Injectable tissue prosthesis for instantaneous closed-loop rehabilitation.

To construct tissue-like prosthetic materials, soft electroactive hydrogels are the best candidate owing to their physiological mechanical modulus, low electrical resistance and bidirectional stimulating and recording capability of electrophysiological signals from biological tissues1,2. Nevertheless, until now, bioelectronic devices for such prostheses have been patch type, which cannot be applied onto rough, narrow or deep tissue surfaces3-5. Here we present an injectable tissue prosthesis with instantaneous bidirectional electrical conduction in the neuromuscular system. The soft and injectable prosthesis is composed of a biocompatible hydrogel with unique phenylborate-mediated multiple crosslinking, such as irreversible yet freely rearrangeable biphenyl bonds and reversible coordinate bonds with conductive gold nanoparticles formed in situ by cross-coupling. Closed-loop robot-assisted rehabilitation by injecting this prosthetic material is successfully demonstrated in the early stage of severe muscle injury in rats, and accelerated tissue repair is achieved in the later stage.

Stretchable Functional Nanocomposites for Soft Implantable Bioelectronics.

Material advances in soft bioelectronics, particularly those based on stretchable nanocomposites─functional nanomaterials embedded in viscoelastic polymers with irreversible or reversible bonds─have driven significant progress in translational medical device research. The unique mechanical properties inherent in the stretchable nanocomposites enable stiffness matching between tissue and device, as well as its spontaneous mechanical adaptation to in vivo environments, minimizing undesired mechanical stress and inflammation responses. Furthermore, these properties allow percolative networks of conducting fillers in the nanocomposites to be sustained even under repetitive tensile/compressive stresses, leading to stable tissue-device interfacing. Here, we present an in-depth review of materials strategies, fabrication/integration techniques, device designs, applications, and translational opportunities of nanocomposite-based soft bioelectronics, which feature intrinsic stretchability, self-healability, tissue adhesion, and/or syringe injectability. Among many, applications to brain, heart, and peripheral nerves are predominantly discussed, and translational studies in certain domains such as neuromuscular and cardiovascular engineering are particularly highlighted.

Strain-Dependent Photoacoustic Characteristics of Free-Standing Carbon-Nanocomposite Transmitters.

In this paper we demonstrate strain-dependent photoacoustic (PA) characteristics of free-standing nanocomposite transmitters that are made of carbon nanotubes (CNT) and candle soot nanoparticles (CSNP) with an elastomeric polymer matrix. We analyzed and compared PA output performances of these transmitters which are prepared first on glass substrates and then in a delaminated free-standing form for strain-dependent characterization. This confirms that the nanocomposite transmitters with lower concentration of nanoparticles exhibit more flexible and stretchable property in terms of Young's modulus in a range of 4.08-10.57 kPa. Then, a dynamic endurance test was performed revealing that both types of transmitters are reliable with pressure amplitude variation as low as 8-15% over 100-800 stretching cycles for a strain level of 5-28% with dynamic endurance in range of 0.28-2.8%. Then, after 2000 cycles, the transmitters showed pressure amplitude variation of 6-29% (dynamic endurance range of 0.21-1.03%) at a fixed strain level of 28%. This suggests that the free-standing nanocomposite transmitters can be used as a strain sensor under a variety of environments providing robustness under repeated stretching cycles.

A Dual-Mode CMOS Power Amplifier with an External Power Amplifier Driver Using 40 nm CMOS for Narrowband Internet-of-Things Applications.

The narrowband Internet-of-Things (NB-IoT) has been developed to provide low-power, wide-area IoT applications. The efficiency of a power amplifier (PA) in a transmitter is crucial for a longer battery lifetime, satisfying the requirements for output power and linearity. In addition, the design of an internal complementary metal-oxide semiconductor (CMOS) PA is typically required when considering commercial applications to include the operation of an optional external PA. This paper presents a dual-mode CMOS PA with an external PA driver for NB-IoT applications. The proposed PA supports an external PA mode without degrading the performances of output power, linearity, and stability. In the operation of an external PA mode, the PA provides a sufficient gain to drive an external PA. A parallel-combined transistor method is adopted for a dual-mode operation and a third-order intermodulation distortion (IMD3) cancellation. The proposed CMOS PA with an external PA driver was implemented using 40 nm-CMOS technology. The PA achieves a gain of 20.4 dB, a saturated output power of 28.8 dBm, and a power-added efficiency (PAE) of 57.8% in high-power (HP) mode at 920 MHz. With an NB-IoT signal (200 kHz π/4-differential quadrature phase shift keying (DQPSK)), the proposed PA achieves 24.2 dBm output power (Pout) with a 31.0% PAE, while satisfying -45 dBc adjacent channel leakage ratio (ACLR). More than 80% of the current consumption at 12 dBm Pout could be saved compared to that in HP mode when the proposed PA operates in low-power (LP) mode. The implemented dual-mode CMOS PA provides high linear output power with high efficiency, while supporting an external PA mode. The proposed PA is a good candidate for NB-IoT applications.

Defect-Engineered Semiconducting van der Waals Thin Film at Metal-Semiconductor Interface of Field-Effect Transistors.

The significance of metal-semiconductor interfaces and their impact on electronic device performance have gained increasing attention, with a particular focus on investigating the contact metal. However, another avenue of exploration involves substituting the contact metal at the metal-semiconductor interface of field-effect transistors with semiconducting layers to introduce additional functionalities to the devices. Here, a scalable approach for fabricating metal-oxide-semiconductor (channel)-semiconductor (interfacial layer) field-effect transistors is proposed by utilizing solution-processed semiconductors, specifically semiconducting single-walled carbon nanotubes and molybdenum disulfide, as the channel and interfacial semiconducting layers, respectively. The work function of the interfacial MoS2 is modulated by controlling the sulfur vacancy concentration through chemical treatment, which results in distinctive energy band alignments within a single device configuration. The resulting band alignments lead to multiple functionalities, including multivalued transistor characteristics and multibit nonvolatile memory (NVM) behavior. Moreover, leveraging the stable NVM properties, we demonstrate artificial synaptic devices with 88.9% accuracy of MNIST image recognition.

Sticky and Strain-Gradient Artificial Epineurium for Sutureless Nerve Repair in Rodents and Nonhuman Primates.

The need for the development of soft materials capable of stably adhering to nerve tissues without any suturing followed by additional damages is at the fore at a time when success in postoperative recovery depends largely on the surgical experience and/or specialized microsuturing skills of the surgeon. Despite fully recognizing such prerequisite conditions, designing the materials with robust adhesion to wet nerves as well as acute/chronic anti-inflammation remains to be resolved. Herein, a sticky and strain-gradient artificial epineurium (SSGAE) that overcomes the most critically challenging aspect for realizing sutureless repair of severely injured nerves is presented. In this regard, the SSGAE with a skin-inspired hierarchical structure entailing strain-gradient layers, anisotropic Janus layers including hydrophobic top and hydrophilic bottom surfaces, and synergistic self-healing capabilities enables immediate and stable neurorrhaphy in both rodent and nonhuman primate models, indicating that the bioinspired materials strategy significantly contributes to translational medicine for effective peripheral nerve repair.

Conductive and Adhesive Granular Alginate Hydrogels for On-Tissue Writable Bioelectronics.

Conductive hydrogels are promising materials in bioelectronics that ensure a tissue-like soft modulus and re-enact the electrophysiological function of damaged tissues. However, recent approaches to fabricating conductive hydrogels have proved difficult: fixing of the conductive hydrogels on the target tissues hydrogels requires the aids from other medical glues because of their weak tissue-adhesiveness. In this study, an intrinsically conductive and tissue-adhesive granular hydrogel consisting of a PEDOT:PSS conducting polymer and an adhesive catechol-conjugated alginate polymer was fabricated via an electrohydrodynamic spraying method. Because alginate-based polymers can be crosslinked by calcium ions, alginate-catechol polymers mixed with PEDOT:PSS granular hydrogels (ACP) were easily fabricated. The fabricated ACP exhibited not only adhesive and shear-thinning properties but also conductivity similar to that of muscle tissue. Additionally, the granular structure makes the hydrogel injectable through a syringe, enabling on-tissue printing. This multifunctional granular hydrogel can be applied to soft and flexible electronics to connect humans and machines.

Wearable Liquid Metal Composite with Skin-Adhesive Chitosan-Alginate-Chitosan Hydrogel for Stable Electromyogram Signal Monitoring.

In wearable bioelectronics, various studies have focused on enhancing prosthetic control accuracy by improving the quality of physiological signals. The fabrication of conductive composites through the addition of metal fillers is one way to achieve stretchability, conductivity, and biocompatibility. However, it is difficult to measure stable biological signals using these soft electronics during physical activities because of the slipping issues of the devices, which results in the inaccurate placement of the device at the target part of the body. To address these limitations, it is necessary to reduce the stiffness of the conductive materials and enhance the adhesion between the device and the skin. In this study, we measured the electromyography (EMG) signals by applying a three-layered hydrogel structure composed of chitosan-alginate-chitosan (CAC) to a stretchable electrode fabricated using a composite of styrene-ethylene-butylene-styrene and eutectic gallium-indium. We observed stable adhesion of the CAC hydrogel to the skin, which aided in keeping the electrode attached to the skin during the subject movement. Finally, we fabricated a multichannel array of CAC-coated composite electrodes (CACCE) to demonstrate the accurate classification of the EMG signals based on hand movements and channel placement, which was followed by the movement of the robot arm.

Soft and Conductive Polyethylene Glycol Hydrogel Electrodes for Electrocardiogram Monitoring.

The measurement of biosignals in the clinical and healthcare fields is fundamental; however, conventional electrodes pose challenges such as incomplete skin contact and skin-related issues, hindering accurate biosignal measurement. To address these challenges, conductive hydrogels, which are valuable owing to their biocompatibility and flexibility, have been widely developed and explored for electrode applications. In this study, we fabricated a conductive hydrogel by mixing polyethylene glycol diacrylate (PEGDA) with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) polymers dissolved in deionized water, followed by light-triggered crosslinking. Notably, this study pioneered the use of a PEGDA-PEDOT:PSS hydrogel for electrocardiogram (ECG) monitoring- a type of biosignal. The resulting PEGDA-PEDOT:PSS hydrogel demonstrated remarkable conductivity while closely approximating the modulus of skin elasticity. Additionally, it demonstrated biocompatibility and a high signal-to-noise ratio in the waveforms. This study confirmed the exceptional suitability of the PEGDA-PEDOT:PSS hydrogel for accurate biosignal measurements with potential applications in various wearable devices designed for biosignal monitoring.

Injection-on-Skin Granular Adhesive for Interactive Human-Machine Interface.

Realization of interactive human-machine interfaces (iHMI) is improved with development of soft tissue-like strain sensors beyond hard robotic exosuits, potentially allowing cognitive behavior therapy and physical rehabilitation for patients with brain disorders. Here, this study reports on a strain-sensitive granular adhesive inspired by the core-shell architectures of natural basil seeds for iHMI as well as human-metaverse interfacing. The granular adhesive sensor consists of easily fragmented hydropellets as a core and tissue-adhesive catecholamine layers as a shell, satisfying great on-skin injectability, ionic-electrical conductivity, and sensitive resistance changes through reversible yet robust cohesion among the hydropellets. Particularly, it is found that the ionic-electrical self-doping of the catecholamine shell on hydrosurfaces leads to a compact ion density of the materials. Based on these physical and electrical properties of the sensor, it is demonstrated that successful iHMI integration with a robot arm in both real and virtual environments enables robotic control by finger gesture and haptic feedback. This study expresses benefits of using granular hydrogel-based strain sensors for implementing on-skin writable bioelectronics and their bridging into the metaverse world.

Stretchable Gold Nanomembrane Electrode with Ionic Hydrogel Skin-Adhesive Properties.

Skin has a dynamic surface and offers essential information through biological signals originating from internal organs, blood vessels, and muscles. Soft and stretchable bioelectronics can be used in wearable machines for long-term stability and to continuously obtain distinct bio-signals in conjunction with repeated expansion and contraction with physical activities. While monitoring bio-signals, the electrode and skin must be firmly attached for high signal quality. Furthermore, the signal-to-noise ratio (SNR) should be high enough, and accordingly, the ionic conductivity of an adhesive hydrogel needs to be improved. Here, we used a chitosan-alginate-chitosan (CAC) triple hydrogel layer as an interface between the electrodes and the skin to enhance ionic conductivity and skin adhesiveness and to minimize the mechanical mismatch. For development, thermoplastic elastomer Styrene-Ethylene-Butylene-Styrene (SEBS) dissolved in toluene was used as a substrate, and gold nanomembranes were thermally evaporated on SEBS. Subsequently, CAC triple layers were drop-casted onto the gold surface one by one and dried successively. Lastly, to demonstrate the performance of our electrodes, a human electrocardiogram signal was monitored. The electrodes coupled with our CAC triple hydrogel layer showed high SNR with clear PQRST peaks.

Radiologic Progression of Interstitial Lung Abnormalities following Surgical Resection in Patients with Lung Cancer.

In this study, we aimed to assess the prevalence of interstitial lung abnormalities (ILAs) and investigate the rates and risk factors associated with radiologic ILA progression among patients with lung cancer following surgical resection. Patients who underwent surgical resection for lung cancer at our institution from January 2015 to December 2020 were retrospectively evaluated and grouped according to their ILA status as having no ILAs, equivocal ILAs, or ILAs. Progression was determined by simultaneously reviewing the baseline and corresponding follow-up computed tomography (CT) scans. Among 346 patients (median age: 67 (interquartile range: 60-74) years, 204 (59.0%) men), 22 (6.4%) had equivocal ILAs, and 33 (9.5%) had ILAs detected upon baseline CT. Notably, six patients (6/291; 2.1%) without ILAs upon baseline CT later developed ILAs, and 50% (11/22) of those with equivocal ILAs exhibited progression. Furthermore, 75.8% (25/33) of patients with ILAs upon baseline CT exhibited ILA progression (76.9% and 71.4% with fibrotic and non-fibrotic ILAs, respectively). Multivariate analysis revealed that ILA status was a significant risk factor for ILA progression. ILAs and equivocal ILAs were associated with radiologic ILA progression after surgical resection in patients with lung cancer. Hence, early ILA detection can significantly affect clinical outcomes.

Resealable Antithrombotic Artificial Vascular Graft Integrated with a Self-Healing Blood Flow Sensor.

Coronary artery bypass grafting is commonly used to treat cardiovascular diseases by replacing blocked blood vessels with autologous or artificial blood vessels. Nevertheless, the availability of autologous vessels in infants and the elderly and low long-term patency rate of grafts hinder extensive application of autologous vessels in clinical practice. The biological and mechanical properties of the resealable antithrombotic artificial vascular graft (RAAVG) fabricated herein, comprising a bioelectronic conduit based on a tough self-healing polymer (T-SHP) and a lubricious inner coating, match with the functions of autologous blood vessels. The self-healing and elastic properties of the T-SHP confer resistance against mechanical stimuli and promote conformal sealing of suturing regions, thereby preventing leakage (stable fixation under a strain of 50%). The inner layer of the RAAVG presents antibiofouling properties against blood cells and proteins, and antithrombotic properties, owing to its lubricious coating. Moreover, the blood-flow sensor fabricated using the T-SHP and carbon nanotubes is seamlessly integrated into the RAAVG via self-healing and allows highly sensitive monitoring of blood flow at low and high flow rates (10- and 100 mL min-1, respectively). Biocompatibility and feasibility of RAAVG as an artificial graft were demonstrated via ex vivo, and in vivo experiment using a rodent model. The use of RAAVGs to replace blocked blood vessels can improve the long-term patency rate of coronary artery bypass grafts.

A Water-Resistant, Self-Healing Encapsulation Layer for a Stable, Implantable Wireless Antenna.

Polymers for implantable devices are desirable for biomedical engineering applications. This study introduces a water-resistant, self-healing fluoroelastomer (SHFE) as an encapsulation material for antennas. The SHFE exhibits a tissue-like modulus (approximately 0.4 MPa), stretchability (at least 450%, even after self-healing in an underwater environment), self-healability, and water resistance (WVTR result: 17.8610 g m-2 day-1). Further, the SHFE is self-healing in underwater environments via dipole-dipole interactions, such that devices can be protected from the penetration of biofluids and withstand external damage. With the combination of the SHFE and antennas designed to operate inside the body, we fabricated implantable, wireless antennas that can transmit information from inside the body to a reader coil that is outside. For antennas designed considering the dielectric constant, the uniformity of the encapsulation layer is crucial. A uniform and homogeneous interface is formed by simply overlapping two films. This study demonstrated the possibility of wireless communication in vivo through experiments on rodents for 4 weeks, maintaining the maximum communication distance (15 mm) without chemical or physical deformation in the SHFE layer. This study illustrates the applicability of fluoroelastomers in vivo and is expected to contribute to realizing the stable operation of high-performance implantable devices.

Hepatocellular carcinoma incidence is decreasing in Korea but increasing in the very elderly.

BACKGROUND/AIMS: A comprehensive analysis of trends in the incidence of hepatocellular carcinoma (HCC) is important for planning public health initiatives. We aimed to analyze the trends in HCC incidence in South Korea over 10 years and to predict the incidence for the year 2028. METHODS: Data from patients with newly diagnosed HCC between 2008 and 2018 were obtained from Korean National Health Insurance Service database. Age-standardized incidence rates (ASRs) were calculated to compare HCC incidence. A poisson regression model was used to predict the future incidence of HCC. RESULTS: The average crude incidence rate (CR) was 22.4 per 100,000 person-years, and the average ASR was 17.6 per 100,000 person-years between 2008 and 2018. The CR (from 23.9 to 21.2 per 100,000 person-years) and ASR (from 21.9 to 14.3 per 100,000 person-years) of HCC incidence decreased during the past ten years in all age groups, except in the elderly. The ASR of patients aged ≥80 years increased significantly (from 70.0 to 160.2/100,000 person-years; average annual percent change, +9.00%; P<0.001). The estimated CR (17.9 per 100,000 person-years) and ASR (9.7 per 100,000 person-years) of HCC incidence in 2028 was declined, but the number of HCC patients aged ≥80 years in 2028 will be quadruple greater than the number of HCC patients in 2008 (from 521 to 2,055), comprising 21.3% of all HCC patients in 2028. CONCLUSION: The ASRs of HCC in Korea have gradually declined over the past 10 years, but the number, CR, and ASR are increasing in patients aged ≥80 years.

Comparison of Prophylactic Effects between Localized Biomimetic Minocycline and Systematic Amoxicillin on Implants Placed Immediately in Infected Sockets.

This study evaluated the prophylactic effect of localized biomimetic minocycline and systemic amoxicillin on immediate implant placement at infected extraction sites. Twelve mongrels with six implants each were randomly assigned to five groups: uninfected negative control (Group N); infected with oral complex bacteria (Group P); infected and treated with amoxicillin one hour before implant placement (Group A); infected and treated with minocycline during implant placement (Group B); and infected and treated with amoxicillin one hour before implant placement and with minocycline during implant placement (Group C). Radiographic bone level, gingival index (GI), probing depth (PD), papillary bleeding index (PBI), and removal torque (RT) were recorded. There was no significant difference between Groups A, B, and C for bone loss. Group A showed the highest RT, the lowest PBI, and significantly lower GI and PD values than Group P. Group B exhibited significantly higher RT value than Group N and significantly smaller PD value than Group P at 6 w postoperatively. Localized minocycline could improve implant success by reducing bone loss and increasing RT and systemic amoxicillin could maintain the stability of the peri-implant soft tissue. However, combined use of these two antibiotics did not augment the prophylactic effect.

A Hemispherical Image Sensor Array Fabricated with Organic Photomemory Transistors.

Hemispherical image sensors simplify lens designs, reduce optical aberrations, and improve image resolution for compact wide-field-of-view cameras. To achieve hemispherical image sensors, organic materials are promising candidates due to the following advantages: tunability of optoelectronic/spectral response and low-temperature low-cost processes. Here, a photolithographic process is developed to prepare a hemispherical image sensor array using organic thin film photomemory transistors with a density of 308 pixels per square centimeter. This design includes only one photomemory transistor as a single active pixel, in contrast to the conventional pixel architecture, consisting of select/readout/reset transistors and a photodiode. The organic photomemory transistor, comprising light-sensitive organic semiconductor and charge-trapping dielectric, is able to achieve a linear photoresponse (light intensity range, from 1 to 50 W m-2 ), along with a responsivity as high as 1.6 A W-1 (wavelength = 465 nm) for a dark current of 0.24 A m-2 (drain voltage = -1.5 V). These observed values represent the best responsivity for similar dark currents among all the reported hemispherical image sensor arrays to date. A transfer method was further developed that does not damage organic materials for hemispherical organic photomemory transistor arrays. These developed techniques are scalable and are amenable for other high-resolution 3D organic semiconductor devices.

Molecular Rationale for the Design of Instantaneous, Strain-Tolerant Polymeric Adhesive in a Stretchable Underwater Human-Machine Interface.

Strain-tolerant reversible adhesion under harsh mechanical deformation is important for realizing long-lasting polymeric adhesives. Despite recent advances, cohesive failure within adhesives remains a critical problem that must be solved to achieve adhesion that is robust against humidity, heat, and mechanical stress. Here, we report a molecular rationale for designing an instantaneous polymeric adhesive with high strain tolerance (termed as iPASTE) even in a stretchable human-machine interface. The iPASTE consists of two biocompatible and eco-friendly polymers, linearly oligomerized green tea extracts, and poly(ethylene glycol) for densely assembled networks via dynamic and reversible hydrogen bonds. Other than the typical approach containing nanoclay or branched adhesive precursors, the linear configuration and conformation of such polymer chains within iPASTE lead to strong and moisture-resistant cohesion/adhesion. Based on the strain-tolerant adhesion of iPASTE, it was demonstrated that a subaqueous interactive human-machine interface integrated with a robot arm and a gold nanomembrane strain-sensitive electronic skin can precisely capture a slithery artificial fish by using finger gesture recognition.

Tissue Adhesive, Conductive, and Injectable Cellulose Hydrogel Ink for On-Skin Direct Writing of Electronics.

Flexible and soft bioelectronics used on skin tissue have attracted attention for the monitoring of human health. In addition to typical metal-based rigid electronics, soft polymeric materials, particularly conductive hydrogels, have been actively developed to fabricate biocompatible electrical circuits with a mechanical modulus similar to biological tissues. Although such conductive hydrogels can be wearable or implantable in vivo without any tissue damage, there are still challenges to directly writing complex circuits on the skin due to its low tissue adhesion and heterogeneous mechanical properties. Herein, we report cellulose-based conductive hydrogel inks exhibiting strong tissue adhesion and injectability for further on-skin direct printing. The hydrogels consisting of carboxymethyl cellulose, tannic acid, and metal ions (e.g., HAuCl4) were crosslinked via multiple hydrogen bonds between the cellulose backbone and tannic acid and metal-phenol coordinate network. Owing to this reversible non-covalent crosslinking, the hydrogels showed self-healing properties and reversible conductivity under cyclic strain from 0 to 400%, as well as printability on the skin tissue. In particular, the on-skin electronic circuit printed using the hydrogel ink maintained a continuous electrical flow under skin deformation, such as bending and twisting, and at high relative humidity of 90%. These printable and conductive hydrogels are promising for implementing structurally complicated bioelectronics and wearable textiles.

Soft Liquid Metal-Based Conducting Composite with Robust Electrical Durability for a Wearable Electrocardiogram Sensor.

Liquid metals not only have the electrical property of conductivity, but they also have a unique characteristic of existing in a liquid state at room temperature, unlike ordinary stiff solid metals. However, in bioelectronics, the modulus matching well between a device and skin or tissue is considered very advantageous, because high-quality biological signals can be recorded. Therefore, it is possible to implement soft electronics with stable and robust electrical characteristics by using LM as a conductive liquid-state filler. In this study, we changed a type of liquid metal, Eutectic Gallium Indium (EGaIn), into a particle form via tip sonication and mixed it with a solution that dissolved Styrene-Ethylene-Butylene-Styrene (SEBS) in toluene to fabricate a composite. The EGaIn-SEBS composite has high conductivity, excellent electrical durability under mechanically harsh conditions, and a degree of modulus similar to that of bare SEBS, which is lower than that of solid-filler-based SEBS composite. Finally, we demonstrated electrocardiogram signal monitoring using an EGaIn-Alginate two-layer electrode (EATE) that was fabricated by simply coating the surface of the composite with alginate hydrogel, which demonstrates excellent performance in bioelectronics.