January 10, 2023 | Laser diodes many times stronger than the brightness of light-emitting diodes (LEDs) found on the back of Apple Watches and Fitbits are enabling development of a photoacoustic skin patch capable of continuously monitoring the amount and location of hemoglobin in deep tissues. This opens the possibility of noninvasively detecting organ dysfunction, cerebral or gut hemorrhages, cancer, and COVID complications with the convenience of a wearable, according to Sheng Xu, professor of nanoengineering at the University of California, San Diego.
Wearable devices flooding the market all have a common denominator—they are limited to making measurements on the skin or in tissues less than 5 millimeter (mm) below the surface layer, he says. But in their in vivo experiments, a group of engineers at UC San Diego demonstrated their tiny electronic device could monitor chemical signals to the 1-centimeter (cm) mark and, in porcine tissue, to a depth of 2 cm. Consumer fitness trackers, by way of comparison, penetrate to a depth of about 0.2 cm.
Hemoglobin is currently the featured example of the device’s capabilities, as covered in an article that published in Nature Communications (DOI: 10.1038/s41467-022-35455-3). Since the photoacoustic signal correlates with the temperature of the light absorber (i.e., hemoglobin), the patch could likewise provide a way to measure core temperature quickly and precisely.
A consulting oncologist on the project told the study team that blood in breast cysts is a strong indicator of cancer while other liquids potentially in the cavity (i.e., water, milk, or lipids) are generally harmless. “This means we could use the [patch] technology to differentiate blood from the other kinds of liquids ... [to] screen high-risk populations for breast cancers, and we can do this regularly, on a daily basis, at home,” says Xu. From a convenience standpoint alone, that would be a godsend for people living in remote, resource-limited areas.
The flexible patch, which measures about 2.0 by 1.6 cm with a thickness of around 1.2 mm, can be applied to any part of the body, says Xiaoxiang Gao, a postdoctoral researcher in Xu’s lab and lead author of the study. The device performs three-dimensional mapping of hemoglobin with a submillimeter spatial resolution in deep tissues, although it currently doesn’t have enough optical power for imaging the cardiac region.
As Xu describes it, the laser diode is composed of a semiconductive wafer housing a bunch of electrodes. “It’s a bare die [or chip], which means it doesn’t have any packaging material.” The so-called “vertical-cavity surface-emitting laser (VCSEL) diodes were ordered from a vendor in China. “To the best of our knowledge, no one has ever used laser bare dies in a wearable skin patch format before.”
The UC San Diego team came up with their own methods to encapsulate the VCSEL die in an elastomeric matrix, says Gao. The device integrates an array of high-power VCSEL diodes and piezoelectric transducers that are interconnected by serpentine-shaped metal electrodes. When it emits high-intensity laser pulses into the tissues, biomolecules respond by absorbing the optical energy and radiating acoustic waves into the surrounding media.
Fabrication of the photoacoustic patch begins with patterning of the stretchable multilayered electrodes, Gao says. The device can survive mechanical deformations such as being bent, wrapped, twisted, or stretched.
The main hurdle to overcome was achieving a high signal-to-noise ratio with the VCSEL diode, which was accomplished in part by using a relatively long pulse—much the same duration as used on other studies using LEDs or laser diodes as light sources, says Gao. Multiple other measures were also taken to amplify the signal, including integrating an array of multiple VCSEL diodes in the patch and averaging the photoacoustic signals 3,000 times to reduce the incoherent noise.
Other papers have demonstrated that certain contrast agents, including carbon nanotubes and gold nanoparticles, could further enhance the signal intensity, increase the detection depth, and improve detection specificity, he adds.
Hemoglobin is the current “low-hanging fruit” for the photoacoustic patch, providing critical information about blood perfusion or accumulation in specific locations, says Xu. Low blood perfusion inside the body may cause severe organ dysfunctions and is associated with a range of ailments, including heart attacks and vascular diseases of the extremities. At the same time, abnormal blood accumulation in areas such as the brain, abdomen, or cysts can indicate cerebral or visceral hemorrhage or malignant tumors.
The new sensor overcomes significant limitations of existing methods of monitoring biomolecules—namely, MRI and CT techniques that rely on bulky equipment that can be hard to procure and usually only provide snapshot information on the immediate status of the molecule, he adds.
Potentially, the technology could be extended to the monitoring of multiple other biomolecules by creating laser diodes with corresponding wavelengths to make them discoverable, Xu says. The possibilities include detection of melanin, glucose, lipid, cytochrome, nucleic acid, antibodies, and other proteins.
The most immediate beneficiary of the device could be either consumers or hospitals, Xu continues, depending on the disease in question. For patients arriving in the emergency room with an injury involving internal bleeding, for example, physicians might deploy the patch to map out bleeding location and severity. It might also be used to monitor deep tissue hemoglobin concentrations of COVID-19 patients, helping to overcome the limitations of existing at-home and point-of-care solutions—among them pulse oximeters, which can only monitor hemoglobin in shallow tissues in extremities.
But to be market-ready, the development team needs to make this device more robust and user-friendly, says Xu. Anyone, without training, should be able to use it to get accurate, reliable measurement results.
The control electronics also still need to be integrated with the sensors, and the entire device should be made wireless, he adds. While the current design eliminates bulky ultrasound probes and sophisticated laser machines, the photoacoustic patch is still tethered to a backend system for signal acquisition and data processing. “Hopefully over the next two to three years we will have a prototype that doctors can use in large-scale clinical trials.”
Temperature is a long-recognized vital sign, and one of the first to be taken when patients arrive at the hospital, points out Xu. But the surface temperature of the body is what’s being measured and that’s vulnerable to many confounding factors, including sweating and room temperature.
A more stable and reliable signal comes from core body temperature in deep tissues, which is known to cycle with the 24-hour circadian rhythm and is more strongly correlated with metabolism and physiological status, he says. A significant deviation of the core temperature suggests failing thermoregulation, which is sometimes life-threatening.
Body temperature control is normally a self-regulating process, points out Xu, and proportional to the photoacoustic signal amplitude. Since some diseased populations have “hot spots,” such as tissues that are inflamed or cancerous, they could be monitored based on the temperature deviations.
The UC San Diego research team has demonstrated core temperature monitoring only in ex-vivo experiments,” Gao says. Before the novel patch can be used to monitor blood temperature in the human body, a gold standard measurement technique is needed to calibrate the photoacoustic amplitude and more advanced laser technology to eliminate the influence of extraneous factors (notably blood perfusion) affecting the photoacoustic signals.