Geometry-mediated bridging drives nonadhesive stripe wound healing.

Wound healing through reepithelialization of gaps is of profound importance to the medical community. One critical mechanism identified by researchers for closing non-cell-adhesive gaps is the accumulation of actin cables around concave edges and the resulting purse-string constriction. However, the studies to date have not separated the gap-edge curvature effect from the gap size effect. Here, we fabricate micropatterned hydrogel substrates with long, straight, and wavy non-cell-adhesive stripes of different gap widths to investigate the stripe edge curvature and stripe width effects on the reepithelialization of Madin-Darby canine kidney (MDCK) cells. Our results show that MDCK cell reepithelization is closely regulated by the gap geometry and may occur through different pathways. In addition to purse-string contraction, we identify gap bridging either via cell protrusion or by lamellipodium extension as critical cellular and molecular mechanisms for wavy gap closure. Cell migration in the direction perpendicular to wound front, sufficiently small gap size to allow bridging, and sufficiently high negative curvature at cell bridges for actin cable constriction are necessary/sufficient conditions for gap closure. Our experiments demonstrate that straight stripes rarely induce cell migration perpendicular to wound front, but wavy stripes do; cell protrusion and lamellipodia extension can help establish bridges over gaps of about five times the cell size, but not significantly beyond. Such discoveries deepen our understanding of mechanobiology of cell responses to curvature and help guide development of biophysical strategies for tissue repair, plastic surgery, and better wound management.

Actin-ring segment switching drives nonadhesive gap closure.

Gap closure to eliminate physical discontinuities and restore tissue integrity is a fundamental process in normal development and repair of damaged tissues and organs. Here, we demonstrate a nonadhesive gap closure model in which collective cell migration, large-scale actin-network fusion, and purse-string contraction orchestrate to restore the gap. Proliferative pressure drives migrating cells to attach onto the gap front at which a pluricellular actin ring is already assembled. An actin-ring segment switching process then occurs by fusion of actin fibers from the newly attached cells into the actin cable and defusion from the previously lined cells, thereby narrowing the gap. Such actin-cable segment switching occurs favorably at high curvature edges of the gap, yielding size-dependent gap closure. Cellular force microscopies evidence that a persistent rise in the radial component of inward traction force signifies successful actin-cable segment switching. A kinetic model that integrates cell proliferation, actin fiber fusion, and purse-string contraction is formulated to quantitatively account for the gap-closure dynamics. Our data reveal a previously unexplored mechanism in which cells exploit multifaceted strategies in a highly cooperative manner to close nonadhesive gaps.

Mechano-Based Transductive Sensing for Wearable Healthcare.

Wearable healthcare presents exciting opportunities for continuous, real-time, and noninvasive monitoring of health status. Even though electrochemical and optical sensing have already made great advances, there is still an urgent demand for alternative signal transformation in terms of miniaturization, wearability, conformability, and stretchability. Mechano-based transductive sensing, referred to the efficient transformation of biosignals into measureable mechanical signals, is claimed to exhibit the aforementioned desirable properties, and ultrasensitivity. In this Concept, a focus on pressure, strain, deflection, and swelling transductive principles based on micro-/nanostructures for wearable healthcare is presented. Special attention is paid to biophysical sensors based on pressure/strain, and biochemical sensors based on microfluidic pressure, microcantilever, and photonic crystals. There are still many challenges to be confronted in terms of sample collection, miniaturization, and wireless data readout. With continuing efforts toward solving those problems, it is anticipated that mechano-based transduction will provide an accessible route for multimode wearable healthcare systems integrated with physical, electrophysiological, and biochemical sensors.

Synergistic Lysosomal Activatable Polymeric Nanoprobe Encapsulating pH Sensitive Imidazole Derivative for Tumor Diagnosis.

Developing optical tumor imaging probes with minimal background noise is very important for its early detection of small lesions and accurate diagnosis of cancer. To overcome the bottleneck of low signal to noise ratio and sensitivity, it needs further improvement in fluorescent probe design and understanding of tumor development process. Recent reports reveal that lysosome's acidity in cancer cells can be below 4.5 with high Na+ /H+ exchange activity, which makes it an ideal target intracellular organelle for cancer diagnosis based on the variation of pH. Herein, a boron 2-(2'-pyridyl) imidazole complex derivative (BOPIM-N) is developed, with the ability to show a pH-activatable "OFF-ON" fluorescent switch by inhibiting twisted intramolecular charge transfer upon protonation at pH 3.8-4.5, which is studied for its selective viable cancer cell imaging ability in both in vitro and in vivo experiments. Interestingly, BOPIM-N can specifically emit green fluorescence in lysosomes of cancer cells, indicating its promising cancer cell specific imaging ability. More importantly, nanoformulated BOPIM-N probes can be specifically light-ON in tumor bearing site of nude mice with resolution up to cellular level, indicating its potential application in tumor diagnosis and precision medicine.

Nanoparticles strengthen intracellular tension and retard cellular migration.

Nanoparticles can have profound effects on cell biology. Here, we show that after TiO2, SiO2, and hydroxyapatite nanoparticles treatment, TR146 epithelial cell sheet displayed slower migration. Cells after exposure to the nanoparticles showed increased cell contractility with significantly impaired wound healing capability however without any apparent cytotoxicity. We showed the mechanism is through nanoparticle-mediated massive disruption of the intracellular microtubule assembly, thereby triggering a positive feedback that promoted stronger substrate adhesions thus leading to limited cell motility.

An Antidehydration Hydrogel Based on Zwitterionic Oligomers for Bioelectronic Interfacing.

Hydrogels are ideal interfacing materials for on-skin healthcare devices, yet their susceptibility to dehydration hinders their practical use. While incorporating hygroscopic metal salts can prevent dehydration and maintain ionic conductivity, concerns arise regarding metal toxicity due to the passage of small ions through the skin barrier. Herein, an antidehydration hydrogel enabled by the incorporation of zwitterionic oligomers into its network is reported. This hydrogel exhibits exceptional water retention properties, maintaining ≈88% of its weight at 40% relative humidity, 25 °C for 50 days and about 84% after being heated at 50 °C for 3 h. Crucially, the molecular weight design of the embedded oligomers prevents their penetration into the epidermis, as evidenced by experimental and molecular simulation results. The hydrogel allows stable signal acquisition in electrophysiological monitoring of humans and plants under low-humidity conditions. This research provides a promising strategy for the development of epidermis-safe and biocompatible antidehydration hydrogel interfaces for on-skin devices.

Gold nanotip array for ultrasensitive electrochemical sensing and spectroscopic monitoring.

A gold nanotip array platform with a combination of ultrasensitive electrochemical sensing and spectroscopic monitoring capability is reported. Adenosine triphosphate is detected down to 1 pM according to the impedance changes in response to aptamer-specific binding. Furthermore, the local molecular information can be monitored at the individual plasmonic nanotips, and hence provide the capability for a better understanding of complex biological processes.

Boosting the Piezoelectric Sensitivity of Amino Acid Crystals by Mechanical Annealing for the Engineering of Fully Degradable Force Sensors.

Biodegradable piezoelectric force sensors can be used as implantable medical devices for monitoring physiological pressures of impaired organs or providing essential stimuli for drug delivery and tissue regeneration without the need of additional invasive removal surgery or battery power. However, traditional piezoelectric materials, such as inorganic ceramics and organic polymers, show unsatisfactory degradability, and cytotoxicity. Amino acid crystals are biocompatible and exhibit outstanding piezoelectric properties, but their small crystal size makes it difficult to align the crystals for practical applications. Here, a mechanical-annealing strategy is reported for engineering all-organic biodegradable piezoelectric force sensors using natural amino acid crystals as piezoelectric materials. It is shown that the piezoelectric constant of the mechanical-annealed crystals can reach 12 times that of the single crystal powders. Moreover, mechanical annealing results in flat and smooth surfaces, thus improving the contact of the crystal films with the electrodes and leading to high output voltages of the devices. The packaged force sensors can be used to monitor dynamic motions, including muscle contraction and lung respiration, in vivo for 4 weeks and then gradually degrade without causing obvious inflammation or systemic toxicity. This work provides a way to engineer all-organic and biodegradable force sensors for potential clinical applications.

Contact Lens Sensor with Anti-jamming Capability and High Sensitivity for Intraocular Pressure Monitoring.

Contact lens sensors provide a noninvasive approach for intraocular pressure (IOP) monitoring in patients with glaucoma. Accurate measurement of this imperceptible pressure variation requires highly sensitive sensors in the absence of simultaneously amplifying IOP signal and blinking-induced noise. However, current noise-reduction methods rely on external filter circuits, which thicken contact lenses and reduce signal quality. Here, we introduce a contact lens strain sensor with an anti-jamming ability by utilizing a self-lubricating layer to reduce the coefficient of friction (COF) to remove the interference from the tangential force. The sensor achieves exceptionally high sensitivity due to the strain concentration layout and the confined occurrence of sympatric microcracks. The animal tests prove our lens can accurately detect IOP safely and reliably.

Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta-Defensome.

Osteoarthritis (OA) is a low-grade inflammatory and progressive joint disease, and its progression is closely associated with an imbalance in M1/M2 synovial macrophages. Repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype is emerging as a strategy to alleviate OA progression but is compromised by unsatisfactory efficiency. In this study, the reprogramming of mitochondrial dysfunction is pioneered with a camouflaged meta-Defensome, which can transform M1 synovial macrophages into the M2 phenotype with a high efficiency of 82.3%. The meta-Defensome recognizes activated macrophages via receptor-ligand interactions and accumulates in the mitochondria through electrostatic attractions. These meta-Defensomes are macrophage-membrane-coated polymeric nanoparticles decorated with dual ligands and co-loaded with S-methylisothiourea and MnO2 . Meta-Defensomes are demonstrated to successfully reprogram the mitochondrial metabolism of M1 macrophages by scavenging mitochondrial reactive oxygen species and inhibiting mitochondrial NO synthase, thereby increasing mitochondrial transcription factor A expression and restoring aerobic respiration. Furthermore, meta-Defensomes are intravenously injected into collagenase-induced osteoarthritis mice and effectively suppress synovial inflammation and progression of early OA, as evident from the Osteoarthritis Research Society International score. Therefore, reprogramming the mitochondrial metabolism can serve as a novel and practical approach to repolarize M1 synovial macrophages. The camouflaged meta-Defensomes are a promising therapeutic agent for impeding OA progression in tclinic.

Haptically Quantifying Young's Modulus of Soft Materials Using a Self-Locked Stretchable Strain Sensor.

Simple and rapid Young's modulus measurements of soft materials adaptable to various scenarios are of general significance, and they require miniaturized measurement platforms with easy operation. Despite the advances made in portable and wearable approaches, acquiring and analyzing multiple or complicated signals necessitate tethered bulky components and careful preparation. Here, a new methodology based on a self-locked stretchable strain sensor to haptically quantify Young's modulus of soft materials (kPa-MPa) rapidly is reported. The method demonstrates a fingertip measurement platform, which endows a prosthetic finger with human-comparable haptic behaviors and skills on elasticity sensing without activity constraints. A universal strategy is offered toward ultraconvenient and high-efficient Young's modulus measurements with wide adaptability to various fields for unprecedented applications.

Chemosynthesis of poly(ε-lysine)-analogous polymers by microwave-assisted click polymerization.

Poly(ε-lysine) (ε-PL)-analogous click polypeptides with not only similar α-amino side groups but also similar main chain to ε-PL were chemically synthesized for the first time through click polymerization from aspartic (or glutamic)-acid-based dialkyne and diazide monomers. With microwave-assisting, the reaction time of click polymerization was compressed into 30 min. The polymers were fully characterized by NMR, ATR-FTIR, and SEC-MALLS analysis. The deprotected click polypeptides had similar pK(a) value (7.5) and relatively low cytotoxicity as ε-PL and could be used as substitutes of ε-PL in biomedical applications, especially in endotoxin selective removal. Poly(ethylene glycol) (PEG)-containing alternating copolymers with α-amino groups were also synthesized and characterized. After deprotection, the polymers could be used as functional gene vector with PEG shadowing system and NCA initiator to get amphiphilic graft polymers.

Mechanomaterials: A Rational Deployment of Forces and Geometries in Programming Functional Materials.

The knowledge of mechanics of materials has been extensively implemented in developing functional materials, giving rise to recent advances in soft actuators, flexible electronics, mechanical metamaterials, tunable mechanochromics, regenerative mechanomedicine, etc. While conventional mechanics of materials offers passive access to mechanical properties of materials in existing forms, a paradigm shift is emerging toward proactive programming of materials' functionality by leveraging the force-geometry-property relationships. Here, such a rising field is coined as "mechanomaterials". To profile the concept, the design principles in this field at four scales is first outlined, namely the atomic scale, the molecular scale, the manipulation of nanoscale materials, and the microscale design of structural materials. A variety of techniques have been recruited to deliver the multiscale programming of functional mechanomaterials, such as strain engineering, capillary assembly, topological interlocking, kirigami, origami, to name a few. Engineering optical and biological functionalities have also been achieved by implementing the fundamentals of mechanochemistry and mechanobiology. Nonetheless, the field of mechanomaterials is still in its infancy, with many open challenges and opportunities that need to be addressed. The authors hope this review can serve as a modest spur to attract more researchers to further advance this field.

Structural Regulation of Myocytes in Engineered Healthy and Diseased Cardiac Models.

The development of cardiac models that faithfully recapitulate heart conditions is the goal of cardiac biomedical research. Among the numerous limitations of current models, replication of the cardiac microenvironment is one of the key challenges, and the effect of mechanical cues remains obscure in cardiac tissue. In this paper, different topological structures in the engineered cardiac models are summarized, and mechanical regulation of myocyte morphology and functional responses are discussed. Microenvironmental cues in vivo are influencing cardiac functions from cellular to tissue levels, and replications of these micro and macro features in the in vitro cardiac model shed light on cardiac research from a mechanistic point of view. With simple manipulation of topology, both physiological and pathological cardiac constructs can be remodeled to investigate the origin of abnormal cell phenotypes and functional responses in cardiac diseases. The integration of topological guidance with heart-on-a-chip devices is covered briefly and limitations of the current cardiac constructs are also addressed for future advancements in personalized medicine.

Artificial Sense Technology: Emulating and Extending Biological Senses.

Biological senses are critical for the survival of organisms. A great deal of attention has focused on elucidating the underlying physiological mechanisms of the senses, inspiring various sensing techniques. Despite progress in this area, gaps remain between the biological senses and conventional sensing techniques. In this Perspective, we propose the concept of artificial sense technology, which mimics the biological senses but differs in terms of objective sensing and intelligent feedback capabilities. We first summarize recent progress in the use of nanotechnologies to emulate the biological senses and then outline the advantages of artificial sense technology, which extend the capabilities of its biological counterparts. We envision artificial sense technology as a powerful perceptual interface that will play key roles in sensation substitution, digital healthcare, animal interactions, plant electronics, smart robots, and other areas that enrich the connections of the physical and virtual worlds.

Spatiotemporal Oscillation in Confined Epithelial Motion upon Fluid-to-Solid Transition.

Fluid-to-solid phase transition in multicellular assembly is crucial in many developmental biological processes, such as embryogenesis and morphogenesis. However, biomechanical studies in this area are limited, and little is known about factors governing the transition and how cell behaviors are regulated. Due to different stresses present, cells could behave distinctively depending on the nature of tissue. Here we report a fluid-to-solid transition in geometrically confined multicellular assemblies. Under circular confinement, Madin-Darby canine kidney (MDCK) monolayers undergo spatiotemporally oscillatory motions that are strongly dependent on the confinement size and distance from the periphery of the monolayers. Nanomechanical mapping reveals that epithelial tensional stress and traction forces on the substrate are both dependent on confinement size. The oscillation pattern and cellular nanomechanics profile appear well correlated with stress fiber assembly and cell polarization. These experimental observations imply that the confinement size-dependent surface tension regulates actin fiber assembly, cellular force generation, and cell polarization. Our analyses further suggest a characteristic confinement size (approximates to MDCK's natural correlation length) below which surface tension is sufficiently high and triggers a fluid-to-solid transition of the monolayers. Our findings may shed light on the geometrical and nanomechanical control of tissue morphogenesis and growth.

Devising Materials Manufacturing Toward Lab-to-Fab Translation of Flexible Electronics.

Flexible electronics have witnessed exciting progress in academia over the past decade, but most of the research outcomes have yet to be translated into products or gain much market share. For mass production and commercialization, industrial adoption of newly developed functional materials and fabrication techniques is a prerequisite. However, due to the disparate features of academic laboratories and industrial plants, translating materials and manufacturing technologies from labs to fabs is notoriously difficult. Therefore, herein, key challenges in the materials manufacturing of flexible electronics are identified and discussed for its lab-to-fab translation, along the four stages in product manufacturing: design, materials supply, processing, and integration. Perspectives on industry-oriented strategies to overcome some of these obstacles are also proposed. Priorities for action are outlined, including standardization, iteration between basic and applied research, and adoption of smart manufacturing. With concerted efforts from academia and industry, flexible electronics will bring a bigger impact to society as promised.

Artificial Sensory Memory.

Sensory memory, formed at the beginning while perceiving and interacting with the environment, is considered a primary source of intelligence. Transferring such biological concepts into electronic implementation aims at achieving perceptual intelligence, which would profoundly advance a broad spectrum of applications, such as prosthetics, robotics, and cyborg systems. Here, the recent developments in the design and fabrication of artificial sensory memory devices are summarized and their applications in recognition, manipulation, and learning are highlighted. The emergence of such devices benefits from recent progress in both bioinspired sensing and neuromorphic engineering technologies and derives from abundant inspiration and benchmarks from an improved understanding of biological sensory processing. Increasing attention to this area would offer unprecedented opportunities toward new hardware architecture of artificial intelligence, which could extend the capabilities of digital systems with emotional/psychological attributes. Pending challenges are also addressed to aspects such as integration level, energy efficiency, and functionality, which would undoubtedly shed light on the future development of translational implementations.

An artificial sensory neuron with visual-haptic fusion.

Human behaviors are extremely sophisticated, relying on the adaptive, plastic and event-driven network of sensory neurons. Such neuronal system analyzes multiple sensory cues efficiently to establish accurate depiction of the environment. Here, we develop a bimodal artificial sensory neuron to implement the sensory fusion processes. Such a bimodal artificial sensory neuron collects optic and pressure information from the photodetector and pressure sensors respectively, transmits the bimodal information through an ionic cable, and integrates them into post-synaptic currents by a synaptic transistor. The sensory neuron can be excited in multiple levels by synchronizing the two sensory cues, which enables the manipulating of skeletal myotubes and a robotic hand. Furthermore, enhanced recognition capability achieved on fused visual/haptic cues is confirmed by simulation of a multi-transparency pattern recognition task. Our biomimetic design has the potential to advance technologies in cyborg and neuromorphic systems by endowing them with supramodal perceptual capabilities.

A Compliant Ionic Adhesive Electrode with Ultralow Bioelectronic Impedance.

Simultaneous implementation of high signal-to-noise ratio (SNR) but low crosstalk is of great importance for weak surface electromyography (sEMG) signals when precisely driving a prosthesis to perform sophisticated activities. However, due to gaps with the curved skin during muscle contraction, many electrodes have poor compliance with skin and suffer from high bioelectrical impedance. This causes serious noise and error in the signals, especially the signals from low-level muscle contractions. Here, the design of a compliant electrode based on an adhesive hydrogel, alginate-polyacrylamide (Alg-PAAm) is reported, which eliminates those large gaps through the strong electrostatic interaction and abundant hydrogen bond with the skin. The obtained compliant electrode, having an ultralow bioelectrical impedance of ≈20 kΩ, can monitor even 2.1% maximal voluntary contraction (MVC) of muscle. Furthermore, benefiting from the high SNR of >5:1 at low-level MVC, the crosstalk from irrelevant muscle is minimized through reducing the electrode size. Finally, a prosthesis is successfully demonstrated to precisely grasp a needle based on a 9 mm2 Alg-PAAm compliant electrode. The strategy to design such compliant electrodes provides the potential for improving the quality of dynamically weak sEMG signals to precisely control prosthesis in performing purposefully dexterous activity.