround time, metrics, and yields to manual library prep.

"We haven't actually found a library prep that doesn't work on our system," he said, highlighting that the platform was able to conduct miniaturized Oxford Nanopore library prep using 25 percent of the recommended starting volume. He also emphasized that while NGS library prep is considered one of the "core applications" for the instrument, it has also shown capabilities for DNA extraction as well as sample prep for proteomics and synthetic biology studies. Similarly, the system is also, for now, limited to liquid sample types.

However, unlike Volta's platform — which purportedly is engineered to process multiple samples at once — Miro Canvas is primarily designed to accommodate one sample each time. Tocigl noted the company is aiming to address the "clear need on the lower-throughput segment," and cross-contamination between samples is less of a concern for Miroculus. To prevent environmental contamination, the company's engineering team has designed "a closed environment" so that "the droplets are always contained" within the cartridge.

As for accommodating stopping points for quality control, Tocigl said the company is "trying to automate as much as we can, while still giving flexibility to the user to incorporate steps that sometimes they used to do, or sometimes they prefer to."

So far, Miroculus has filed over 40 patent applications "covering the ins and outs of the technology," according to Tocigl. He said there is no patent overlap between Miroculus and Volta Labs to his knowledge. Umapathi said the company has filed more than five families of patents and has had several patents granted, including one on differential wetting.

In spite of the competition, both Tocigl and Umapathi said they are confident their respective products will find adaption, given the vast sequencing market and the huge void to fill the automated sequencing sample prep space. "I think the opportunity here is so big," Tocigl said. "I'm sure we're going to see so many more products coming up in different companies."

Umapathi said with the money raised in the Series A, Volta Labs is aiming to have a limited release program this year, followed by a commercial launch early next year. Although the company has "a long roadmap" to eventually tackle samples preparation outside NGS, such as proteomics, metabolomics, and synthetic biology, he said the first instrument will focus on sequencing samples. "We want to do well in one thing," Umapathi said. "Then we will start tackling adjacent fields."