Foremost among the symptoms affecting critically ill COVID-19 patients is respiratory failure. During the first wave of the pandemic in the spring of 2020, patients admitted to critical care were more likely to receive invasive ventilation within the first few days than those admitted in the second wave in late summer and early fall—when noninvasive respiratory support such as high-flow nasal oxygen, continuous positive airway pressure (CPAP), or Bilevel Positive Airway Pressure (BiPAP) by machine became more common.

This shift was based on data associating invasive ventilation with low survival rates—it can lead to infections and requires some minimal level of lung strength—as well as from the practical reality of a shortage of ventilators. Even in regions where there were not ventilator shortages, trained respiratory therapists who could administer the treatment were stretched thin.

In the early days of the pandemic, the U.S. Food and Drug Administration (FDA) began granting Emergency Use Authorization (EUA) for the use of previously unapproved medical products such as pharmaceuticals, biologics and vaccines, and devices such as diagnostic tests and ventilators, as well as for the use of approved products in new ways in the fight against COVID-19. A group at Stanford University led by David Camarillo had just recruited Sam Raymond, a skilled mechanical engineer and computer scientist, as a postdoctoral fellow. Raymond decided that building a new ventilator that addressed early challenges of the pandemic would be his first project in the lab, which spurred the Camarillo team into action with a desire to use their bioengineering skills to meet the moment.

Working remotely, but with a common goal

Working almost completely remotely from their homes beginning in March 2020, the Stanford group enlisted design help from local firm 219 Design, and after a few months brought in consultant Mike Horzewski, a veteran of early-stage medical device startups. With financial and legal support from Chan Zuckerberg Biohub—with COO Gajus Worthington and co-President Steve Quake acting in a marshaling role—and in collaboration with regulatory specialist Peggy McLaughlin at MPM Advisors, they began working in earnest under EUA guidance for emergency-use ventilators, meeting just a few times in person, and never as a full team.

Within the first months of the pandemic, many ventilators received EUA approval, including ones based on rudimentary designs. One approach involved automating common manual resuscitators that use a bladder or what is known as a bag valve mask, or “Ambu bag.” More sophisticated ventilators, which employ an internal compressor and mixer to moderate and control the gas mixture, can have upwards of 1,000 individual parts.

Faced with a global shortage of standard parts as they began designing their emergency-response ventilator, the Stanford team, including pulmonologist Ryan Van Wert, began with a simplified design, requiring as few easy-to-source parts as possible, which would also limit the cost of producing it and allow for scaling up the manufacturing of the device. Raymond says that minimizing the specialized features of the device would serve to maximize the number of people it could help.

The process of working with the FDA was ever-evolving, as treatment recommendations changed, but also as the standards changed with ventilators being granted EUA approval – by April 2020, 42 different ventilators were approved for emergency use. McLaughlin says that FDA officials worked closely with the Stanford group on their machine, making themselves readily available to address questions that would swiftly make the device available to patients.

Evolving recommendations require rapid design changes

In the latter part of 2020, the pace of EUA approvals for ventilators was slower than earlier in the year, and recommendations for the use of ventilators in treatment were changing. One major change was the recommendation to move patients off of ventilators that use intubation in favor of other forms of oxygen support, such as with high-flow nasal cannula that deliver pressurized oxygen through the nose. In true Bay Area–startup fashion, the Stanford team had to make design decisions in real time and evolve to meet these changing standards.

One of their more creative solutions came about from a shortage of airflow sensors. In an early design, the group had to use a printed table that connected the air volumes and delivery times to quantitate the flow rate. Given the high pace of ventilator approvals, the team also had to determine their place in a crowded field, and they wanted their machine to be deployed in places where there was an overload of patients. At the same time, the nature of the fast-moving and deadly virus placed a lot of stress on the RT workforce, so the group needed to land on a machine that trained RTs could easily use. In the latter part of the project and even during the review process after submission to the FDA, the team began to employ some of the standard parts that were fortunately starting to become available—such as controls, alarms, and displays that RTs are familiar with.

Ultimately, the machine they used for bench-testing was one that could be used at all stages of a patient’s treatment journey—starting as passive support with a high-flow nasal cannula that places less stress on lungs during early hospitalization, to invasive ventilation with sedation, and any additional non-invasive nasal cannula or CPAP/BiPAP to ease patients off of ventilation and sedation. In the hospital setting COVID-19 already complicates bringing ventilators back into commission between patients because they must be thoroughly decontaminated and their performance must be verified between patients, so the multimodal Stanford machine is a particularly attractive. While such multimodality is not uncommon for traditional ventilators, the team’s advance was to cut down on the number of parts needed, and ultimately the price—theirs can be built at approximately one-tenth the price of standard ventilators.

The machine also needed to be built by an independent facility to ensure compliance, and it had to be tested in certified labs—to establish electrical safety and to ensure it was robust under alarm parameters including on over-pressurization. They also conducted lengthy biocompatibility and oxygen safety assessments, and ultimately the team submitted their machine for EUA approval in September 2020.

In March 2021, almost exactly a year after the first Camarillo lab meeting where they committed themselves to this project, the team’s ventilator, dubbed “O2U,” received EUA approval. At long last, there was a small outdoor gathering of some of the team to celebrate and to meet in person as a larger group for the first time.

While the ventilator that received EUA approval, described in a preprint, was a highly functional low-cost device, the team continued to iterate on the design while it was being considered by the FDA and have since added new functions. They have yet to pursue deploying it internationally, which comes with its own challenges, but with sufficient investment, O2U ventilators could be mass-produced in a cost-effective way.