Monitoring mitochondria: Laser device tells whether oxygen is sufficient

Shining a laser-based device on a tissue or organ may someday allow doctors to assess whether it’s getting enough oxygen, a team reports today in the journal Science Translational Medicine.

Placed near the heart, the device can potentially predict life-threatening cardiac arrest in critically ill heart patients, according to tests in animal models. The technology was developed through a collaboration between Boston Children’s Hospital and device maker Pendar Technologies (Cambridge, Mass.).

“With current technologies, we cannot predict when a patient’s heart will stop,” says John Kheir, MD, of Boston Children’s Heart Center, who co-led the study. “We can examine heart function on the echocardiogram and measure blood pressure, but until the last second, the heart can compensate quite well for low oxygen conditions. Once cardiac arrest occurs, its consequences can be life-long, even when patients recover.”

In critically ill patients with compromised circulation or breathing, oxygen delivery is often impaired. The new device measures, in real time, whether enough oxygen is reaching the mitochondria, the organelles that provide cells with energy.

a mitochondrion
(AlexAnimation, ShutterStock, John Kheir)

Under low-oxygen conditions, mitochondrial energy production slows or shuts down, and cell death may be triggered. This sets the stage for cardiac dysfunction and, in the worst case, cardiac arrest, says Kheir.

The current standard for measuring tissue oxygenation, known as mixed venous saturation (SvO2), requires repeated blood draws, adding extra risk in critically ill patients. More importantly, SvO2 cannot tell whether oxygen supply is sufficient to meet the dynamic demands of heart muscle.

Using light to monitor mitochondria

mitochondrial oxygenation as measured by resonance Raman spectroscopy

These resonance Raman spectroscopy images (click to enlarge) show the intensity and wavelengths of reflected light from mitochondrial cytochrome, myoglobin and hemoglobin. The red spectra were produced when the proteins were oxygenated; blue, de-oxygenated. Reprinted with permission from Perry DA et al, Sci Trans Med, Sept. 20, 2017

The device uses laser light and a technology called resonance Raman spectroscopy. It measures how light is scattered when the laser is shined on three mitochondrial proteins — cytochrome, myoglobin and hemoglobin. Under low-oxygen conditions, these molecules accumulate extra electrons. This causes chemical bonds in the proteins’ porphyrin rings to bend and stretch, making the proteins scatter light differently. A complex algorithm distills the information, producing a real-time metric the team calls 3RMR.

“The system tells us how satisfied the mitochondria are with their oxygen supply,” Kheir explains.

Pendar Technologies had already been already applying resonance Raman spectroscopy to study hemoglobin saturation in blood. The Heart Center’s Translational Research Lab, co-led by Kheir and Brian Polizzotti, PhD, collaborated with Pendar to study mitochondria in the live, beating heart, hoping to find an early warning sign of inadequate oxygenation.

“Distinguishing mitochondrial signals from other biological signals with accuracy and speed was the most significant scientific advance here,” says Pendar CEO Daryoosh Vakhshoori, PhD, who oversaw the engineering aspect of the project.

Predicting cardiac arrest

Joshua Salvin, MD, MPH and Dorothy Perry, MBChB of the Heart Center, the study’s co-first authors, tested the device in rat models. They found that reduced oxygenation of the heart corresponded with elevations in 3RMR, regardless of the cause of reduced oxygen delivery.

measuring mitochondrial oxygenationElevations of more than 40 percent, measured after 10 minutes of low-oxygen conditions, predicted reduced heart contractility and subsequent cardiac arrest with 97 percent specificity and 100 percent sensitivity, outperforming all other measurement techniques.

The team further tested the device during simulated congenital heart surgery in a pig model, with similarly good results.

Kheir and colleagues believe the technology could be used to monitor tissue viability in exposed tissues and organs. The first use would likely be to monitor oxygen delivery during and after heart surgery. Eventually, the team would like to develop a probe small enough to be left inside the chest, so patients could be monitored in the ICU during highest-risk times (the current probe is the size of a pen).

Future applications

Other potential applications might include monitoring organs intended for transplantation and detection of dangerously reduced blood flow in limbs.

“I think there would be many surgical uses,” says Vakhshoori, co-corresponding author on the study. “There really is no technology currently that can assess, in real time, whether oxygen delivery to a tissue is adequate at the level of the mitochondrion.”

Kheir also thinks the tool could be helpful in cancer research, since mitochondrial function is central to cancer biology.

The team’s goal is to seek FDA approval and commercialize a bedside monitor of mitochondrial oxygenation. In the meantime, Kheir and colleagues plan to seek approval to test the device to monitor heart patients.

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Other coauthors on the study were Padraic Romfh, Peili Chen and Kalyani Krishnamurthy of Pendar Technologies; Lindsay M. Thomson and Brian D. Polizzotti of Boston Children’s and Francis X. McGowan of the Children’s Hospital of Philadelphia. Pendar Technologies holds an exclusive license to U.S. patent 7,113,814 entitled “Tissue Interrogation Spectroscopy.” The study was funded by AHA IRG (14IRG18430027), DOD ATTDA (W81XWH-15-1-0544), DOD BRA (W81XWH-11-2-0041), Smith Family President’s Innovator Award and Hess Family Philanthropic Fund.

Read about Kheir’s research on intravenous oxygen delivery and learn more about research and innovation at the Heart Center.