Applications for Flexible TFT Arrays Emerge in the Biomedical Domain

Time：2021-08-16Department：

Initial Non-Display Markets and Active-Matrix Mesh Electronics Arrays

TFT technology already has been applied in non-display-related applications, mainly in the medical imaging domain. However, today's x-ray detectors are produced on glass substrates, making them heavy, difficult to transport, and breakable. X-ray detectors processed on plastic substrates would be much less vulnerable than the current glass-based designs, decreasing the amount of protective material needed for transport. Moreover, they would be lighter, easing mobility.

To make a full-chest x-ray image, a flat-panel detector must be as large as 30 × 40 cm2, a heavy and rigid piece of equipment (Fig. 1a–b). Flexible digital radiography could reduce the discomfort caused by these rigid flat panels. Recently, Holst Centre, The Netherlands, demonstrated a prototype of a curved x-ray detector based on the flexible TFT backplane technology repurposed from flexible display technology (Fig. 1c). The prototype was integrated into a medical cone-beam computed tomography system. Curved x-ray detectors provide a more compact imaging x-ray system with better and more uniform 3D image quality.1, 2

To broaden TFT technology's scope into non-display-related medical application domains, active-matrix TFT arrays will need to be more biocompatible. Strategies to render electronics (on foil) compatible with biomedical environments include minimizing the exposure of either tissue or cellular or biochemical materials to non-native materials. Risks to human subjects from these materials may include immune responses and decreased cell viability in in vitro applications.3 Another strategy involves removing the substrate and nonfunctional materials as much as possible, creating a meshed 2D network of functional electronics at each cross point with gaps of empty space in between—so-called voids.

Compared to standard TFT process flows and backplane design, the first step in the realization of active-matrix mesh electronics arrays consists of adapting the backplane design layers in the stack. Normally, these material layers would be patterned locally to form via interconnects and therefore would be fully present throughout the rest of the backplane array. Design adaptations include removing the material layers where the final voids in the complete mesh electronics stack would have to be realized during these TFT layers' photolithographic patterning. After this TFT backplane manufacturing process with adapted design is complete, a sacrificial resist layer is applied to cover the full backplane array, protecting the electrically functioning arrays. Next, using a hard mask in combination with dry etching, the flexible substrate is patterned to realize voids in between pixels, resulting in membrane-like TFT arrays on foil, the active-matrix mesh electronics arrays (Fig. 2).4 This type of mesh electronics arrays enhances the possibilities for TFT technology suppliers to enter new “stretchable” application domains.

New TFT Array Applications in the Medical Domain

WHOLE-BODY DIAGNOSTICS

A person's heartbeat is measured easily. A simple algorithm is used to extract the peak-to-peak time difference in the small volume changes of blood flowing through a person's arteries. Valuable information, for instance, on the risk of cardiovascular diseases, can be derived from the photoplethysmography (PPG) signal's full morphology, if it is of high-enough quality. The systolic and diastolic peaks can be recognized accurately from the analysis of the first derivative of the PPG signal.5

Photoplethysmography: Heart Rate Monitoring from Home

On the basis of a 400-pixels-per-inch (PPI) OLED display and a large-area 200-PPI photodetector realized with display manufacturing technology, we have been able to record PPG signals with a high temporal and spatial resolution (Fig. 3).2 The OLED display acts as a pixelated backlight, which is used to generate circular light spots of different colors and sizes. Peripheral blood oxygenation (SpO2) can be assessed by using light sources with at least two different wavelengths. Light that has penetrated deeper into the body before being reflected will result in a larger, more diffused light spot than light with a smaller penetration depth. This information can be used to estimate the optical path difference for different wavelengths and therefore can improve the accuracy of SpO2 measurements. Furthermore, PPG signals' spatiotemporal recording over large(r) areas also provides a direct way to measure pulse wave velocity (PWV; that is, the velocity of the pulse wave of blood traveling a certain distance within the arterial system). PWV is an index of arterial stiffness and, therefore, can be used as a marker of atherosclerosis and (raised) blood pressure.6

INTEGRATION IN HEALTH PATCHES

Effective health management relies on accurate, long-term monitoring. This requires medical devices that are comfortable and reliable enough to be worn on the body for long periods of time. Recently, many solutions have been developed for vital-sign monitoring in patches.7, 8 By combining expertise in TFT arrays with that in biocompatible materials, comfortable and reliable on-body monitoring solutions can be created, such as bandages, clothing, or dedicated patches for use in hospitals, at-home care, and telehealth programs for remote communities. A wide range of sensing options can be incorporated into a single on-body monitoring solution, including (core body) temperature and pressure. Combined with smart algorithms and data analysis, it is possible to develop tailored solutions for applications as varied as vital signs and blood oxygen saturation measurement for sepsis detection, chronic illness monitoring, and orthopedic rehabilitation.

ORGAN AND TISSUE-LEVEL DIAGNOSTICS

In addition to monitoring and measuring vital signs in the whole body, the diagnostic focus can be narrowed down to the (electrical) activity of parts of the body's systems. Skin patches can be used to measure, in a non-invasive manner, the functioning of specifically the heart (via electrocardiography), the muscular system (through electromyography; EMG), or the brain (through electroencephalography). However, present electronic hardware often involves relatively rigid, bulky device components that are affixed to the skin in ways that can lead to irritation and discomfort after prolonged application. Moreover, the large weight often requires immobilization of the subject during measurement, limiting their use to controlled laboratory settings. Therefore, a need exists for flexible and ultrathin electronic patches that can conform to the human body's shape, and thus enable unobtrusive ambulatory monitoring and improved user comfort, in combination with high-resolution, spatially resolved information.

HIGH-DENSITY SURFACE EMG PATCH

By using indium gallium zinc oxide TFT-array-technology on foil to multiplex signals and to perform in-pixel front-end amplification9 and inlaying the arrays in biocompatible soft materials (e.g., thermoplastic polyurethanes), we recently developed high-density surface EMG patches (Fig. 4). The patches can retrieve high-resolution spatiotemporal information from EMG features, such as signal direction and conduction velocity in the muscle. This technique can be applied as a diagnostic tool in clinical neurophysiology. Furthermore, it can also provide sensory input for exoskeletons in the field of robotics, and it can serve as a solution in antenatal care by detecting premature contractions through an electrohysterogram or EHG. EHG measures electrical signals from uterine muscles, which are closely correlated to labor contractions.

The EMG patch should be highly permeable. When worn on the skin, this allows sweat to pass through the patch. Active-matrix mesh electronics TFT arrays can further enhance the permeability by creating voids between spatially distributed pixels. Increased flexibility and less skin irritation make patches more comfortable to wear, increasing the chance of long-term monitoring capabilities.

The Leap from Medical to Biomedical

In light of broadening the scope of TFT array applications, we foresee further added value of active-matrix mesh electronics arrays in the area of biomedical applications, which we differentiate from the current setting by diving deeper into obtaining information on cellular functioning.

CELL-LEVEL DIAGNOSTICS

Integrated Electrophysiology

In vitro electrophysiology revolves around experiments in a form that is compatible with laboratory-based studies. In organ-on-a-chip devices, cell and tissue cultures are grown, simulating the physiology of organs from living organisms.10 Ideally, human body functions are mimicked to understand microbiological mechanisms of diseases or to determine the efficacy or adverse effects of potential new drugs through high-throughput screening. To provide a close-to-native environment for cells, cultures are grown in integrated (micro)fluidic channels, in which they receive nutrients, waste products are removed, and the cell cultures are perfused (fluidic circulation).

In addition to standard methods of microbiological analysis (such as staining assays and fluorescence microscopy), more (real-time) insight into the status of cell cultures in organ-on-a-chip devices is in demand. Integrated electrophysiology and future (chemical) sensor technology are key candidates to monitor the status of the cell culture on chips more accurately.

SMART MICROWELL PLATES

Within microbiological and pharmaceutical laboratories, the standard tool for experimentation is the microwell plate (with integrated electrical/sensor readouts and microfluidic functionalities), which has resulted in massive parallelization of test conditions in separate wells. Together with automated pipetting robots, among others, this has resulted in significantly improved throughput of experiments. Thus, the introduction—and market uptake—of organ-on-a-chip modalities will depend on successfully incorporating the microwell format to seamlessly integrate it in laboratory workflows. With the American National Standards Institute and Society for Laboratory Automation and Screening standard size of a microwell plate of 85.5 × 127.8 mm, large-area electronics/flat-panel-display-compatible processing technology is ideally positioned (in our opinion) to cost-effectively integrate electronics in the microwell format. Currently, passive metal-electrode arrays are used, as higher numbers of electrodes (at higher resolution) are limited by input and output periphery space limitations.11, 12

TFT technology, therefore, is poised to become a cost-effective multiplexing platform technology for the realization of smart microwell plates. Multiplexing in membrane-like forms provides even further opportunities in this domain. With a minimal surface area, the arrays provide cells the opportunity to grow as unimpeded as possible while being monitored by an electrode array. This strategy not only works on the bottom of microwells, it presents an attractive opportunity to realize free-hanging (suspended) membrane-like electrophysiology structures in a microwell format, as schematically demonstrated in Fig. 5a, as well as in developed prototypes in Fig. 5b This provides the opportunity to perform electrical characterization from the inside of cell cultures, organoids, and tissue, as compared to only the outside.

Fig. 5 demonstrates a smart microwell plate prototype with a suspended 200-PPI electrophysiology array. Separately, two distinct halves of the microwell plate were 3D printed from a cyclic olefin copolymer using fused-filament 3D printing, in between which the mesh electronics array was laminated.

Suspended electrode arrays can be employed to capacitively measure cells or provide a spatially distributed map of cell cultures' impedance, providing insight into the quality of cultures, such as those employed in trans-epithelial electrical resistance characterization, which probes the quality of the epithelial barrier function.13 Full-fledged manufacturing of smart multiwell plates will revolve around integrating TFT arrays on foil with injection-molded plastic parts.

Vision for the Future

FROM CELL-LEVEL DIAGNOSTICS TO ELECTROCEUTICAL TREATMENT

TFT technology also may be used to monitor and stimulate neural cell activity, thereby extending neuroscience methods to the brain. Here, Holst Centre's ultimate vision is that of an electronic implant that can regulate large parts of the brain, thus restoring physical functions and well-being.

ELECTROCORTICOGRAPHY: MEASURING ACTIVITY IN THE CEREBRAL CORTEX

For in vivo electrophysiology implantable arrays, the goal is to spatially measure electrical activity from the cerebral cortex (i.e., electrocorticography; ECoG).14-16 ECoG could be the basis for so-called electroceuticals—devices to treat diseases with electrical signals—and is a promising technique for brain-computer interfaces. However, two challenges must be resolved for this application: non-invasiveness and array stiffness (Fig. 6).

Patterning of the substrate within active-matrix arrays minimizes its invasiveness by decreasing the surface area of non-native material on the brain. Additionally, the voids between electrode pixels ensure that bodily fluids can pass directly through the array instead of diffusing at a far slower rate along the array's surface. In combination with metal-meander technology, patterning of the substrate also provides a means to tune mechanical properties, most importantly the stiffness of TFT arrays on foil. For neural implants, an empirical correlation has been uncovered between implant-bending stiffness and the severity of the tissue's immune response.17 The immuno-response limits implants' lifespan, so lowering implant stiffness is expected to prolong an implant's lifespan. More flexible TFT arrays, therefore, may provide longer-term electrophysiology implants.

SMART MICROWELL PLATES AND ORGAN-ON-A-CHIP APPLICATIONS

In the domain of smart microwell plates, manufactured products will not be realized using 3D printing in combination with large-area array manufacturing. Instead, we foresee injection-molded parts, which indicate the added value of TFT arrays with patterned foil substrates.

Our longer-term vision on functional developments of mesh-electronics arrays for organ-on-a-chip microwell plates revolves around varying and optimizing parameters, such as resolution, stiffness, and material (compatibilities), as well as optical transparency, which is needed for compatibility with standard fluorescence microscopy. Furthermore, we foresee integration as well as direct manufacturing of functional microfluidics with large-area thin-film technology—together with TFT arrays on patterned flexible substrates—to enable vertical flow through the electrode arrays and microwells.

Within the fast-evolving organ-on-a-chip domain, we see an exciting future for large-area TFT to realize applications that will revolve around integrating electronics, microfluidics, and sensor technology in a microwell format (Fig. 7).

From：SID-Wiley Online Library