New tiny wireless implant that can provide real-time measurements of tissue oxygen levels deep underneath the skin


Engineers at the University of California, Berkeley, have created a tiny wireless implant that can provide real-time measurements of tissue oxygen levels deep underneath the skin.

The device, which is smaller than the average ladybug and powered by ultrasound waves, could help doctors monitor the health of transplanted organs or tissue and provide an early warning of potential transplant failure.

The technology, created in collaboration with physicians at the University of California, San Francisco, also paves the way for the creation of a variety of miniaturized sensors that could track other key biochemical markers in the body, such as pH or carbon dioxide. These sensors could one day provide doctors with minimally invasive methods for monitoring the biochemistry inside functioning organs and tissues.

“It’s very difficult to measure things deep inside the body,” said Michel Maharbiz, a professor of electrical engineering and computer sciences at UC Berkeley and a Chan Zuckerberg Biohub Investigator. “The device demonstrates how, using ultrasound technology coupled with very clever integrated circuit design, you can create sophisticated implants that go very deep into tissue to take data from organs.”

Maharbiz is the senior author of a new paper describing the device, which appears in the journal Nature Biotechnology.

Oxygen is a key component to cells’ ability to harness energy from the food that we eat, and nearly all tissues in the body require a steady supply in order to survive. Most methods for measuring tissue oxygenation can only provide information about what is happening near the surface of the body.

That is because these methods rely on electromagnetic waves, such as infrared light, which can only penetrate a few centimeters into skin or organ tissue. While there are types of magnetic resonance imaging that can provide information about deep tissue oxygenation, they require long scanning times, and so are unable to provide data in real time.

Since 2013, Maharbiz has been designing miniaturized implants that use ultrasonic waves to wirelessly communicate with the outside world. Ultrasonic waves, which are a form of sound too high in frequency to be detected by the human ear, can travel harmlessly through the body at much longer distances than electromagnetic waves and are already the basis of ultrasound imaging technology in medicine.

One example of such a device is Stimdust, designed in collaboration with UC Berkeley electrical engineering and computer sciences assistant professor Rikky Muller, which can detect and stimulate electrical nerve firings in the body.

Tiny wireless implant detects oxygen deep within the body
A schematic of the oxygen-detecting implant, which measures 4.5 centimeters long by 3 centimeters wide. The µLED, O2-sensing film, and optical filter make up the oxygen sensor, and are controlled by an integrated circuit (IC). The piezo-crystal converts an electronic signal from the IC into ultrasonic waves that can be transmitted safely through living tissue. Credit: UC Berkeley image by Soner Sonmezoglu

Soner Sonmezoglu, a postdoctoral researcher in engineering at UC Berkeley, led the effort to expand the implant’s capabilities to include oxygen sensing. Incorporating the oxygen sensor involved integrating both an LED light source and an optical detector into the tiny device, as well as designing a more complicated set of electronic controls to operate and read out the sensor. The team tested the device by monitoring the oxygen levels inside the muscles of live sheep.

Sonmezoglu points out that this type of oxygen sensor differs from the pulse oximeters that are used to measure oxygen saturation in the blood. While pulse oximeters measure the proportion of hemoglobin in the blood that is oxygenated, the new device is able to directly measure the amount of oxygen in tissue.

“One potential application of this device is to monitor organ transplants, because in the months after organ transplantation, vascular complications can occur, and these complications may lead to graft dysfunction,” Sonmezoglu said. “It could be used to measure tumor hypoxia, as well, which can help doctors guide cancer radiation therapy.”

a, Schematic of the system as demonstrated in this paper for local tissue O2 monitoring in sheep. The free-floating wireless O2 implant is surgically placed beneath the biceps femoris muscle, and the wound is closed with sutures. The external US transducer, placed on top of the closed surgical site, establishes a wireless acoustic link to the implant. The external transducer powers the implanted sensor by delivering acoustic energy through the tissue and then listens for backscatter reflections from the sensor’s piezoelectric crystal, in which O2 data are encoded. The external transducer is driven by a custom mixed signal system, including decoding and storage of the wireless O2 data received by the external transducer. b, An expanded view of the wireless sensor platform, including a lead zirconate titanate (PZT) piezocrystal and a luminescence sensor, consisting of a µLED, a 3D-printed µLED holder, an O2-sensing film, an optical filter and an IC. c, The following steps were used for wireless sensor fabrication: (1) a piezocrystal was bonded with conductive silver epoxy, wire-bonded to a flexible printed circuit board (PCB) and encapsulated with parylene-C; (2) other sensor components were assembled on the flex board, and only the regions where the wire bonds are located were encapsulated with ultraviolet (UV)-curable epoxy; (3) the small gap (~50 µm) between the film and the µLED holder was filled by PDMS and (4) sensor parts excluding the piezocrystal were encapsulated with highly O2-permeable black silicone. d,e, Schematic (d) and photograph of the wireless sensor before black silicone encapsulation and size comparison to a finger (e); scale bar, 5 mm. f, Top view of the 4.5-mm3 packaged wireless sensor with the piezocrystal at the bottom, the luminescence sensor at the top and a size comparison to a United States dime.

“In premature infants, for example, we frequently need to give supplemental oxygen but don’t have a reliable tissue readout of oxygen concentration,” Maltepe said. “Further miniaturized versions of this device could help us better manage oxygen exposure in our preterm infants in the intensive care nursery setting and help minimize some of the negative consequences of excessive oxygen exposure, such as retinopathy of prematurity or chronic lung disease.”

Study co-authors Jeffrey Fineman and Emin Maltepe, who both are pediatricians at UCSF and members of the Initiative for Pediatric Drug and Device Development, became involved in the work because of its potential for monitoring fetal development and caring for premature babies.

The technology could be further improved, Sonmezoglu said, by housing the sensor so that it could survive long term in the body. Further miniaturizing the device would also simplify the implantation process, which currently requires surgery. In addition, he said, the optical platform in the sensor could be readily adapted to measure other biochemistry in the body.

“By just changing this platform that we built for the oxygen sensor, you can modify the device to measure, for example, pH, reactive oxygen species, glucose or carbon dioxide,” Sonmezoglu said.

“Also, if we could modify the packaging to make it smaller, you could imagine being able to inject into the body with a needle, or through laparoscopic surgery, making the implantation even easier.”

Near infrared spectroscopy (NIRS) is a non-invasive tool for tissue characterization and monitoring [1]. NIRS can retrieve the concentration of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), and consequently the total amount of hemoglobin (tHb = O2Hb + HHb) and the tissue oxygen saturation (StO2= O2Hb/tHb) by estimating the absorption coefficient at two or more wavelengths in the near infrared region (between 600 nm and 1000 nm) [2]. The continuous monitoring of these parameters can give important information about tissue (e.g., brain, muscle) activity and can have a high impact on clinical applications [3].

NIRS has been implemented in three main modalities that differ from each other based on the temporal characteristics of the employed light: continuous-wave NIRS (CW-NIRS: light with constant intensity [4]), frequency-domain NIRS (FD-NIRS: modulated light intensity) and time-domain NIRS (TD-NIRS: pulsed light intensity) [5].

Regardless the type of technique, the possibility to successfully apply NIRS instruments in clinical environment requires the following main features: accuracy, depth sensitivity, and selectivity (the capability to distinguish between the different tissue layers), reliability, robustness, and compactness. TD-NIRS can disentangle scattering from absorption information, improving the accuracy in the hemodynamics assessment [5].

The depth information naturally encoded in the TD-NIRS measurements also improves its depth sensitivity [6] and its rejection capability of measurement artifacts (movement artifacts, instrument drifts, etc.) ensures more reliable results compared to other techniques [7].

The complexity of TD-NIRS devices, mainly related to the need for narrow-pulse laser sources, time-resolved single-photon detectors, and high-precision timing electronics, usually brings to bulkiness, high cost and difficult usage. These issues limited the widespread adoption of TD-NIRS instruments, despite their interesting features [5]. In previous works [8,9] we demonstrated the possibility to improve robustness and reduce the dimension of a dual-wavelength, one detection channel TD-NIRS system employing custom photodetectors and pulsed-diode lasers. In this work, we present the in-depth characterization of such a device and demonstrate its capabilities in muscle and brain measurements.

The device is now wearable, battery-operated, and remotely controlled. These features bring tremendous advantages for in-vivo measurements, leading to the possibility of brain and muscle monitoring on freely moving subjects with comparable accuracy and reliability to the state-of-the-art TD-NIRS instruments.

reference link:

More information: Soner Sonmezoglu et al, Monitoring deep-tissue oxygenation with a millimeter-scale ultrasonic implant, Nature Biotechnology (2021). DOI: 10.1038/s41587-021-00866-y


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