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.

Computed Tomography-Derived Skeletal Muscle Radiodensity Predicts Peak Weight-Corrected Jump Power in Older Adults: The Korean Urban Rural Elderly (KURE) Study.

Computed tomography (CT)-derived skeletal muscle area (SMA) and skeletal muscle radiodensity (SMD) reflect distinctive quantitative and qualitative characteristics of skeletal muscles. However, data on whether CT-based muscle parameters, especially SMD, can predict muscle function is limited. In a prospective cohort, 1523 community-dwelling older adults who underwent abdominal CT scans and the countermovement two-legged jumping test on a ground reaction force platform were analyzed (mean age 74.7 years, 65.1% women). SMA and SMD were measured at third lumbar vertebra level (L3). Individuals with low jump power (peak weight-corrected jump power < 23.8 W/kg in men and < 19.0 W/kg in women using clinically validated threshold) were older; had lower SMA, SMD, and maximal grip strength values; and had lower chair rise test and timed up and go test performance than those without low jump power. SMD was positively associated with peak weight-corrected jump power (adjusted ß = 0.33 and 0.23 per 1 HU increase in men and women, respectively, p < 0.001). One HU decrement in SMD was associated with 10% elevated odds of low jump power (adjusted OR [aOR] 1.10, p < 0.001) after adjusting for age, sex, height, inflammation, and insulin resistance markers, whereas the association of SMA with low jump power was attenuated (aOR 1.00, p = 0.721). SMD showed better discrimination for low jump power than SMA (AUC 0.699 vs. 0.617, p < 0.001), with additional improvement when added to SMA and conventional risk factors (AUC 0.745 to 0.773, p < 0.001). Therefore, CT-measured L3 SMD can be a sensitive surrogate marker for muscle function along with SMA in older adults, which merits further investigation.

Effect of the Mandibular Orthopedic Repositioning Appliance (MORA) on Forearm Muscle Activation and Grasping Power during Pinch and Hook Grip.

[Purpose] This study verified the changes in muscle activities and grasping power during maximal isometric exercise of the forearm and masseter muscle with and without a mandibular orthopedic repositioning appliance (MORA). It also offers basic data for defining the correlation of function of hand with mouth. [Methods] EMG was used to measure masticatory muscle, flexor bundle and extensor bundle activities with or without MORA while subjects performed the hook grip and pinch grip. The measuring tool used for measuring grip strength was the same as that used for measuring pinch and hook strength. The subjects were 28 healthy young adults. [Result] Muscle activity and grasping power significantly increased when wearing the MORA. [Conclusion] The result indicates that wearing MORA can increase muscle activity and grasping power of forearm and masseter muscle. We think wearing MORA might help improve the function of the forearm because it activates the function of the masseter.

A Wireless, CRISPR-Polymer Dot Electrochemical Sensor for the Diagnosis of Bacterial Pneumonia and Multi-Drug Resistance.

Rapid and accurate diagnosis is crucial for managing the global health threat posed by multidrug-resistant bacterial infections; however, current methods have limitations in either being time-consuming, labor-intensive, or requiring instruments with high costs. Addressing these challenges, we introduce a wireless electrochemical sensor integrating the CRISPR/Cas system with electroconductive polymer dot (PD) nanoparticles to rapidly detect bacterial pathogens from human sputum. To enhance the electroconductive properties, we synthesized copper-ion-immobilized PD (PD-Cu), followed by conjugation of the deactivated Cas9 protein (dCas9) onto PD-Cu-coated Si electrodes to generate the dCas9-PD-Cu sensor. The dCas9-PD-Cu sensor integrated with isothermal amplification can specifically detect target nucleic acids of multidrug-resistant bacteria, such as the antibiotic resistance genes kpc-2 and mecA. The dCas9-PD-Cu sensor exhibits high sensitivity, allowing for the detection of ∼54 femtograms of target nucleic acids, based on measuring the changes in resistivity of the Si electrodes through target capture by dCas9. Furthermore, a wireless sensing platform of the dCas9-PD-Cu sensor was established using a Bluetooth module and a microcontroller unit for detection using a smartphone. We demonstrate the feasibility of the platform in diagnosing multidrug-resistant bacterial pneumonia in patients' sputum samples, achieving 92% accuracy. The current study presents a versatile biosensor platform that can overcome the limitations of conventional diagnostics in the clinic.

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.

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.

A Rotatable Paper Device Integrating Reverse Transcription Loop-Mediated Isothermal Amplification and a Food Dye for Colorimetric Detection of Infectious Pathogens.

In this study, we developed a rotatable paper device integrating loop-mediated isothermal amplification (RT-LAMP) and a novel naked-eye readout of the RT-LAMP results using a food additive, carmoisine, for infectious pathogen detection. Hydroxyl radicals created from the reaction between CuSO4 and H2O2 were used to decolor carmoisine, which is originally red. The decolorization of carmoisine can be interrupted in the presence of DNA amplicons produced by the RT-LAMP reaction due to how DNA competitively reacts with the hydroxyl radicals to maintain the red color of the solution. In the absence of the target DNA, carmoisine is decolored, owing to its reaction with hydroxyl radicals; thus, positive and negative samples can be easily differentiated based on the color change of the solution. A rotatable paper device was fabricated to integrate the RT-LAMP reaction with carmoisine-based colorimetric detection. The rotatable paper device was successfully used to detect SARS-CoV-2 and SARS-CoV within 70 min using the naked eye. Enterococcus faecium spiked in milk was detected using the rotatable paper device. The detection limits for the SARS-CoV-2 and SARS-CoV targets were both 103 copies/µL. The rotatable paper device provides a portable and low-cost tool for detecting infectious pathogens in a resource-limited environment.

Soft Stretchable Conductive Carboxymethylcellulose Hydrogels for Wearable Sensors.

Hydrogels that have a capability to provide mechanical modulus matching between time-dynamic curvilinear tissues and bioelectronic devices have been considered tissue-interfacing ionic materials for stably sensing physiological signals and delivering feedback actuation in skin-inspired healthcare systems. These functionalities are totally different from those of elastomers with low ionic conductivity and higher stiffness. Despite such remarkable progress, their low conductivity remains limited in transporting electrical charges to internal or external terminals without undesired information loss, potentially leading to an unstable biotic-abiotic interfaces in the wearable electronics. Here, we report a soft stretchable conductive hydrogel composite consisting of alginate, carboxymethyl cellulose, polyacrylamide, and silver flakes. This composite was fabricated via sol-gel transition. In particular, the phase stability and low dynamic modulus rates of the conductive hydrogel were confirmed through an oscillatory rheological characterization. In addition, our conductive hydrogel showed maximal tensile strain (≈400%), a low deformations of cyclic loading (over 100 times), low resistance (≈8.4 Ω), and a high gauge factor (≈241). These stable electrical and mechanical properties allowed our composite hydrogel to fully support the operation of a light-emitting diode demonstration under mechanical deformation. Based on such durable performance, we successfully measured the electromyogram signals without electrical malfunction even in various motions.

Self-Healing, Stretchable, Biocompatible, and Conductive Alginate Hydrogels through Dynamic Covalent Bonds for Implantable Electronics.

Implantable electronics have recently been attracting attention because of the promising advances in personalized healthcare. They can be used to diagnose and treat chronic diseases by monitoring and applying bioelectrical signals to various organs. However, there are challenges regarding the rigidity and hardness of typical electronic devices that can trigger inflammatory reactions in tissues. In an effort to improve the physicochemical properties of conventional implantable electronics, soft hydrogel-based platforms have emerged as components of implantable electronics. It is important that they meet functional criteria, such as stretchability, biocompatibility, and self-healing. Herein, plant-inspired conductive alginate hydrogels composed of "boronic acid modified alginate" and "oligomerized epigallocatechin gallate," which are extracted from plant compounds, are proposed. The conductive hydrogels show great stretchability up to 500% and self-healing properties because of the boronic acid-cis-diol dynamic covalent bonds. In addition, as a simple strategy to increase the electrical conductivity of the hydrogels, ionically crosslinked shells with cations (e.g., sodium) were generated on the hydrogel under physiological salt conditions. This decreased the resistance of the conductive hydrogel down to 900 ohm without trading off the original properties of stretchability and self-healing. The hydrogels were used for "electrophysiological bridging" to transfer electromyographic signals in an ex vivo muscle defect model, showing a great bridging effect comparable to that of a muscle-to-muscle contact model. The use of plant-inspired ionically conductive hydrogels is a promising strategy for designing implantable and self-healable bioelectronics.

Mechanically and electrically durable, stretchable electronic textiles for robust wearable electronics.

A monolithic integration of high-performance soft electronic modules into various fabric materials has enabled a paradigm shift in wearable textile electronics. However, the current textile electronics have struggled against fatigue under repetitive deformation due to the absence of materials and structural design strategies for imparting electrical and mechanical robustness to individual fibers. Here, we report a mechanically and electrically durable, stretchable electronic textile (MED-ET) enabled by a precisely controlled diffusion of tough self-healing stretchable inks into fibers and an adoption of the kirigami-inspired design. Remarkably, the conductive percolative pathways in the fabric of MED-ET even under a harshly deformed environment were stably maintained due to an electrical recovery phenomenon which originates from the spontaneous rearrangement of Ag flakes in the self-healing polymer matrix. Specifically, such a unique property enabled damage-resistant performance when repetitive deformation and scratch were applied. In addition, the kirigami-inspired design was capable of efficiently dissipating the accumulated stress in the conductive fabric during stretching, thereby providing high stretchability (a tensile strain of 300%) without any mechanical fracture or electrical malfunction. Finally, we successfully demonstrate various electronic textile applications such as stretchable micro-light-emitting diodes (Micro-LED), electromyogram (EMG) monitoring and all-fabric thermoelectric devices (F-TEG).

Genetic Analysis and Clinical Characteristics of Hereditary Pheochromocytoma and Paraganglioma Syndrome in Korean Population.

BACKGROUND: Pheochromocytoma and paragangliomas (PPGL) are hereditary in approximately 30% to 40% cases. With the advancement of genetic analysis techniques, including next-generation sequencing (NGS), there were attempts to classify PPGL into molecular clusters. With NGS being applied to clinical settings recently, we aimed to review the results of genetic analysis, including NGS, and investigate the association with clinical characteristics in Korean PPGL patients. METHODS: We reviewed the medical records of PPGL patients who visited Severance hospital from 2006 to 2019. We documented the clinical phenotype of those who underwent targeted NGS or had known germline mutations of related genes. RESULTS: Among 57 PPGL patients, we found 28 pathogenic germline mutations of susceptibility genes. Before the targeted NGS was implemented, only obvious syndromic feature lead to the Sanger sequencing for the specific genes. Therefore, for the exact prevalence, only patients after the year 2017, when targeted NGS was added, were included (n=43). The positive germline mutations were found in 14 patients; thus, the incidence rate is 32.6%. Patients with germline mutations had a higher likelihood of family history. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate, presence of other tumors, and biochemical profile among three molecular clusters: pseudohypoxic tricarboxylic acid cycle-related, pseudohypoxic von Hippel-Lindau (VHL)/endothelial PAS domain-containing protein 1-related, and kinase-signaling group. Germline mutations were identified in seven PPGL-related genes (SDHB, RET, VHL, NF1, MAX, SDHA, and SDHD). CONCLUSION: We report the expected prevalence of germline mutations in Korean PPGL patients. NGS is a useful and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification is needed for precise management.

The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity.

Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.