Selective Cell-Cell Adhesion Regulation via Cyclic Mechanical Deformation Induced by Ultrafast Nanovibrations.

The adoption of dynamic mechanomodulation to regulate cellular behavior is an alternative to the use of chemical drugs, allowing spatiotemporal control. However, cell-selective targeting of mechanical stimuli is challenging due to the lack of strategies with which to convert macroscopic mechanical movements to different cellular responses. Here, we designed a nanoscale vibrating surface that controls cell behavior via selective repetitive cell deformation based on a poroelastic cell model. The vibrating indentations induce repetitive water redistribution in the cells with water redistribution rates faster than the vibrating rate; however, in the opposite case, cells perceive the vibrations as a one-time stimulus. The selective regulation of cell-cell adhesion through adjusting the frequency of nanovibration was demonstrated by suppression of cadherin expression in smooth muscle cells (fast water redistribution rate) with no change in vascular endothelial cells (slow water redistribution rate). This technique may provide a new strategy for cell-type-specific mechanical stimulation.

Development of Organic/Inorganic Hybrid Materials for Fully Degradable Reactive Oxygen Species-Releasing Stents for Antirestenosis.

Despite innovative advances in stent technology, restenosis remains a crucial issue for the clinical implantation of stents. Reactive oxygen species (ROS) are known to potentially accelerate re-endothelialization and lower the risk of restenosis by selectively controlling endothelial cells and smooth muscle cells. Recently, several studies have been conducted to develop biodegradable polymeric stents. As biodegradable polymers are not electrically conductive, double metallic layers are required to constitute a galvanic couple for ROS generation. Here, we report a new biodegradable hybrid material composed of a biodegradable polymer substrate and double anodic/cathodic metallic layers for enhancing re-endothelialization and suppressing restenosis. Pure Zn and Mg films (3 µm thick) were deposited onto poly-l-lactic acid (PLLA) substrates by DC magnetron sputtering, and a long-term immersion test using biodegradable hybrid materials was performed in phosphate-buffered solution (PBS) for 2 weeks. The concentrations of superoxide anions and hydrogen peroxide generated by the corrosion of biodegradable metallic films were monitored every 1 or 2 days. Both superoxide anions and hydrogen peroxide were seamlessly generated even after the complete consumption of the anodic Mg layer. It was confirmed that the superoxide anions and hydrogen peroxide were formed not only by the galvanic corrosion between the anode and cathode layers but also by the corrosion of a single Mg or Zn layer. The corrosion products of the Mg and Zn films in PBS were phosphate, oxide, or chloride of the biodegradable metals. Thus, it is concluded that ROS generation by the corrosion of PLLA-based hybrid materials can be sustained until the exhaustion of the cathode metal layer.

Delivery of nitric oxide-releasing silica nanoparticles for in vivo revascularization and functional recovery after acute peripheral nerve crush injury.

Nitric oxide (NO) has been shown to promote revascularization and nerve regeneration after peripheral nerve injury. However, in vivo application of NO remains challenging due to the lack of stable carrier materials capable of storing large amounts of NO molecules and releasing them on a clinically meaningful time scale. Recently, a silica nanoparticle system capable of reversible NO storage and release at a controlled and sustained rate was introduced. In this study, NO-releasing silica nanoparticles (NO-SNs) were delivered to the peripheral nerves in rats after acute crush injury, mixed with natural hydrogel, to ensure the effective application of NO to the lesion. Microangiography using a polymer dye and immunohistochemical staining for the detection of CD34 (a marker for revascularization) results showed that NO-releasing silica nanoparticles increased revascularization at the crush site of the sciatic nerve. The sciatic functional index revealed that there was a significant improvement in sciatic nerve function in NO-treated animals. Histological and anatomical analyses showed that the number of myelinated axons in the crushed sciatic nerve and wet muscle weight excised from NO-treated rats were increased. Moreover, muscle function recovery was improved in rats treated with NO-SNs. Taken together, our results suggest that NO delivered to the injured sciatic nerve triggers enhanced revascularization at the lesion in the early phase after crushing injury, thereby promoting axonal regeneration and improving functional recovery.

Biodegradable Metallic Glass for Stretchable Transient Electronics.

Biodegradable electronics are disposable green devices whose constituents decompose into harmless byproducts, leaving no residual waste and minimally invasive medical implants requiring no removal surgery. Stretchable and flexible form factors are essential in biointegrated electronic applications for conformal integration with soft and expandable skins, tissues, and organs. Here a fully biodegradable MgZnCa metallic glass (MG) film is proposed for intrinsically stretchable electrodes with a high yield limit exploiting the advantages of amorphous phases with no crystalline defects. The irregular dissolution behavior of this amorphous alloy regarding electrical conductivity and morphology is investigated in aqueous solutions with different ion species. The MgZnCa MG nanofilm shows high elastic strain (≈2.6% in the nano-tensile test) and offers enhanced stretchability (≈115% when combined with serpentine geometry). The fatigue resistance in repeatable stretching also improves owing to the wide range of the elastic strain limit. Electronic components including the capacitor, inductor, diode, and transistor using the MgZnCa MG electrode support its integrability to transient electronic devices. The biodegradable triboelectric nanogenerator of MgZnCa MG operates stably over 50 000 cycles and its fatigue resistant applications in mechanical energy harvesting are verified. In vitro cell toxicity and in vivo inflammation tests demonstrate the biocompatibility in biointegrated use.

Identification of urban particulate matter-induced disruption of human respiratory mucosa integrity using whole transcriptome analysis and organ-on-a chip.

BACKGROUND: Exposure to air particulate matter (PM) is associated with various diseases in the human respiratory system. To date, most in vitro studies showing cellular responses to PM have been performed in cell culture using a single cell type. There are few studies considering how multicellular networks communicate in a tissue microenvironment when responding to the presence of PM. Here, an in vitro three-dimensional (3D) respiratory mucosa-on-a-chip, composed of human nasal epithelial cells, fibroblasts, and endothelial cells, is used to recapitulate and better understand the effects of urban particulate matter (UPM) on human respiratory mucosa. RESULTS: We hypothesized that the first cells to contact with UPM, the nasal epithelial cells, would respond similar to the tissue microenvironment, and the 3D respiratory mucosa model would be a suitable platform to capture these events. First, whole transcriptome analysis revealed that UPM induced gene expression alterations in inflammatory and adhesion-related genes in human nasal epithelial cells. Next, we developed an in vitro 3D respiratory mucosa model composed of human nasal epithelial cells, fibroblasts, and endothelial cells and demonstrated that the model is structurally and functionally compatible with the respiratory mucosa. Finally, we used our model to expose human nasal epithelial cells to UPM, which led to a disruption in the integrity of the respiratory mucosa by decreasing the expression of zonula occludens-1 in both the epithelium and endothelium, while also reducing vascular endothelial cadherin expression in the endothelium. CONCLUSIONS: We demonstrate the potential of the 3D respiratory mucosa model as a valuable tool for the simultaneous evaluation of multicellular responses caused by external stimuli in the human respiratory mucosa. We believe that the evaluation strategy proposed in the study will move us toward a better understanding of the detailed molecular mechanisms associated with pathological changes in the human respiratory system.

Interface Engineering of Fully Metallic Stents Enabling Controllable H2O2 Generation for Antirestenosis.

Despite significant advances in the design of metallic materials for bare metal stents (BMSs), restenosis induced by the accumulation of smooth muscle cells (SMCs) has been a major constraint on improving the clinical efficacy of stent implantation. Here, a new strategy for avoiding this issue by utilizing hydrogen peroxide (H2O2) generated by the galvanic coupling of nitinol (NiTi) stents and biodegradable magnesium-zinc (Mg-Zn) alloys is reported. The amount of H2O2 released is carefully optimized via the biodegradability engineering of the alloys and by controlling the immersion time to selectively inhibit the proliferation and function of SMCs without harming vascular endothelial cells. Based on demonstrations of its unique capabilities, a fully metallic stent with antirestenotic functionality was successfully fabricated by depositing Mg layers onto commercialized NiTi stents. The introduction of surface engineering to yield a patterned Mg coating ensured the maintenance of a stable interface between Mg and NiTi during the process of NiTi stent expansion, showing high feasibility for clinical application. This new concept of an inert metal/degradable metal hybrid system based on galvanic metal coupling, biodegradability engineering, and surface patterning can serve as a novel way to construct functional and stable BMSs for preventing restenosis.