Recent advances in microsystem approaches for mechanical characterization of soft biological tissues

Abstract

Microsystem technologies for evaluating the mechanical properties of soft biological tissues offer various capabilities relevant to medical research and clinical diagnosis of pathophysiologic conditions. Recent progress includes (1) the development of tissue-compliant designs that provide minimally invasive interfaces to soft, dynamic biological surfaces and (2) improvements in options for assessments of elastic moduli at spatial scales from cellular resolution to macroscopic areas and across depths from superficial levels to deep geometries. This review summarizes a collection of these technologies, with an emphasis on operational principles, fabrication methods, device designs, integration schemes, and measurement features. The core content begins with a discussion of platforms ranging from penetrating filamentary probes and shape-conformal sheets to stretchable arrays of ultrasonic transducers. Subsequent sections examine different techniques based on planar microelectromechanical system (MEMS) approaches for biocompatible interfaces to targets that span scales from individual cells to organs. One highlighted example includes miniature electromechanical devices that allow depth profiling of soft tissue biomechanics across a wide range of thicknesses. The clinical utility of these technologies is in monitoring changes in tissue properties and in targeting/identifying diseased tissues with distinct variations in modulus. The results suggest future opportunities in engineered systems for biomechanical sensing, spanning a broad scope of applications with relevance to many aspects of health care and biology research.

Keywords: Electrical and electronic engineering; Engineering.

Fig. 1

A summary graphical abstract for recently established microsystem technologies for biomechanical evaluations. Illustrations of each technology involve key features and corresponding biological measurement targets.

Fig. 2. Emerging classes of flexible/stretchable microsystem platforms for evaluating the elastic moduli of soft tissues.

a Schematic illustration of microstructures in soft biological tissues, with a focus on the skin. Reproduced with permission. Copyright 2015, Nature Publishing Group. b The resultant mechanical properties exhibit “J-shaped” stress–strain behavior. Reproduced with permission. Copyright 2017, Royal Society of Chemistry. c–e Various flexible/stretchable microsystem approaches, with upper insets showing the material engineering and manufacturing technologies. c Needle-shaped flexible probe for tissue modulus measurements based on an ultrathin actuator and sensor placed on biological tissue. Reproduced with permission. Copyright 2018, Nature Publishing Group. d Photograph of a conformal device on a silicone sheet substrate for characterization of the elastic modulus of skin. Reproduced with permission. Copyright 2015, Nature Publishing Group. e Optical image of a stretchable phased array consisting of 12 × 12 interconnected ultrasonic transducers during bending and stretching. Inset: the magnified image of four transducer units in the array, with a spacing pitch of ~0.8 mm. Scale bars, 300 µm (inset). Reproduced with permission. Copyright 2021, Nature Publishing Group

Fig. 3. Planar microsystems using MEMS-based processing approaches.

a Atomic force microscopy (AFM) image. A 10 × 10 µm² area with a representative alveolar cell from a rat lung (dotted square) probed mechanically with 121 indentations. b Resultant AFM elastography mapping of the elastic modulus, rendered at an indentation depth of 300 nm. Reproduced with permission. Copyright 2008, The American Physiological Society. c Scanning electron microscope (SEM) image of a piezoresistive microcantilever (left), consisting of a SU-8 indentation tip and doped silicon-ribbon cantilever as a piezoresistor, with a corresponding optical image of a microcantilever supported by a silicon wafer (right). Reproduced with permission. Copyright 2014, Royal Society of Chemistry. d Ultrasound-on-chip (UoC) designs based on MEMS approaches. Photograph, SEM images, and schematic illustration of an ultrasound-on-chip design (left) that includes 8960 MEMS transducers (upper right) on a CMOS chip, each with control/processing circuitry for sending and receiving ultrasound signals (lower right). e Results of measured ultrasound images across cardiac and thyroid tissues, with color Doppler results showing small parts of the thyroid nodule. f, g Illustration of ultrasound-on-chip circuitry and chip integration. f A photograph of the electronic modules across the CMOS design. g Schematic illustration of the module-level communication architecture. Reproduced with permission. Copyright 2021, National Academy of Sciences

Fig. 4. Miniaturized MEMS devices for the characterization of tissue biomechanics.

a Exploded-view schematic illustration of the system. The upper inset shows a circuit diagram (upper-right). The lower inset is a photograph of the back side of the system. b Photograph of the device on the fingertip. c Experimental (E, symbols) and simulation (FEA, line) results of sensor voltages as a function of sample thicknesses with various moduli. d Dynamic measurements for modulus sensing on the human body. Left: Photographs of the forearm before (upper) and after (lower) lifting a dumbbell. Right: sensor voltages as a function of time during signal recording. Reproduced with permission. Copyright 2021, Nature Publishing Group

Fig. 5. Summary of microsystem technologies with various measurement scales.

Illustration of the approximate ranges of measurement depths and spatial resolutions for various biological targets via different types of evaluation methods, including AFM, cantilever-based measurement (CBM), piezoelectric-actuator/sensor techniques (PAT), optical coherence elastography (OCE), electromechanical modulus (EMM) sensors, ultrasound techniques (US) and magnetic resonance elastography (MRE)

Fig. 6. Clinical applications of mechanical sensing/monitoring.

a Left: Topography image of a 100 × 100 µm² area of a section of 9-d-old granulation tissue in a rat model. Right: the mean elastic moduli determined via the AFM method applied to granulation wound tissue from a rat after 7, 8, and 9 days as a function of different weight ratios of the base to crosslinker in PDMS with comparable moduli (right). The error bars correspond to standard deviations for measurements among 12 rats. Reproduced with permission. Copyright 2006, Rockefeller University Press. b Left: microcantilever indenting a sample of breast tissue associated with breast cancer. Right: sensor voltages during measurements on cancer epithelial/stromal tissues and benign epithelial/stromal tissues. Reproduced with permission. Copyright 2014, Royal Society of Chemistry. c Photographs of a piezoelectric device mounted near the nose to map the elastic modulus in lesion regions associated with dermatologic malignancy. Reproduced with permission. Copyright 2015, Nature Publishing Group. d Left: magnetic resonance electrographs of a cirrhotic explanted human liver with a tumor. Right: modulus values measured from healthy and cancerous tissues using needle-shaped PZT-based probes. Copyright 2018, Nature Publishing Group. e Microsystem approaches for MA measurements. Left: Schematic illustration of skin-mounted electronics for MA sensing, with an inset that shows an image of a device on a human subject. Right: Continuous MA-signal recording of human body orientations. Reproduced with permission. Copyright 2020, Nature Publishing Group. f Left: schematic illustration of measurements of brachial arterial-pulse via ultrasonic devices. Right: recording of BP waveforms correlated with ECG results, in which the pulse wave velocity can be calculated as 5.4 m/s. Reproduced with permission. Copyright 2018, Nature Publishing Group