Programmable Stimulation and Actuation in Flexible and Stretchable Electronics

Flexible and stretchable electronics represent a rapidly growing class of microsystem technologies that are revolutionizing human lives with pioneering applications in digital healthcare, personalized medicine, human–machine interface, and Internet of Things, among others. As an important aspect of smart devices, the on‐demand output capability of flexible/stretchable electronic devices, characterized by stimulation or actuation, enables active feedback and interaction to form a closed‐loop system, in combination with versatile sensing capabilities. This review summarizes some of the most important progresses on the stimulating/actuating capabilities (e.g., electrical, thermal, mechanical, optical, and chemical stimulation) of flexible/stretchable electronics, covering different mechanisms of stimulation and actuation, as well as diverse venues of applications. The stimulating/actuating capabilities in flexible/stretchable electronics play crucial roles in driving both fundamental and applied advances in research, such as medical measurement, biological study, medical therapy, and human–machine interface. Most of the existing flexible/stretchable systems use functional components to fulfill the demand of stimulation and/or actuation, with intricate strategies for system integration. Sustained advances in mechanics design concepts and high‐performance materials are the key to ensuring the evolution of flexible/stretchable electronics with enhanced stimulation and actuation capabilities. Finally, outlooks on the remaining challenges and open opportunities are provided.

(for sensing strain, pressure, temperature, flow, light, etc.), chemical sensors (pH, ions, chemical species, etc.), and biosensors. Many excellent reviews that summarize the achievements in sensing with flexible/stretchable electronics can be found in the literature. [2,9,11,15,17,19,[24][25][26][27][28] Information processing typically relies on integrated microcontrollers and/or communication modules to external instruments or cloud computing. Apart from miniaturized integrated circuits with rigid packaging, flexible processing engines attract increasing attention. [29,30] Feedback from flexible/stretchable devices and systems is another important aspect. For example, haptic feedback is gaining increasing attention, as the skin possesses rich, valuable information and serves as an important means of human's interaction with his/her surroundings. Apart from haptic sensation, thermal and electrical actuations offer additional means of communication/feedback to human bodies. In terms of active regulation offered by smart electronic systems, the various forms (electrical, thermal, mechanical, optical, chemical, acoustic, magnetic, radio frequency [RF], etc.) of stimulation/actuation could all play crucial roles in specific application scenarios.
Smart feedback and active regulation heavily rely on the advances of actuators and stimulators, as they offer indispensable options in feedback/regulation to assist human beings. Soft actuators and stimulators incorporated in flexible/stretchable devices could provide feedback and locomotion in the context of wearable and soft robotics. Wearable and prosthetic robotic parts can also benefit by introducing advanced capabilities in both feedback (to transmit sensation to human) and direct actuation (to initiate actions), as a physical extension of human bodies. Neuralink, [31] an American neurotechnology company, launched in August 2020 its LINK V0.9 implantable brainmachine interface prototype with 1024 recording channels/ electrodes. Though still at its fetal stage, the brain-machine interface is gaining rapidly increasing attention, and is envisioned to reshape human life in near future, when human beings are expected to control and communicate with robots wirelessly through the brain-machine interface. Both the capabilities of sensing and stimulation/actuation are foundational pillars to achieve the charming blueprint.
Note that as an equally important aspect, the stimulation/actuation with flexible/stretchable electronics remains underexplored in comparison to the sensing capabilities, on which numerous great review papers are available. Therefore, the current review focuses on the recent advances in the stimulation-type actuation capabilities of flexible and stretchable electronic systems, with an emphasis on the feedback and regulation aspects. In this review, the actuation is used, in a broader sense, to denote many different types of stimulation. With the scope of this review being presented here, it starts by highlighting different categories of stimulation/actuation routes and the advances in materials, structural designs, and manufacturing techniques, as shown in Figure 1. The numerous application scenarios of the stimulation and actuation functions of flexible and stretchable electronics are discussed in the third section. The summary of achievements and outlook for the future advancement come at the end. The actuation and stimulation capabilities of flexible and stretchable electronics have significantly broadened the areas of applications and suggested numerous opportunities for future developments.

Categories of Programmable Stimulation/ Actuation
Flexible and stretchable electronic platforms offer a versatile, multifunctional avenue to integrate a diversity of stimulators and actuators, such as those targeted for heating, vibration, optogenetics, and so forth. As a system, the actuation/stimulation elements pose as an active frontier for both the fundamental and applied research of flexible/stretchable electronics. Based on the distinct mechanisms of actuation and stimulation, they can be classified into different forms, including, for example, the electrical/electromagnetic, thermal, mechanical/vibratile, optical, and chemical (pharmacological) stimulation/actuation. Note that the general visual and auditory stimulations belong to optical and mechanical ones in a broader sense. In this section, five typical mechanisms of stimulation and actuation are presented and discussed, with an emphasis on the achievable capabilities.

Programmable Electrical Stimulation/Actuation
Powered by the electrical energy, flexible and stretchable electronic devices can conveniently generate programmed electrical stimulations by discharging to wide-ranging targets. This kind of electrical stimulation relies on either direct (DC) or alternating (AC) current in the pulsed or continuous mode. The most common form of electrical stimulation is applied directly by supplying electric current and voltage to the target through electrodes by integrating the target into an electrical circuit. The choice of magnitude of electric voltage and current depends on the nature of electrical stimulation. Compliant flexible or stretchable electrodes [32] enable a reliable and gentle contact onto soft biological tissues, without causing disturbing mechanical stress/strain. The overall mechanical compliance and stretchability contribute to the ease of biointegration as well.
At the level of cells and tissues, the electrical stimulation delivered by biointegrated flexible/stretchable electronics can influence biological functions and regulate disorders, such as the epilepsy and Parkinson's disease. Figure 2a shows two implanted arrays of electrodes, made of transparent graphene and opaque platinum, respectively, [33] which are developed for in vivo electrical stimulation. Fully transparent, carbon-based graphene electrodes pose edges over opaque metallic electrodes in certain scenarios such as fluorescence imaging of neural activity in transgenic GCaMP6f (a genetically encoded fluorescent calcium indicator) mice. [33] When delivering electrical pulses using the stimulation electrode to the cortex of a GCaMP6f mouse, the opaque metallic electrodes block the fluorescence intensity, which is proportional to the neural response in GCaMP6f mice during electrical stimulation, and may lose important information such as the region with peak neural activity. By contrast, fully transparent graphene electrodes pose little restriction in fluorescence imaging.
Conformal contact ensures high-quality electrical stimulation as well as sensing/monitoring performance. Innovative mechanics designs facilitate the integration of flexible and stretchable electronic devices onto soft tissues in a conformal fashion. As an example, Zhang et al. reported a bioinspired approach to achieve stimuli-responsive twining electrodes made of serpentine gold traces and polyimide thin film on a shape-memory polymer substrate. [34] As shown in Figure 2b, the shape-memory effect enables the self-climbing of stretchable electrode system onto a peripheral nerve after reaching body temperature, which is inspired by twining plants. The electrode system remains conformally interfaced to the nerve under normal motion/ deformation, with stable stimulation and recording performance. 3D, hierarchical geometries are ubiquitous in biology. Advanced flexible/stretchable electronic systems with complex 3D layouts not only adapt to the geometries of those biological tissues, but also have the potential of interfacing with complex, hierarchical tissues in a conformal, seamless manner. Stimulation electrodes integrated in 3D architectures, such as tissue scaffolds, can provide electrical pulses to natural or artificial tissues with complicated geometries. Among various existing strategies to access 3D flexible/stretchable electronics, the mechanically guided assembly approaches by controlled compressive buckling are the most promising, due to the broad-ranging applicability of material types and length scales. [35][36][37][38][39][40][41] Figure 2c shows a 3D architecture, assembled by guided compressive buckling, in the shape of a "cage" with polyimide (7 μm thick) narrow filaments, gold traces (300 nm thick), and eight individually addressable gold electrodes (diameter 25 μm, 300 nm thick) for electrical stimulation and recording. [42] This kind of electrical stimulation can provide active control and regulation over cardiac and neural tissues.
Skin, the largest organ in human body, serves as an important medium for electrical stimulation to stimulate skin itself or to conduct electrical pulses to other internal organs. Skin-interfaced electrical stimulation can be used for external defibrillation of heart and electroconvulsive therapy of brain to provide lifecritical treatments. In skin itself, spatially distributed cutaneous mechanoreceptors can perceive the flowing-by stimulating electric current, referred to as electrotactile stimulation, to generate tactile sensation (Figure 2d). [8,43,44] The electric current can  [145] Copyright 2015, Wiley-VCH. 1) Types of stimulation and actuation routes, including electrical, thermal, mechanical, optical, and chemical stimulations. Electrical: Reproduced with permission. [42] Copyright 2017, National Academy of Sciences. Thermal: Reproduced with permission. [46] Copyright 2015, American Chemistry Society. Mechanical: Reproduced with permission. [69] Copyright 2008, IEEE. Optical: Reproduced with permission. [16] Copyright 2020, Elsevier. Chemical: Reproduced with permission. [86] Copyright 2015, Elsevier. 2) Application scenarios, including human-machine interaction, medical measurement, medical therapy, biological research, entertainment, training, and so forth. Human-machine interaction: Reproduced with permission. [55] Copyright 2019, Springer Nature. Medical measurement: Reproduced with permission. [13] Copyright 2018, The Royal Society of Chemistry. Medical therapy: Reproduced with permission. [116] Copyright 2015, Wiley-VCH. Biological research: Reproduced with permission. [127] Copyright 2016, Springer Nature. Entertainment: Reproduced with permission. [55] Copyright 2019, Springer Nature. Training: Reproduced with permission. [103] Copyright 2016, Wiley-VCH.
be carefully modulated to produce prompt and favorable electrotactile sensation. Figure 2e shows a wearable finger-tube with an integrated array of electrodes on the inside surface for electrotactile stimulation. [44] The gold electrode array adopts a 2-by-3 layout connected by stretchable serpentine interconnects, and is multiplexed by silicon diodes. These inorganic electronics benefit from the ultrathin geometry and serpentine-shaped layout to form intimate contact between the electrodes and finger. Each pair of gold anode and cathode can deliver programmed electric current to induce localized tingling sensation. A proper combination of voltage and stimulation frequency is important to generate favorably sensible electrotactile stimulation on a human finger. The sensation intensity from electrotactile stimulation, delivered by electrodes, depends largely on the impedance of the electrode-skin interface, which could be easily changed with unconformal contact and sweat accumulation. [43] Akhtar et al. proposed a route to maintain the electrotactile sensation intensity by modulating key stimulation parameters under changing impedance. [43]

Programmable Thermal Stimulation/Actuation
Common thermal stimulation in flexible and stretchable electronics includes the Joule heating and the thermoelectric heating/cooling. Joule heating, also termed as resistive heating, relies on the passage of electric current through a conductor to produce heat. Figure 3a shows a stretchable array of 4-by-4 gold resistors in the shape of periodic long serpentines connected by horseshoe-shaped interconnects, with encapsulation of polyimide. [45] The long, narrow, and thin geometry gives rise to the resistance necessary for resistive thermal stimulation/ actuation, and associated temperature sensing according to the change in resistivity with respect to temperature. The horseshoe interconnects provide the stretchability of the entire device. The array of gold resistors is transfer printed onto human skin supported by a layer of water-soluble tape in poly(vinyl alcohol) (PVA). This kind of stretchable epidermal electronics, which is mechanically invisible to human skin due to the flexible and conformable interface, is capable of locally heating tissues for treatment and measurement. Figure 3b shows another type of stretchable, wearable heater array, which is made of a highly conductive nanocomposite of silver nanowires and a thermoplastic elastomer formed through a ligand exchange reaction. [46] The serpentine mesh design facilitates the stretching and bending of the heater array near a joint, which is well suited for articular thermotherapy. Moreover, transparent heaters with networks of metallic nanowires (e.g., Ag nanowires, Cu-Zr nanotroughs) embedded in the transparent elastomer demonstrate high stretchability while maintaining preferable thermal stability, paving the way for use as wearable heaters. [47,48] Compliant heating Figure 2. Programmable electrical stimulation with flexible and stretchable electronics. a) Fluorescence images of transparent graphene electrodes and opaque platinum electrodes, both of which can deliver the electrical stimulation to the cortex in a mouse model. In both images, a typical electrode site is marked by a red triangle. Reproduced with permission. [33] Copyright 2018, American Chemical Society. b) An optical image of an implantable, stimuliresponsive twining electrodes (inner diameter, %1 mm) composed of polyimide (thickness, %2 μm) with serpentine gold electrodes (thickness, %200 nm) on a shape-memory polymer substrate (top). The twining electrodes can be conformally integrated with a peripheral nerve (rabbit model) for stimulation and recording (bottom). Reproduced with permission. [34] Copyright 2019, American Association for the Advancement of Science. c) An optical image of a 3D "cage" (made of polyimide of 7 μm thickness) with eight individually addressable gold microelectrodes (diameter, 50 μm; thickness, 300 nm) for stimulation and recording. A scanning electron microscope (SEM) image of a gold microelectrode (inset). Reproduced with permission. [42] Copyright 2017, National Academy of Sciences. d) A schematic of electrotactile stimulation on the human skin using a pair of electrodes. The mechanoreceptors are stimulated by electric current to generate the sensation. The sensation intensity is changeable with respect to the impedance. Reproduced with permission. [43] Copyright 2018, American Association for the Advancement of Science. e) A finger-tube with an integrated array of electrodes made of gold and silicon nanomembranes for electrotactile stimulation. The left panel shows the electrodes on a finger mold, and the right one illustrates the combination of voltage and stimulation frequency to produce sensible electrotactile sensation on a human finger. (left) Reproduced with permission. [8] Copyright 2014, Mary Ann Liebert, Inc. (right) Reproduced with permission. [44] Copyright 2012, Institute of Physics (IOP). units can be integrated with self-conformable substrates (e.g., bistable electroactive polymers) to provide thermal stimulation, as part of the smart skin. [49] Different from the Joule heating, a thermocouple under electric voltage produces a temperature difference and vice versa, according to the thermoelectric effect. [50] The thermoelectric effect includes three individually defined processes, i.e., the Seebeck effect, the Peltier effect, and the Thomson effect. In Figure 3c, a stretchable thermal device capable of both heating and cooling is enabled by both Joule heating and the Peltier effect. [51] This system consists of a stretchable elastomer substrate and separate serpentine copper electrodes, and maintains stable cooling and heating performances up to 250% tensile strain. In a thermoelectric device, the total heat generated is controlled by the Peltier effect, Joule heating, and thermal-gradient effects. A thermoelectric cooler is also known as a Peltier device, with a circuit schematic shown in Figure 3d. For a circuit of thermocouple with an electric current passing through, the heating and cooling occur simultaneously at the two different conductors, transferring heat from the cold to the hot junction. Peltier devices can be used in flexible/stretchable devices as a binodal thermal element capable of both heating and cooling. Electrocaloric cooling is also a promising strategy for solid-state refrigeration in flexible electronics. [52]

Programmable Mechanical/Tactile Stimulation/Actuation
Actuators integrated in the flexible and stretchable electronic systems can generate mechanical and tactile stimulation/actuation. In wearable electronics, the entire devices need to be compliant, flexible/stretchable. With proper consideration of compliant mechanics at a system level, both soft, flexible actuators and rigid, miniaturized actuators can be exploited in the design of wearable electronics to generate tactile sensation. Arrays of miniaturized, rigid actuators connected by flexible and stretchable interconnects can sustain extreme deformations such as bending, stretching, and twisting, without undermining the performance. Electric haptic motors for vibrational actuation are popular in electronic devices, such as mobile phones and smart watches. Three different types of haptic actuators (vibration motors) have been seen in Apple iPhones and Watches, including, for example, an eccentric rotating mass (ERM) actuator used in Apple iPhone 5s, a linear resonance actuator (LRA) used in Apple iPhone 6, and Apple Taptic Engines (customized LRAs by Apple) used in Apple Watches and recent iPhones. [53] LRAs take less time to reach their maximum vibratory intensity, allowing them to start and stop with less latency than ERM actuators. Actuators based on stiff functional materials (e.g., shapememory alloys) also have the potential of being integrated in Figure 3. Programmable thermal stimulation with flexible and stretchable electronics. a) An optical image of a compliant, 4-by-4 array of electroresistive elements connected by serpentine interconnects interfaced with human skin using a water-soluble PVA tape. The stretchable device can simultaneously achieve local heating and temperature mapping on skin surface. A magnified view of a single heater/temperature sensor and the cross-sectional stackup [11] are shown on the right panel. Reproduced with permission. [45] Copyright 2013, Springer Nature. b) A thin, stretchable heater made of ligand exchanged silver nanowire nanocomposite suitable for wearable articular thermotherapy. The left panel provides an optical image with an inset showing the material composition, and the right one shows an infrared (IR) image of the working heater attached around a human wrist. Reproduced with permission. [46] Copyright 2015, American Chemistry Society. c) An optical image of a stretchable cooling and heating device that can produce artificial thermal sensation (left). The device offers a stable performance of cooling and heating under stretching up to 250% and other deformations (right). Reproduced with permission. [51] Copyright 2020, Wiley-VCH. d) A circuit schematic of a thermoelectric cooler based on the Peltier effect. (This is a selfmade image based on a diagram from Wikipedia.).
www.advancedsciencenews.com www.advintellsyst.com . Reproduced with permission. [56] Copyright 2015, Springer Nature. c) A schematic illustration of a soft, transparent dielectric elastomer actuator with compliant hydrogel electrodes. Reproduced with permission. [67] Copyright 2013, American Association for the Advancement of Science. d) An optical image of a flexible, wearable tactile display enabled by soft dielectric elastomer actuators. Reproduced with permission. [69] Copyright 2008, IEEE. e) An optical image of a dielectric elastomer actuator with ultrathin, compliant carbon nanotube electrodes. Reproduced with permission. [71] Copyright 2008, Wiley-VCH. f ) An optical image of a pH-responsive, chemomechanical hydrogel actuator. Reproduced with permission. [74] Copyright 2015, The Royal Society of Chemistry. g) Optical images of undeformed and actuated configurations of a hydrogel actuator with three independently addressable, embedded fan-shaped heaters. Reproduced with permission. [73] Copyright 2013, Wiley-VCH. h) Optical (top) and thermal (bottom) images of a liquid crystalline elastomer tubular actuator with three independently controllable, serpentine heaters. Reproduced with permission. [77] Copyright 2019, American Association for the Advancement of Science.
www.advancedsciencenews.com www.advintellsyst.com flexible, wearable systems. [54] Figure 4a shows customized vibrational actuator composed of a polyimide circular cantilever, a circular magnet, a soft polydimethylsiloxane (PDMS) ring, and a copper coil. [55] The actuator vibrates with programmed attraction or repulsion between the magnet and the coil driven by pulsed direct current around 200 Hz. A wirelessly powered, flexible system can integrate 32 actuators with the cantilever to tap on skin for wearable haptic stimulation. Figure 4b shows a strategy of using piezoelectric materials as mechanical actuators. In piezoelectric actuators (and sensors), mechanical strain results from an applied electrical field (and vice versa). In an epidermal application setting, the mechanical actuation from the piezoelectric material impacts the nearsurface skin region around the actuator. Here, epidermal piezoelectric actuators and sensors made of lead zirconate titanate (PZT) can sense applied pressure or probe viscoelastic properties of tissues. [56][57][58] Diverse classes of novel soft actuators are suitable to deliver mechanical stimulation in flexible and stretchable electronics. For example, soft pneumatic actuators emerge as an important category, as widely used in wearable devices and soft robotics. [59] Soft electromagnetic actuators with liquid metal channels inside the soft elastomer, placed in a changing electromagnetic field, can be actuated by Lorentz force. [60] Thin, flexible hydraulically amplified electrostatic actuators, each with a fluid-filled cavity, compress the periphery of the cavity to force the fluid into a raised bump upon applied voltage to deliver normal and shear forces to human skin. [61] Soft actuators based on active, functional materials of low Young's modulus are attractive for use in biointegrated devices. Electroactive polymers (EAPs), also known as artificial muscles, are intrinsically soft, and respond rapidly to electrical stimulation with noticeable shape changes. Dielectric elastomers (DEs), a class of EAP, have profound popularity in soft actuation. [62,63] Detailed theory exists to guide the design of DE actuators of large deformation. [64][65][66] Figure 4c shows the layout of a typical dielectric elastomer actuator, with the elastomer sandwiched by two compliant electrodes. [67,68] With an applied electric voltage between the electrodes, the elastomer is electrostatically compressed to induce programmed in-plane or out-of-plane deformation. Figure 4d shows a wearable tactile display enabled by soft dielectric elastomer actuators. [69] In the flexible and stretchable actuator systems based on soft elastomers, the stretchable electrodes represent a key design consideration because they need to be sufficiently compliant and stretchable such that minimal mechanical constraints are posed on the actuators. [32,70] Figure 4e shows a dielectric elastomer actuator capable of 200% areal strain with ultrathin electrodes, which are mechanically compliant. [71] Here, the carbon nanotube electrodes enable the actuators to tolerate minor damages, similar to that of biological muscles. In addition, the fluid electrodes can be used in DE actuators for submersible applications. [72] Hydrogel-based soft actuators represent another important type of soft mechanical actuators, which can be activated by electrochemical and thermal cues (Figure 4f,g). [73,74] The stretchable mesh electrodes in these actuators can be used as heaters and electrochemical reactors. Another example of stretchable thermal actuators (which here refer to actuators converting thermal energy to motion) exploits a layer of highly flexible Ag nanowires on PDMS substrate as low-voltage, rapid heater, together with intricate mechanical design, to actuate bending deformations up to 720 . [75] A class of soft electrothermal actuators based on laser-induced graphene can enable the assembly of complex reconfigurable 3D mesostructures, and achieve on-demand interactions with human users, for example, in gesture recognition and electrocardiography (ECG) measurement. [76] Among EAPs, liquid crystalline elastomers can also be thermally actuated to yield reversible deformations, governed by the polymer backbone relaxing from oriented into random coil configuration at an elevated temperature above the clearing temperature. Figure 4h shows a liquid crystalline elastomer actuator with three embedded serpentine heating electrodes. [77] The demonstrated liquid crystalline elastomer shrinks when heated, and as a result, the tubular-shaped actuator can be transformed into bending or shrinking configurations based on the number of active heating elements.
Apart from fully artificial systems, biohybrids with tissues and thin-film flexible electronics provide another platform to highperformance mechanical actuators for biointegrated applications, such as biorobotics. [78,79]

Programmable Optical Stimulation/Actuation
Fiber optic cables and light-emitting diodes (LEDs) serve as the most common forms of light source for optical stimulation in flexible and stretchable electronics. Skin-interfaced optical stimulators are usually equipped with high-performance light sources and designed based on the reflection, scattering, and absorption properties of skin. Figure 5a shows the optical pathways during illumination/optical stimulation on human skin. [13] Pulse oximeters provide access to photoplethysmogram (PPG) by illuminating the skin and measuring changes in light absorption. A reflection-mode pulse oximeter, as shown in Figure 5b, illuminates the skin by micro-LEDs of three different wavelengths and measures the light absorption by photodetectors on the same side. [80][81][82] Another transmission-mode pulse oximeter appears in Figure 5c, where the photodetectors and LEDs are placed on the opposite sides of a body part, such as finger. [83] As a form of neuromodulation, the light emission in optogenetics can stimulate or inhibit the response of genetically modified neurons with light-sensitive ion channels. Kim et al. proposed ultraflexible organic LEDs for optogenetic nerve stimulation. [84] Examples of target neurons, including those in brain, spinal, and peripheral neural circuits, have been demonstrated. [85][86][87][88][89] Figure 5d shows a series of silicon neural probes with micro-LEDs for high-resolution optogenetics. [90] A multifunctional, injectable brain probe with capabilities of optogenetic and electrical stimulation is shown in Figure 5e. [88] This system includes micro-LEDs for optogenetic stimulation, microelectrodes for electrophysiological recording and electrical stimulation, temperature sensors for thermal measurement, and photodiodes for light intensity sensing. Incorporation of stretchable wireless radio power and control systems allows the development of wireless optogenetics for implanted applications (Figure 5f ). [91] Figure 5g shows a wireless, closed-loop optoelectronic system for optogenetic modulation of peripheral nerves. [92] Reviews on optogenetics based on flexible/stretchable electronics provide detailed summary of the additional progress in this field. [16,[93][94][95][96] www.advancedsciencenews.com www.advintellsyst.com

Programmable Chemical Stimulation/Actuation
Chemical/pharmacological stimulation in flexible and stretchable electronic systems is essential in therapeutics and regulation. It can be delivered by microfluidic channels (sometimes referred to as chemotrodes), dissolvable layers, and other routes. A neural probe in Figure 6a utilizes a microfluidic channel for electrophoretic drug delivery. [97] The presence of an ion exchange membrane facilitates the precise drug delivery by electrophoretically delivering only the drug ions and not the solvent, without inducing noticeable pressure increase to the brain tissue. Figure 6b shows a type of wireless optofluidic brain probes capable of chronic neuropharmacology and optogenetics. [98,99] In this system, the pharmacological stimulation is enabled by microfluidic delivery of drug fluid. A soft electronic dura mater (e-dura) specifically designed for the spinal cord is shown in Figure 6c. [100] The e-dura incorporates electrodes and chemotrodes to deliver both electrical and chemical stimulations for spinal neuromodulation for restoring locomotion after paralyzing injury in spinal cord. Figure 6d shows using iontophoresis to locally induce sweat excretion for sweat analysis, through chemical stimulation of the sweat gland from a flexible electronic system. [101] A small electric current aids in passing the charged chemical substance through the intact skin. A closed-loop system with the capability of sensing glucose levels in sweat and delivering drugs transcutaneously to regulate the glucose level appears in Figure 6e. [102] 3. Diverse Applications of Programmable Stimulation and Actuation with Flexible/ Stretchable Electronics Integration of hard and soft functional components in inorganic and organic materials enables a diverse range of hybrid flexible Figure 5. Programmable optical stimulation with flexible and stretchable electronics. a) A schematic diagram of optical pathways (reflection, scattering, and absorption) in human skin. Reproduced with permission. [13] Copyright 2018, The Royal Society of Chemistry. b) A schematic illustration of a skin-interfaced optoelectronic device for measurement of blood oxygen based on the optical difference method. Reproduced with permission. [80] Copyright 2020, Oxford Academic. c) Schematic illustration of the pulse oximetry using two organic LED arrays (for optical illumination) and two organic photodetectors (for detection) on a flexible plastic substrate. Reproduced with permission. [83] Copyright 2014, Springer Nature. d) An optical image of a multishank silicon neural probes with inorganic LEDs for optogenetic stimulation. A magnified view of the dashed rectangle is shown on the right. Reproduced with permission. [90] Copyright 2015, Elsevier. e) An exploded-view illustration of a multifunctional recording and stimulation probe, including micro-LED arrays for optical stimulation and microelectrodes, together with components for electrical/thermal stimulations and electrophysiological/optical/temperature measurements. Reproduced with permission. [88] Copyright 2013, American Association for the Advancement of Science. f ) A schematic illustration of a soft, implantable optoelectronic system for wireless optogenetic stimulation of the peripheral nerve in a mouse model. Reproduced with permission. [91] Copyright 2015, Springer Nature. g) An optical image of a soft, implantable optoelectronic system for wireless, closed-loop optogenetic modulation of bladder function (left). Reproduced with permission. [16] Copyright 2020, Elsevier. A schematic illustration of the location of a strain gauge around the bladder and a control and power module subcutaneously implanted anterior to the bladder (middle). Optical images of a strain gauge and a pair of LEDs wrapped around a rat bladder in contracted and expanded states, respectively (right). Reproduced with permission. [92] Copyright 2019, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com Figure 6. Programmable chemical stimulation with flexible and stretchable electronics. a) Optical images of an injectable microfluidic ion pump for on-demand electrophoretic drug delivery across an ion exchange membrane. Reproduced with permission. [97] Copyright 2018, American Association for the Advancement of Science. b) An optical image of an optofluidic system with replaceable drug cartridge for programmable optogenetic and pharmacological stimulations. Reproduced with permission. [98] Copyright 2019, Springer Nature. c) An optical image of a soft, flexible electronic dura mater, tailored for the spinal cord, with microfluidic channels (for chemical stimulation) (left). SEM images of the dashes rectangular regions are shown as insets. Recording data from a mouse (flexor/extensor muscle activities) with electrochemical stimulation during bipedal locomotion under robotic support, with the stick diagram on the right top showing hindlimb movements (right). Reproduced with permission. [100] Copyright 2015, American Association for the Advancement of Science. d) Optical images of a skin-interfaced autonomous sweat extraction and sensing platform, and the iontophoresis/sweat sensor electrodes, underneath which a thin layer of agonist agent hydrogel is placed. The graph on the right shows the sweat rate profile of sweat induction using acetylcholine 1%-based hydrogel with iontophoresis current of 1 mA for 10 s. Reproduced with permission. [101] Copyright 2017, National Academy of Sciences. e) Optical images of a pair of stretchable, epidermal graphene-based electrochemical devices under stretching and compression, as well as magnified views of the sensing and therapy units. The device system senses glucose levels in sweat and delivers drugs transcutaneously in response to elevated glucose level. Reproduced with permission. [102] Copyright 2016, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com and stretchable electronic microsystems. With the specifically tailored stimulators and actuators, and additional capabilities of wireless power and communication, the flexible and stretchable electronics assume revolutionary roles in consumer electronics, digital healthcare, and assisted living.

Application in Human-Machine Interaction
Actuators suitable for soft robotics are attracting increasing attention, and there have been notable review articles on this topic. Apart from robotic actuation commanded by human users, control and sensation feedbacks by the robot/machine are expected as an equally important aspect in human-machine interface. Superior to visual or auditory signals, programmable tactile feedbacks enabled by electrical stimulators or mechanical actuators convey touch sensation from robots to human users more realistically. Figure 7a shows an epidermal human-machine interactive system, where the electric current stimulation is delivered to human skin via four stimulation electrodes as control feedback and the electromyogram (EMG) of human user is sensed as control signal through separate sensors. [103] The stimulative feedback can effectively assist human user to rotate the robotic arm to an arbitrary angle or to adjust the robotic gripping force in actions such as holding an object in closed-loop control. For example, in the case of robotic gripping, the stimulation feedback helps the user to exert a steady force. The intensity of electric current delivered by opposite stimulation electrodes controls the location of the stimulation sensation, which is in the middle during stimulation of equal intensity and moves toward the electrode with less current intensity. Figure 7b shows the utilization of wireless skin-interfaced haptic array (shown in Figure 4a) to assist human user to virtually feel the shape of an object grasped by the prosthetic hand via tactile feedback, with the sensing signals captured by an associated sensor array. Figure 7c shows an electronic skin with inorganic humidity, strain, pressure, and temperature sensor arrays, and resistive heating actuators. [104] The sophisticated functional components and flexible electronics are arranged in a multilayer, staggered geometric layout to accommodate large deformation and mitigate restriction from each other. The sensing signals potentially have a transferring route to human brain by including a soft stretchable interface to electrically stimulate peripheral nerves. Apart from sensing external stimuli, the presented artificial skin can maintain its temperature close to human skin with serpentine-shaped stretchable heating actuators, mimicking a human touch (Figure 7d). [104,105] Sim et al. reported an ultrathin, stretchable wearable human-machine interface that has a closed loop, where a temperature sensor in the prosthetic skin detects the environmental temperature and, in turn, controls the power of thermal stimulation of an integrated soft microheater to match the detected temperature. [106] Figure 7e,f shows a skin-inspired artificial mechanoreceptor system, termed as the Digital Tactile System, or DiTact, which consists of a pressure-sensitive tactile element and an organic ring oscillator. [107] The signals from sensitive pressure sensors are transformed to frequencymodulated spiky signals, similar to those in animal skin and nerve cells, by organic oscillators to directly stimulate brain cortical neurons in a mouse both electrically and optically. The action potentials of neurons are observed to closely follow the LED stimulation pulses (Figure 7f ).

Application in Medical Measurement
Together with bioelectronic sensors, the stimulators serve as core components in various miniaturized, flexible, stretchable gadgets for medical measurements. For example, the thermal stimulation/actuation provides means for characterizing skin hydration level, blood flow rate, and thermal properties of skin based on the physics of heat transfer. [45,[108][109][110][111] Figure 8a shows an ultrathin, skin-conformal device, based on thermal stimulation and sensing, to precisely and continuously map both macrovascular and microvascular blood flow. [111] A central heating actuator (overall radius 1.5 mm, filament width 15 μm, and thickness Cr 10 nm/ Au 100 nm) and an array of 14 thermal mapping sensors and 1 thermal background sensor (overall radius 500 μm, filament width 10 μm, and thickness Cr 10 nm/Au 100 nm) form a reliable and noninvasive system to measure the blood flow properties across various body parts. The serpentine, filamentary geometry and ultrathin profile enable conformal and intimate thermal contact between the device and skin. The central thermal stimulator serves as a constant heat source, and the reading differences in thermal mapping sensors (anisotropic thermal transport) infer the directionality and flow rate of the subcutaneous blood flow. This measurement approach, assisted by thermal stimulation, shows less sensitivity to body motions, and is, therefore, suitable for continuous monitoring of blood flow during daily activities. Figure 8b shows a flexible and stretchable device for in vivo characterization of the thermal conductivity and diffusivity of human skin using the three omega (3ω) method, an alternating current (AC) method. [110] The resistive elements supply the thermal stimulation necessary for the measurement (Figure 8b, middle left panel). The right panels of Figure 8b show the temperature fluctuations of different materials (including skins tissues at different locations) at a spectrum of oscillating current frequencies with the same input power (1.34 W m À1 ). The thermal conductivity and diffusivity can be determined from these graphs based on the proposed mechanics models.
The mechanical actuation based on piezoelectric effect is useful in measuring the blood pressure and mechanical properties (e.g., Young's moduli) of biotissues. [56,58,112] An ultrathin, flexible piezoelectric microsystem engineered to a needle shape is equipped with a mechanical PZT actuator and an associated PZT sensor, as shown in Figure 8c. Based on the relationship between the input delivered by the actuator and the output measured by the sensor, the elastic modulus of the tissue can be precisely calculated. This mechanical actuation-based method is valuable in distinguishing abnormal tissue during the collection of biopsy samples. This flexible microsystem also enables rapid and reliable measurements of human internal organs, with quantitative agreement with the clinical gold standard for the measurement of tissue modulus. Other forms of mechanical actuation, such as vibrational actuation delivered by skininterfaced devices, are also viable in measuring and characterizing mechanical properties of skin.  Reproduced with permission. [111] Copyright 2015, American Association for the Advancement of Science. b) Optical images of a serpentine 3ω sensor interfaced with the forearm, with the magnified view highlighting the gold heater (5 μm wide) with PI encapsulation (20 μm wide) (left). Measurement of temperature oscillations of different materials at a power input of 1.34 W m À1 across a frequency range from 1 to 1000 Hz (middle right). Measurement of temperature oscillations as a function of frequency using the 3ω sensor on human skin (right). Reproduced with permission. [110] Copyright 2017, Wiley-VCH. c) A tissue modulus probe based on ultrathin PZT actuators and sensors, placed on a biological tissue (left). An exploded-view schematic of the probe (left middle). In vivo measurements on a rat, where the probe is injected into the kidney (right middle). Results of in vivo measurements of tissue modulus of different organs on a live rat (right). Reproduced with permission. [112] Copyright 2018, Springer Nature. d) An optical image of a wireless pulse oximetry device, mounted on a thumbnail, in operation, with the exploded-view schematic of constituent layers shown in the inset (left). Graph of the calculated SpO 2 (peripheral oxygen saturation) during sequential rest (15 s), movement (30 s), and rest (15 s), with the accelerometry showing the X-, Y-, Z-axis movement components (right). Reproduced with permission. [113] Copyright 2017, Wiley-VCH. e) An optical image of a wireless epidermal optoelectronic system, conformally mounted on the forearm, for measuring heart rate and mean arterial pulse (MAP) using LED and photodetector (left). The inset shows an exploded-view schematic of device layout. Graph of the measurement result showing the systolic peak and dicrotic notch of clinical relevance (right). Reproduced with permission. [114] Copyright 2016, American Association for the Advancement of Science.
www.advancedsciencenews.com www.advintellsyst.com The optical stimulation in flexible and stretchable electronic platforms enables the probing of heart rate, blood oxygenation, and temporal patterns of blood flow. [113,114] The flexible system design ensures conformal interface with human body, and the near-field communication (NFC) scheme enables battery-free, wireless power delivery and data transmission. Figure 8d,e shows two examples, including a nail-based wearable systems for reflectance pulse oximetry [113] and an epidermal optoelectronic system for optical characterization of the skin. [114]

Application in Medical Therapy
Digital healthcare has emerged as an increasingly important avenue to monitor and treat various diseases in real time.
Here, flexible and stretchable electronics serve as convenient, versatile tools for in vivo precision medicine in streamlining surgical procedures and understanding disease states. The complaint, flexible, and deformable characteristics of these electronic platforms enable continuous, conformal, and high-fidelity interface with soft biotissues for long-term uses. Apart from measurement approaches driven/assisted by their actuation/stimulation capabilities as discussed in the preceding subsection, flexible and stretchable electronics can offer timely and accurate therapy, which could be of vital importance in critical scenarios such as heart failure. Due to a diverse collection of design concepts and material innovations, effective monitoring and therapeutic devices based on flexible and stretchable electronic platforms have been emerging.
Cardiovascular diseases are the leading cause of death in modern world. [14] Continuous monitoring and in-time therapy are equally important in preventing and rescuing fatal heart failures. Examples of cardiovascular therapy based on flexible and stretchable electronics are pacing, defibrillation, ablation with fine spatial resolution, and so forth. The multifunctional integumentary membranes (Figure 9a,b) adopt mesh geometries with serpentine interconnects, which can be interfaced conformally onto the epicardium. [115][116][117] The integrated fractal-inspired electrodes offer high filling ratio across large area and conform easily to various biological surfaces. Here in Figure 9a, an array of fractal electrodes covers a rabbit heart circumference and serves to deliver electrical stimulation, which is programmable both temporally and spatially, in large-area cardiac electrotherapy to effectively cure arrhythmia. [116] In Figure 9b, the electrical, thermal, and optical stimulations and measurements are all available in the multifunctional integumentary membrane. [115] Figure 9c shows an elastoconductive epicardial mesh made of silver nanowires and styrene-butadiene-styrene (SBS) rubber wrapping around the epicardium of postmyocardial infarction (post-MI) rats for biventricular pacing and defibrillation. [118] Flexible electronics technology also enables the development of wireless, lightweight, fully implantable pacemakers. [119] Inflatable balloon catheters with integrated flexible and stretchable sensors and stimulator/actuators provide access to multimodal functionality of therapy. [120,121] The advanced balloon catheter can be inserted inside the heart and then inflated to contact the endocardium (or other regions) during cardiac surgery. [120] Alternatively, it can also operate outside the heart, depending on the specific need (Figure 9d). The impedance-based contact sensors provide quantitative assessment of the conformal contact with the target surface (Figure 9e). [121] Stimulation electrodes are deployed for electrical stimulation or ablation. Figure 9f shows a recently reported strategy toward multilayered electronic arrays for multiplexed sensing and actuation in cardiac surgery. [120] Flexible surgical sutures with integrated sensors and actuators found their utilization in wound monitoring and assisted healing therapy. [122] Localized, programmable electrical and heating stimulation can promote healing of chronic wounds, by using flexible sutures of thin, narrow, biocompatible polyester fabrics, to serve as the platform of integrated electronic traces, sensors, and heating actuators. Programmed thermal stimulation delivered by flexible wearable systems is also beneficial for pain relief and injury recovery. [46,123] In addition, integrated microheaters on flexible, wearable devices can facilitate the transdermal drug delivery from a drugencapsulated microneedle patch device to mitigate pain. [124] Figure 9g shows an emerging type of flexible electronics, made of fully bioresorbable materials, for bioelectric therapy of injured nerve tissues. [125] This bioresorbable, implantable flexible device features wireless power harvesting mechanism to provide programmable electrical stimulation to accelerate the regeneration and recovery of peripheral nerves in rodent models. The electrical nerve stimulation is delivered through a flexible rolled cuff with exposed electrodes (Mo, 10 μm thick, or Mg, 50 μm thick).

Application in Biological Research
Flexible and stretchable electronics offer enabling modes (e.g., electrical, mechanical, and chemical) of stimulation to facilitate biological research. Figure 10a shows an ultrathin, flexible nanoelectronics array of field-effect transistors (FETs), which is folded into a four-layer 3D tissue scaffold to provide electrical stimulation for the regulation, together with mapping, of action potential propagation in cultured tissues. [126] The independently addressable stimulator electrodes (denoted as purple dots in Figure 10a) allow active spatiotemporal regulation of the propagation direction of action potential within the hybrid cardiac tissues through electrical stimulation, which is of direct relevance in fundamental biological study. Figure 10b shows a rolled 3D tissue scaffold that can initiate electrical and chemical stimulations to engineered hybrid cardiac tissues. [127] 3D electronic scaffolds assembled through mechanically guided compressive buckling render complex geometries as well as capability of electrical and chemical stimulations for hybrid tissues. [42,128] A self-powered electronic device for deep brain stimulation, enabled by flexible PIMNT (an indium-modified crystalline) piezoelectric energy harvester, is shown in Figure 10c. [129] Here, a flexible energy harvester can conform onto the curved body surface of a mouse to transform mechanical motions to electricity, with the generated electric current up to 0.57 mA, sufficient for stimulation of the motor cortex of mice. Figure 10d shows an array of stretchable microelectrodes made of silver nanowire, which offer combined mechanical and electrical stimulation to cells. [130] Figure 10e shows a hybrid cardiac tissue with stretchable and flexible electronic traces capable of both chemical and electrical stimulations. [131] Flexible electronic devices provide platforms for studying the effects of electrical stimulation on immune cells during wound www.advancedsciencenews.com www.advintellsyst.com Figure 9. Programmable stimulation in the medical therapy based on flexible/stretchable electronics. a) An optical image of a fractal electrode array conformally wrapped on a rabbit heart to deliver electrical stimulation and monitor cardiac electrical activity. The white arrows highlight functional components. SEM image of a fractal electrode (inset). Reproduced with permission. [116] Copyright 2015, Wiley-VCH. b) A multifunctional integumentary membrane covering the entire epicardial surface of a rabbit heart for spatiotemporal measurement and stimulation. The white arrows highlight functional components. Magnified views of selected functional components appear on the right. Reproduced with permission. [115] Copyright 2014, Springer Nature. c) A schematic of flexible epicardial meshes made of silver nanowires and SBS rubber, wrapped around the epicardium (left). ECGs before and after electrical pacing using the epicardial mesh (MeshP) in an 8-week postmyocardial infarction (post-MI) rat heart (middle). Influence of the MeshP on the total ventricular activation time (QRS durations [QRSd]; the QRS complex is the combination of Q, R, and S waves, which correspond to the main spike, on a typical ECG) in control and 8-week post-MI rats (right). Reproduced with permission. [118] Copyright 2016, American Association for the Advancement of Science. d) A schematic showing a multifunctional balloon catheter near the heart. Note that the multifunctional balloon catheter can operate inside the heart during cardiac surgery. Reproduced with permission. [120] Copyright 2020, Springer Nature. e) Optical images of a multifunctional balloon catheter in its inflated state and two epicardial ablation lesions generated by two pairs of RF ablation electrodes. Representative RF electrodes and temperature sensors appear in the inset. Reproduced with permission. [121] Copyright 2011, Springer Nature. f ) An exploded-view illustration of a soft, catheter-integrated multilayer electronic arrays, with capabilities in electrical, temperature and pressure sensing, electrical/thermal stimulation, radiofrequency ablation (RFA), and irreversible electroporation (IRE) (left). Optical images of an array of electrodes transferred onto a balloon catheter of silicone and an array of temperature sensors/thermal heaters transferred on a balloon catheter of polyurethane (middle). Graph showing the electrogram and pressure recording during electrical pacing (contact pressure %16 kPa) (right). Reproduced with permission. [120] Copyright 2020, Springer Nature. g) A fully bioresorbable, wireless electrical stimulator that interfaces with injured peripheral nerves to improve functional recovery and accelerate neuroregeneration. . Reproduced with permission. [125] Copyright 2018, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com healing. [132] Electrical stimulation can also potentially accelerate nerve recovery and regeneration (partially shown in Figure 9g). Electrical stimulation of neurite outgrowth through conducting polymer has been demonstrated in vitro. [133] Electrical stimulation through conductive polymer scaffolds can accelerate in vivo axonal regeneration and remyelination in a rat model with severe sciatic nerve defects. [134] These findings, in turn, form the foundations for electrical stimulation-based therapeutics. Furthermore, flexible electronic skins capable of electrical stimulation to neurons serve as an emerging research tool for in vivo characterization of synaptic plasticity in brain, which reflects the formation of long-term memory. [135] Synchronized optical and electrical stimulation, delivered by array of microelectrodes and micro-LEDs, on a flexible, implantable electronic platform capable of sensing biopotential and ion concentration opens new possibilities in fundamental neuroscience and clinical regulation of brain functions. [136] 3.

Application in Entertainment and Social Network
Flexible and stretchable electronics open new opportunities for people to interact remotely and virtually for gaming, personal engagement, social media, and so forth. An immediate opportunity lies in the skin-interfaced haptic and thermal electronic devices, based on the mechanical and thermal stimulations, respectively. Haptic wearable devices based on flexible and stretchable electronics [55] provide elevated experience for gaming by sending programmed haptic actuation to the user as mimicked feelings of touch, strike, or impact to his/her corresponding body parts. Figure 11a shows such kind of combat gaming scenario. In personal engagement and social media, haptic flexible and stretchable devices complement virtual interactions by mimicking touch stimuli apart from visual and auditory feedback. Figure 11b shows a scenario where a girl interacts with her grandmother by touching a graphic user interface to remotely activate the individual vibratory actuators in a customized spatiotemporal pattern. Her grandmother, wearing the flexible haptic devices, feels the haptic stimuli in the form of continuous vibration. The reported strategy of flexible haptic interfaces is wireless and battery-free, due to the development of actuators of low power consumption (%1.75 mW required for each actuator) (Figure 4a). [55] The NFC power harvesting scheme can work as far as %80 cm, with an intermediate coil.
An example of wearable thermal virtual reality (VR) interface [51] is enabled by thermoelectric (Peltier) devices with stretchable, serpentine-shaped geometry, as shown in Figure 11c. With both heating and cooling modes, this flexible device can mimic realtime temperature variation, for example, the thermal signature of beverage bottles of different materials, by modulating the current supplied to the Peltier units. This type of thermal VR devices could offer thermal sensations in entertainment and social media.
Future directions of epidermal virtual and augmented reality (VR/AR) flexible systems can benefit from the capability of operating in mobile settings by including rechargeable batteries or upgraded wireless power harvesting schemes, as well as using Bluetooth Low Energy (BLE) or Wi-Fi communication schemes.

Application in Training and Sports
With flexible and stretchable systems offering broad classes of biointegrated sensors, the health and performance data of athletes are available to help optimize the athletic training strategies in a well-targeted, customizable fashion. The stimulation capabilities of flexible and stretchable electronics provide valuable opportunities in muscle training, pain relief and therapy, active feedback, and so forth. Electrical muscle stimulation applies electric pulses across skeletal muscles to induce repeated muscle contraction, which can assist strength/endurance training and injury/fatigue recovery, and serves as an evaluation tool of muscular/neural function in vivo. [137][138][139] Transcutaneous electrical nerve stimulation, where the stimulating current intensity is usually below the threshold to induce muscle contraction, can relieve pain by inducing sensory nerves to release endorphins or inhibiting signal transmission. Figure 11d shows an epidermal electronic device capable of simultaneous electrical muscle stimulation and EMG monitoring. [103]  Flexible haptic interfaces can potentially promote various professional and athletic training programs. [140,141] Systems capable of providing haptic feedbacks are valuable in medical training. [140] Figure 11e shows a haptic VR system in palpation training. A type of VR suit capable of full body haptic feedback and motion tracking, marketed by Teslasuit, is promising in Figure 10. Programmable stimulation in the biological research based on flexible/stretchable electronics. a) A freestanding, folded nanoelectronic scaffold with nanowire FET arrays (four layers in total) and independently addressable stimulator electrodes (purple dots) (left). Culturing of cardiac cells within the 3D folded scaffold produces a hybrid nanoelectronic tissue. Recordings from nanowire FETs in the top three layers (L1, L2, and L3) with periodic biphasic stimulation spikes (1 ms, 1 V, and 1.25 Hz) in the bottom layer (L4) (middle). Blue asterisks in the L1 recording highlight action potentials (downward spikes) versus capacitive coupling peaks (red dashed lines). 3D isochronal time latency map showing the capability of active spatiotemporal regulation of action potential propagation direction within tissues using a stimulator electrode (denoted by a white arrow on the left panel) (right). The mapping area is approximately 25 mmÂ25 mmÂ200 μm. Reproduced with permission. [126] Copyright 2016, Springer Nature. b) A folded microelectronic cardiac patch after 7-day cultivation with cardiac cells. The flexible hybrid cardiac patch accommodates array of electrodes for sensing of the electrical activity, electrical stimulation, and controlled release of biomolecules. Reproduced with permission. [127] Copyright 2016, Springer Nature. c) A schematic illustration of self-powered deep brain stimulation using a flexible PIMNT energy harvester in a mouse model (left). (M1 cortex: primary motor cortex.) An optical image of the flexible PIMNT stimulator mounted on a mouse model (right). The flexible energy harvester supplies electric energy to a bipolar stimulation electrode localized in the M1 cortex. Reproduced with permission. [129] Copyright 2015, the Royal Society of Chemistry. d) A schematic illustration of stretchable silver nanowire microelectrodes for mechanical and electrical stimulation of cells and alignment/elongation of cell nuclei in response to electromechanical stimulation (left). Histograms of the nuclear alignment of cells between electrodes after 24 h of cell stimulation (mechanical: 2% stretch, 1 Hz; electrical: AE2 V, duration 2 ms, 1 Hz) (right). Moving averages (black line) over the original data with a window size of 20 and fitted lines (red lines) are shown in the graphs. Reproduced with permission. [130] Copyright 2016, Wiley-VCH. e) A stretchable cardiac tissue-integrated electronic device, including recording electrodes (white dashed rectangle), pads for external data acquisition and stimulation (cyan dashed rectangle), drug release electrodes (red dashed rectangle), and serpentine counter electrodes (yellow dashed rectangle) (top left). An SEM image of an electrode for drug release (top right). SEM images of a recording electrode and a magnified image of the highlighted area (bottom). Reproduced with permission. [131] Copyright 2019, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com streamlining public safety and athletic training/rehabilitation. [141] This suit is capable of electrical stimulation to increase immersion and improve muscle memory, and can provide users with touch sensation in VR/AR. Here, the flexible electronic technologies can provide possibilities of lightweight, conformal skin contact, freedom from bulky hardware, and wireless communication and power transmission. [55] The haptic feedback enabled by mechanical actuation in flexible, wearable devices is also valuable in posture correction and gait training. [142] Transcranial direct current stimulation can potentially enhance neurocognition by modulating cortical excitability. Thin, flexible electronic devices simultaneously capable of direct current stimulation and near-infrared spectroscopy may facilitate intellectual training in a more effective manner and realize twoway communication between brain and computer. [143] There is also evidence showing that the modulated, noninvasive electric stimulation to the vagus nerve enhances learning of foreign language sounds (e.g., tones in mandarin Chinese). [144] Figure 11. Programmable stimulation in the social network, entertainment and professional training based on flexible/stretchable electronics. a) Immersive gaming experience enhanced by skin-interfaced haptic devices. The haptic feedback is delivered by haptic actuators to different body locations of a user in sync with the virtual strikes in the game. Reproduced with permission. [55] Copyright 2019, Springer Nature. b) Sense of virtual touch in social media enabled by skin-interfaced haptic devices. Dynamic patterns of haptic actuation are programmed in real time and sent to activate the flexible haptic devices worn by another user. Reproduced with permission. [55] Copyright 2019, Springer Nature. c) Demonstration of generating artificial thermal sensation using skin-interfaced thermohaptic devices in VR space (left). Graph of reconstructed artificial temperature change using the thermohaptic device when virtually "touching" materials of different thermal conductivity in VR space at the same temperature (25 C) (right). Reproduced with permission. [51] Copyright 2020, Wiley-VCH. d) Optical images of an epidermal device with large-area electrodes for electrical muscle stimulation (with a magnified view in the inset). Measurements of the evoked M-waves from the induced bicep contraction at 50, 30, and 10 V electrical stimulation (1 Hz), respectively (right). Reproduced with permission. [103] Copyright 2016, Wiley-VCH. e) A VR system with haptic devices for palpation training. Reproduced with permission. [146] Copyright 2012, IEEE.

Conclusion and Outlook
In conclusion, this review summarizes some of the representative advances of the stimulation and actuation capabilities in flexible and stretchable electronic systems. Electrical, thermal, mechanical, optical, chemical, acoustic, magnetic, RF, and other stimulations are accessible in flexible/stretchable electronic devices, to provide diverse modes of operation. Both the flexible and rigid functional components of stimulation/actuation can be integrated into the flexible/stretchable platforms, following integration strategies in mechanics and materials. These types of stimulation and actuation are significant in providing feedback, transmitting signals to neural systems, initiating deformations/ motions, facilitating measurements, conducting therapy, generating stimuli, and mimicking thermal signature of human body or objects, which constitute enabling functionalities in humanmachine interaction, medical measurement, medical therapy, biological research, social network, entertainment, and athletic and professional training, among others. Despite inspiring progress, challenges remain in this promising area of flexible/stretchable electronics with stimulation and actuation capabilities. Some of the key challenges include 1) incorporating a substantially increased number of functional units in a miniaturized device while maintaining flexibility and stretchability, 2) supplying sufficient power to the functional stimulation/actuation units in a reliable and user-friendly manner, and 3) wirelessly transmitting commands and feedbacks from and to external command/data acquisition modules. Electrical interconnects/wires for power supply and communication could potentially defer the broader applications of flexible/ stretchable electronics in wearable or biointegrated settings. For example, existing miniaturized energy storage and/or harvesting units still fall short in terms of power level and reliability. Wireless power harvesting elements still have a relatively short distance of operation. Future opportunities in expanding and improving the stimulation capabilities of flexible and stretchable electronics lie in developing 1) functional components of high performance and low power consumption, e.g., electrodes, light sources, and high-strain soft actuators; 2) advanced concepts in mechanics and materials for system-level integration of hard/soft components for on-demand stimulation; 3) novel mechanisms and modes of stimulation; 4) wireless, reliable power supply, control and data transmission for personal area networks; and 5) miniaturized, versatile flexible/stretchable devices for multimodal stimulation/actuation, among other research opportunities.
The stimulation and actuation functionalities in flexible/ stretchable electronics are important yet relatively underexplored. The continuous advances in this field could leverage numerous innovations in fundamental sciences, clinical application, and technological frontiers.