Serial monitoring of deep-tissue stiffness using wearable ultrasound patch

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The biomechanical properties of human tissues play a crucial role in maintaining the structure and function of physiological systems. Regular assessment of tissues’ biomechanical properties allows for timely evaluation of tissue growth, metabolic state, immune function, and hormone regulation. Moreover, these properties often have important implications for various diseases. Numerous disease symptoms, such as inflammation, cysts, fibrosis, and carcinoma, affect the stiffness of tissues. For instance, tissues’ stiffness typically elevated in both benign and malignant tumors, mostly as a result of denser collagen fiber growth in the extracellular matrix; on the other end of the spectrum, cysts that are filled with liquid are noticeably less rigid than normal tissue; likewise, musculoskeletal and tendinous tissues that are injured or inflamed exhibit distinctive regional variations in stiffness. As such, the spatial distribution of tissues’ stiffness can be used not only as potential flags for clinical diagnosis, but also as important metrics to proactively identify and protect vulnerable tissue areas. 

During certain developmental stages of pathophysiological conditions, there are always quick changes in stiffness. For instance, rapidly proliferating tumors, like gliomas, found in the brain with a specific growth rate of 4.6% per day, make the traditional one-time clinical testing models incapable of tracking changes; only by monitoring frequently can the condition be managed in real time. A second example is given by a diagnostic approach used to differentiate Parkinson's disease from Parkinsonian syndrome. This approach requires tests of the stiffness of biceps brachii muscles once per minute before and after drug administration. Thus, frequent assessment of tissue biomechanical properties is vital for aiding early detection and management of diseases, as well as for evaluating rehabilitation progress. 

Elastography, which can be performed using magnetic resonance imaging, optical coherence imaging, or ultrasound, is the most prevalent method for evaluating the biomechanical properties of human tissues, because it enables non-invasive, high-resolution, and volumetric reconstruction of the modulus distribution in the subject. Magnetic resonance imaging and optical coherence imaging conduct scans based on the principle of shear wave elastography. The tissue under examination is subjected to low-frequency mechanical vibrations, generating shear waves within it. The propagation of these shear waves can be captured using magnetic resonance imaging and optical coherence imaging. Since the shear wave velocity varies based on the stiffness of the medium, the shear wave velocity and the modulus distribution that follows can be calculated using well-known relationships between modulus and wave speed. 

However, such devices are only appropriate for single clinical examinations. High cost, long detection time, and bulky size are the main reasons that restrict their use to medical environments only. These modalities are unsuitable to be used in various settings for frequent monitoring. Moreover, due to the strong scattering and absorption of light by biological tissues, optical coherence imaging can only detect tissues up to 0.6 mm below the skin, significantly limiting this method’s applicability. 

Ultrasound-based elastography, which benefits from the intrinsic strong penetration of ultrasound waves in tissues, can map the mechanical properties of deep tissues over 4 cm. Ultrasound elastography can be executed based on two principles: shear wave and quasi-static. Shear wave-based ultrasound elastography holds certain advantages over magnetic resonance shear wave elastography and optical coherence shear wave elastography, as it utilizes focused ultrasound waves to generate shear waves and eliminates the need for an external mechanical vibrator. However, it necessitates delivering a significant amount of energy into the tissue, and prolonged scanning durations may cause notable tissue heating. Other downsides include the possibility of wave interference affecting the results and the examination's reliance on the operator's skill. Consequently, ultrasound shear wave elastography is not the optimal method for frequent and serial monitoring. 

In contrast, quasi-static elastography, based on Hooke's Law, does not present the aforementioned issues. Quasi-static elastography compares the tissue deformations before and after a static compression to determine the tissue modulus. Nevertheless, the use of ultrasound in quasi-static elastography can present its own set of issues. A major challenge is that the geometric mismatch between traditional rigid ultrasound probes with planar bases and curved human tissue can result in poor acoustic coupling, leading to information loss and artifacts. Furthermore, current ultrasound devices are manually-handheld probes primarily designed for short-term clinical diagnosis, and the complexity of finding suitable testing sites during the examination, along with the bulky probe housing, makes it inconvenient to move around or carry for an extended period. Therefore, continuous patient monitoring cannot be achieved with the current setup. 

To address this technological gap, we reported a flexible and stretchable ultrasound array, enabling conformal attachment to the skin for long-term modulus monitoring. The innovation of this technology benefits from the novel patch-like design composed of 16 by 16 individual piezoelectric elements, stretchable serpentine copper electrodes, and biocompatible soft encapsulation polymer substrate. The island-bridge structure makes the patch locally rigid, but globally soft. A coherent compounding transmitting-based imaging algorithm was demonstrated to achieve high-resolution and high-contrast elastic images on human body. We can derive the quantitative modulus of tissues by solving an inverse problem, which is a leap forward in comparison to traditional qualitative strain mapping techniques. We verified the application of the wearable patch in continuous tracking of muscular injury in delayed-onset muscle soreness tests (Fig. 1).

a, An optical image showing the device that conforms to upper arm. b, Serial monitoring results of normalized modulus contrast and soreness intensity of the biceps brachii muscle before and after the eccentric exercise. We mapped the modulus distribution of the muscle and then calculated the mean and standard deviations of the biceps brachii area, which were plotted at the top. Each point and error bar represent the result of one measurement. The time interval between adjacent tests is 1 min. In each physiotherapy session, data were normalized by the modulus contrast of the biceps brachii muscle before exercise. At the bottom, soreness scores were evaluated following the pain visual analogue scale.

Fig. 1 | Serial surveillance of delayed-onset muscle soreness in human. a, An optical image showing the device that conforms to upper arm. b, Serial monitoring results of normalized modulus contrast and soreness intensity of the biceps brachii muscle before and after the eccentric exercise. We mapped the modulus distribution of the muscle and then calculated the mean and standard deviations of the biceps brachii area, which were plotted at the top. Each point and error bar represent the result of one measurement. The time interval between adjacent tests is 1 min. In each physiotherapy session, data were normalized by the modulus contrast of the biceps brachii muscle before exercise. At the bottom, soreness scores were evaluated following the pain visual analogue scale.

One of the biggest challenges in developing this technology is creating a transducer array with high sensitivity. Recording the motion of scattering particles in the sample by ultrasound wave and calculating their displacement fields based on the normalized cross-correlation algorithm requires a device with high sensitivity. This is because the size of scattering particles is very small, resulting in the weak reflected signals. However, traditional high-temperature bonding methods caused significant irreversible thermal damage to the epoxy in the piezoelectric materials, degrading the transducer element's sensitivity. To overcome this challenge, researchers developed a low-temperature bonding approach that replaced the solder paste with conductive epoxy, enabling bonding to be completed at room temperature without damaging the element. Additionally, they replaced the single plane wave transmission mode with a coherent plane-wave compounding mode, which provides more energy to boost the signal intensity throughout the entire sample, resulting in higher signal-to-noise ratios. By incorporating these strategies, researchers were able to improve the sensitivity of the device, allowing it to capture even the faintest signals from scattering particles. 

In summary, we have presented the design and microfabrication technology of a wearable ultrasound patch that offers non-invasive and continuous monitoring of deep-tissue modulus. The proposed device features high mechanical compliance, which makes it perfectly attachable to the skin, thereby overcoming the limitation of poor acoustic coupling encountered with traditional rigid ultrasound probes. The patch has demonstrated its potential for long-term monitoring of deep tissue mechanical properties, making it a viable solution for wearable sensor development in the future. We believe that the ultrasound-based sensing mechanism employed in the patch can be widely adopted and further developed to expand the scope of detecting parameters, including physical and chemical characteristics in deep tissues. The ability to continuously and non-invasively monitor deep-tissue modulus using the wearable ultrasound patch offers a novel solution for early detection and treatment of various diseases. Furthermore, this technology opens up opportunities for personalized medicine, where tailored treatment plans can be developed based on individual patient's mechanical properties, contributing to improved therapeutic outcomes. With further technological advancements, we anticipate that the wearable ultrasound patch will pave the way for the development of innovative healthcare solutions that can better serve patients and improve their quality of
life.

This study entitled "Stretchable ultrasonic arrays for the three-dimensional mapping of the modulus of deep tissue" has been published in Nature Biomedical Engineering (https://www.nature.com/articles/s41551-023-01038-w).

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