Tissue bioprinting for biology and medicine.

Bioprinting merges additive manufacturing and tissue engineering to generate functional tissues and organs. The field has experienced tremendous growth over the past few years. Here, we highlight recent breakthroughs in bioprinting and discuss the challenges that are yet to be addressed before this technology can be widely utilized in biology and medicine.

Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury.

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.

Engineered Hemostatic Biomaterials for Sealing Wounds.

Hemostatic biomaterials show great promise in wound control for the treatment of uncontrolled bleeding associated with damaged tissues, traumatic wounds, and surgical incisions. A surge of interest has been directed at boosting hemostatic properties of bioactive materials via mechanisms triggering the coagulation cascade. A wide variety of biocompatible and biodegradable materials has been applied to the design of hemostatic platforms for rapid blood coagulation. Recent trends in the design of hemostatic agents emphasize chemical conjugation of charged moieties to biomacromolecules, physical incorporation of blood-coagulating agents in biomaterials systems, and superabsorbing materials in either dry (foams) or wet (hydrogel) states. In addition, tough bioadhesives are emerging for efficient and physical sealing of incisions. In this Review, we highlight the biomacromolecular design approaches adopted to develop hemostatic bioactive materials. We discuss the mechanistic pathways of hemostasis along with the current standard experimental procedures for characterization of the hemostasis efficacy. Finally, we discuss the potential for clinical translation of hemostatic technologies, future trends, and research opportunities for the development of next-generation surgical materials with hemostatic properties for wound management.

Deep Eutectic Solvents-based Ionogels with Ultrafast Gelation and High Adhesion in Harsh Environments.

Adhesive materials have recently drawn intensive attention due to their excellent sealing ability, thereby stimulating advances in materials science and industrial usage. However, reported adhesives usually exhibit weak adhesion strength, require high pressure for strong bonding, and display severe adhesion deterioration in various harsh environments. In this work, instead of water or organic solvents, a deep eutectic solution (DES) was used as the medium for photopolymerization of zwitterionic and polarized monomers, thus generating a novel ionogel with tunable mechanical properties. Multiple hydrogen bonds and electrostatic interactions between DES and monomers facilitated ultrafast gelation and instant bonding without any external pressure, which was rarely reported previously. Furthermore, high adhesion in different harsh environments (e.g., water, acidic and basic buffers, and saline solutions) and onto hydrophilic (e.g., glass and tissues) and hydrophobic (e.g., polymethyl methacrylate, polystyrene, and polypropylene) adherends was demonstrated. Also, high stretchability of the ionogel at extreme temperatures (-80 and 80 °C) indicated its widespread applications. Furthermore, the biocompatible ionogel showed high burst pressure onto stomach and intestine tissues to prevent liquid leakage, highlighting its potential as an adhesive patch. This ionogel provides unprecedented opportunities in the fields of packaging industry, marine engineering, medical adhesives, and electronic assembly.

Nanofiber Aerogels with Precision Macrochannels and LL-37-Mimic Peptides Synergistically Promote Diabetic Wound Healing.

Fast healing of diabetic wounds remains a major clinical challenge. Herein, this work reports a strategy to combine nanofiber aerogels containing precision macrochannels and the LL-37-mimic peptide W379 for rapid diabetic wound healing. Nanofiber aerogels consisting of poly(glycolide-co-lactide) (PGLA 90:10)/gelatin and poly-p-dioxanone (PDO)/gelatin short electrospun fiber segments were prepared by partially anisotropic freeze-drying, crosslinking, and sacrificial templating with three-dimensional (3D)-printed meshes, exhibiting nanofibrous architecture and precision micro-/macrochannels. Like human cathelicidin LL-37, W379 peptide at a concentration of 3 µg/mL enhanced the migration and proliferation of keratinocytes and dermal fibroblasts in a cell scratch assay and a proliferation assay. In vivo studies show that nanofiber aerogels with precision macrochannels can greatly promote cell penetration compared to aerogels without macrochannels. Relative to control and aerogels with and without macrochannels, adding W379 peptides to aerogels with precision macrochannels shows the best efficacy in healing diabetic wounds in mice in terms of cell infiltration, neovascularization, and re-epithelialization. The fast re-epithelization could be due to upregulation of phospho-extracellular signal-regulated kinase (p38 MAPK) after treatment with W379. Together, the approach developed in this work could be promising for the treatment of diabetic wounds and other chronic wounds.

Injectable Shear-Thinning Hydrogels with Sclerosing and Matrix Metalloproteinase Modulatory Properties for the Treatment of Vascular Malformations.

Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporated doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX was expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results showed that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX were injectable and had a 2-fold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels showed sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells showed MMP inhibition (ca. an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occluded a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.

A Microfluidic Contact Lens to Address Contact Lens-Induced Dry Eye.

The contact lens (CL) industry has made great strides in improving CL-wearing experiences. However, a large amount of CL wearers continue to experience ocular dryness, known as contact lens-induced dry eye (CLIDE), stemming from the reduction in tear volume, tear film instability, increased tear osmolarity followed by inflammation and resulting in ocular discomfort and visual disturbances. In this article, to address tear film thinning between the CL and the ocular surface, the concept of using a CL with microchannels to deliver the tears from the pre-lens tear film (PrLTF) to the post-lens ocular surface using in vitro eye-blink motion is investigated. This study reports an eye-blink mimicking system with microfluidic poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogel with integrated microchannels to demonstrate eye-blink assisted flow through microchannels. This in vitro experimental study provides a proof-of-concept result that tear transport from PrLTF to post-lens tear film can be enhanced by an artificial eyelid motion in a pressure range of 0.1-5 kPa (similar to human eyelid pressure) through poly(HEMA) microchannels. Simulation is conducted to support the hypothesis. This work demonstrates the feasibility of developing microfluidic CLs with the potential to help prevent or minimize CLIDE and discomfort by the enhanced transport of pre-lens tears to the post-lens ocular surface.

Rapid integration of screen-printed electrodes into thermoplastic organ-on-a-chip devices for real-time monitoring of trans-endothelial electrical resistance.

Trans-endothelial electrical resistance (TEER) is one of the most widely used indicators to quantify the barrier integrity of endothelial layers. Over the last decade, the integration of TEER sensors into organ-on-a-chip (OOC) platforms has gained increasing interest for its efficient and effective measurement of TEER in OOCs. To date, microfabricated electrodes or direct insertion of wires has been used to integrate TEER sensors into OOCs, with each method having advantages and disadvantages. In this study, we developed a TEER-SPE chip consisting of carbon-based screen-printed electrodes (SPEs) embedded in a poly(methyl methacrylate) (PMMA)-based multi-layered microfluidic device with a porous poly(ethylene terephthalate) membrane in-between. As proof of concept, we demonstrated the successful cultures of hCMEC/D3 cells and the formation of confluent monolayers in the TEER-SPE chip and obtained TEER measurements for 4 days. Additionally, the TEER-SPE chip could detect changes in the barrier integrity due to shear stress or an inflammatory cytokine (i.e., tumor necrosis factor-α). The novel approach enables a low-cost and facile fabrication of carbon-based SPEs on PMMA substrates and the subsequent assembly of PMMA layers for rapid prototyping. Being cost-effective and cleanroom-free, our method lowers the existing logistical and technical barriers presenting itself as another step forward to the broader adoption of OOCs with TEER measurement capability.

Bio-macromolecular design roadmap towards tough bioadhesives.

Emerging sutureless wound-closure techniques have led to paradigm shifts in wound management. State-of-the-art biomaterials offer biocompatible and biodegradable platforms enabling high cohesion (toughness) and adhesion for rapid bleeding control as well as robust attachment of implantable devices. Tough bioadhesion stems from the synergistic contributions of cohesive and adhesive interactions. This Review provides a biomacromolecular design roadmap for the development of tough adhesive surgical sealants. We discuss a library of materials and methods to introduce toughness and adhesion to biomaterials. Intrinsically tough and elastic polymers are leveraged primarily by introducing strong but dynamic inter- and intramolecular interactions either through polymer chain design or using crosslink regulating additives. In addition, many efforts have been made to promote underwater adhesion via covalent/noncovalent bonds, or through micro/macro-interlock mechanisms at the tissue interfaces. The materials settings and functional additives for this purpose and the related characterization methods are reviewed. Measurements and reporting needs for fair comparisons of different materials and their properties are discussed. Finally, future directions and further research opportunities for developing tough bioadhesive surgical sealants are highlighted.

Co-Electrospun Silk Fibroin and Gelatin Methacryloyl Sheet Seeded with Mesenchymal Stem Cells for Tendon Regeneration.

Silk fibroin (SF) is a promising biomaterial for tendon repair, but its relatively rigid mechanical properties and low cell affinity have limited its application in regenerative medicine. Meanwhile, gelatin-based polymers have advantages in cell attachment and tissue remodeling but have insufficient mechanical strength to regenerate tough tissue such as tendons. Taking these aspects into account, in this study, gelatin methacryloyl (GelMA) is combined with SF to create a mechanically strong and bioactive nanofibrous scaffold (SG). The mechanical properties of SG nanofibers can be flexibly modulated by varying the ratio of SF and GelMA. Compared to SF nanofibers, mesenchymal stem cells (MSCs) seeded on SG fibers with optimal composition (SG7) exhibit enhanced growth, proliferation, vascular endothelial growth factor production, and tenogenic gene expression behavior. Conditioned media from MSCs cultured on SG7 scaffolds can greatly promote the migration and proliferation of tenocytes. Histological analysis and tenogenesis-related immunofluorescence staining indicate SG7 scaffolds demonstrate enhanced in vivo tendon tissue regeneration compared to other groups. Therefore, rational combinations of SF and GelMA hybrid nanofibers may help to improve therapeutic outcomes and address the challenges of tissue-engineered scaffolds for tendon regeneration.

Organ-On-A-Chip Models of the Blood-Brain Barrier: Recent Advances and Future Prospects.

The human brain and central nervous system (CNS) present unique challenges in drug development for neurological diseases. One major obstacle is the blood-brain barrier (BBB), which hampers the effective delivery of therapeutic molecules into the brain while protecting it from blood-born neurotoxic substances and maintaining CNS homeostasis. For BBB research, traditional in vitro models rely upon Petri dishes or Transwell systems. However, these static models lack essential microenvironmental factors such as shear stress and proper cell-cell interactions. To this end, organ-on-a-chip (OoC) technology has emerged as a new in vitro modeling approach to better recapitulate the highly dynamic in vivo human brain microenvironment so-called the neural vascular unit (NVU). Such BBB-on-a-chip models have made substantial progress over the last decade, and concurrently there has been increasing interest in modeling various neurological diseases such as Alzheimer's disease and Parkinson's disease using OoC technology. In addition, with recent advances in other scientific technologies, several new opportunities to improve the BBB-on-a-chip platform via multidisciplinary approaches are available. In this review, an overview of the NVU and OoC technology is provided, recent progress and applications of BBB-on-a-chip for personalized medicine and drug discovery are discussed, and current challenges and future directions are delineated.

Advances and challenges in developing smart, multifunctional microneedles for biomedical applications.

Microneedles (MNs) have been developed as minimally invasive tools for diagnostic and therapeutic applications. However, in recent years, there has been an increasing interest in developing smart multifunctional MN devices to provide automated and closed-loop systems for body fluid extraction, biosensing, and drug delivery in a stimuli-responsive manner. Although this technology is still in its infancy and far from being translated into the clinic, preclinical trials have shown some promise for the broad applications of multifunctional MN devices. The main challenge facing the fabrication of smart MN patches is the integration of multiple modules, such as drug carriers, highly sensitive biosensors, and data analyzers in one miniaturized MN device. Researchers have shown the feasibility of creating smart MNs by integrating stimuli-responsive biomaterials and advanced microscale technologies, such as microsensors and microfluidic systems, to precisely control the transportation of biofluids and drugs throughout the system. These multifunctional MN devices can be envisioned in two distinct strategies. The first type includes individual drug delivery and biosensing MN units with a microfluidic system and a digital analyzer responsible for fluid transportation and communication between these two modules. The second type relies on smart biomaterials that can function as drug deliverers and biosensors by releasing drugs in a stimuli-responsive manner. These smart biomaterials can undergo structural changes when exposed to external stimuli, such as pH and ionic changes, mimicking the biological systems. Studies have demonstrated a high potential of hydrogel-based MN devices for a wide variety of biomedical applications, such as drug and cell delivery, as well as interstitial fluid extraction. Biodegradable hydrogels have also been advantageous for fabricating multifunctional MNs due to their high loading capacity and biocompatibility with the drug of choice. Here, we first review a set of MN devices that can be employed either for biosensing or delivery of multiple target molecules and compare them to the conventional and more simple systems, which are mainly designed for single-molecule sensing or delivery. Subsequently, we expand our insight into advanced MN systems with multiple competencies, such as body fluid extraction, biosensing, and drug delivery at the point of care. The improvement of biomaterials knowledge and biofabrication techniques will allow us to efficiently tune the next generation of smart MNs and provide a realistic platform for more effective personalized therapeutics.

Multifunctional Thermoresponsive Microcarriers for High-Throughput Cell Culture and Enzyme-Free Cell Harvesting.

An effective treatment of human diseases using regenerative medicine and cell therapy approaches requires a large number of cells. Cultivation of cells on microcarriers is a promising approach due to the high surface-to-volume ratios that these microcarriers offer. Here, multifunctional temperature-responsive microcarriers (cytoGel) made of an interpenetrating hydrogel network composed of poly(N-isopropylacrylamide) (PNIPAM), poly(ethylene glycol) diacrylate (PEGDA), and gelatin methacryloyl (GelMA) are developed. A flow-focusing microfluidic chip is used to produce microcarriers with diameters in the range of 100-300 µm and uniform size distribution (polydispersity index of ≈0.08). The mechanical properties and cells adhesion properties of cytoGel are adjusted by changing the composition hydrogel composition. Notably, GelMA regulates the temperature response and enhances microcarrier stiffness. Human-derived glioma cells (U87) are grown on cytoGel in static and dynamic culture conditions with cell viabilities greater than 90%. Enzyme-free cell detachment is achieved at room temperature with up to 70% detachment efficiency. Controlled release of bioactive molecules from cytoGel is accomplished for over a week to showcase the potential use of microcarriers for localized delivery of growth factors to cell surfaces. These microcarriers hold great promise for the efficient expansion of cells for the industrial-scale culture of therapeutic cells.

Bioengineered Multicellular Liver Microtissues for Modeling Advanced Hepatic Fibrosis Driven Through Non-Alcoholic Fatty Liver Disease.

Despite considerable efforts in modeling liver disease in vitro, it remains difficult to recapitulate the pathogenesis of the advanced phases of non-alcoholic fatty liver disease (NAFLD) with inflammation and fibrosis. Here, a liver-on-a-chip platform with bioengineered multicellular liver microtissues is developed, composed of four major types of liver cells (hepatocytes, endothelial cells, Kupffer cells, and stellate cells) to implement a human hepatic fibrosis model driven by NAFLD: i) lipid accumulation in hepatocytes (steatosis), ii) neovascularization by endothelial cells, iii) inflammation by activated Kupffer cells (steatohepatitis), and iv) extracellular matrix deposition by activated stellate cells (fibrosis). In this model, the presence of stellate cells in the liver-on-a-chip model with fat supplementation showed elevated inflammatory responses and fibrosis marker up-regulation. Compared to transforming growth factor-beta-induced hepatic fibrosis models, this model includes the native pathological and chronological steps of NAFLD which shows i) higher fibrotic phenotypes, ii) increased expression of fibrosis markers, and iii) efficient drug transport and metabolism. Taken together, the proposed platform will enable a better understanding of the mechanisms underlying fibrosis progression in NAFLD as well as the identification of new drugs for the different stages of NAFLD.

Cancer-on-a-Chip for Modeling Immune Checkpoint Inhibitor and Tumor Interactions.

Cancer immunotherapies, including immune checkpoint inhibitor (ICI)-based therapies, have revolutionized cancer treatment. However, patient response to ICIs is highly variable, necessitating the development of methods to quickly assess efficacy. In this study, an array of miniaturized bioreactors has been developed to model tumor-immune interactions. This immunotherapeutic high-throughput observation chamber (iHOC) is designed to test the effect of anti-PD-1 antibodies on cancer spheroid (MDA-MB-231, PD-L1+) and T cell (Jurkat) interactions. This system facilitates facile monitoring of T cell inhibition and reactivation using metrics such as tumor infiltration and interleukin-2 (IL-2) secretion. Status of the tumor-immune interactions can be easily captured within the iHOC by measuring IL-2 concentration using a micropillar array where sensitive, quantitative detection is allowed after antibody coating on the surface of array. The iHOC is a platform that can be used to model and monitor cancer-immune interactions in response to immunotherapy in a high-throughput manner.

Micro and Nanoscale Technologies for Diagnosis of Viral Infections.

Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID-19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost-effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip-based integrated platforms, and nano- and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip-based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted.

A Heart-Breast Cancer-on-a-Chip Platform for Disease Modeling and Monitoring of Cardiotoxicity Induced by Cancer Chemotherapy.

Cardiotoxicity is one of the most serious side effects of cancer chemotherapy. Current approaches to monitoring of chemotherapy-induced cardiotoxicity (CIC) as well as model systems that develop in vivo or in vitro CIC platforms fail to notice early signs of CIC. Moreover, breast cancer (BC) patients with preexisting cardiac dysfunctions may lead to different incident levels of CIC. Here, a model is presented for investigating CIC where not only induced pluripotent stem cell (iPSC)-derived cardiac tissues are interacted with BC tissues on a dual-organ platform, but electrochemical immuno-aptasensors can also monitor cell-secreted multiple biomarkers. Fibrotic stages of iPSC-derived cardiac tissues are promoted with a supplement of transforming growth factor-ß 1 to assess the differential functionality in healthy and fibrotic cardiac tissues after treatment with doxorubicin (DOX). The production trend of biomarkers evaluated by using the immuno-aptasensors well-matches the outcomes from conventional enzyme-linked immunosorbent assay, demonstrating the accuracy of the authors' sensing platform with much higher sensitivity and lower detection limits for early monitoring of CIC and BC progression. Furthermore, the versatility of this platform is demonstrated by applying a nanoparticle-based DOX-delivery system. The proposed platform would potentially help allow early detection and prediction of CIC in individual patients in the future.

Strategies for antimicrobial peptide coatings on medical devices: a review and regulatory science perspective.

Indwelling and implanted medical devices are subject to contamination by microbial pathogens during surgery, insertion or injection, and ongoing use, often resulting in severe nosocomial infections. Antimicrobial peptides (AMPs) offer a promising alternative to conventional antibiotics to reduce the incidence of such infections, as they exhibit broad-spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria, microbial biofilms, fungi, and viruses. In this review-perspective, we first provide an overview of the progress made in this field over the past decade with an emphasis on the local release of AMPs from implant surfaces and immobilization strategies for incorporating these agents into a wide range of medical device materials. We then provide a regulatory science perspective addressing the characterization and testing of AMP coatings based on the type of immobilization strategy used with a focus on the US market regulatory niche. Our goal is to help narrow the gulf between academic studies and preclinical testing, as well as to support a future literature base in order to develop the regulatory science of antimicrobial coatings.

Novel Dual-Lumen Drainage Catheter to Enhance the Active Evacuation of Complex Fluid Collections.

PURPOSE: To compare the performance of a dual-lumen flushable drainage catheter to a conventional catheter for complex fluid collection drainage. METHODS: Two prototype catheters (20- and 28-F) were created by incorporating a customized infusion lumen within the wall of a large-bore conventional drainage catheter, which facilitated simultaneous irrigation of the drainage lumen and the targeted collection via inward- and outward-facing infusion side holes. These were tested against unaltered 20- and 28-F conventional catheters to determine if the injection of a dedicated flush lumen improved rapidity and completeness of gravity drainage. In vitro models were created to simulate serous fluid, purulent/exudative fluid, particulate debris, and acute hematoma. RESULTS: In the purulent model, mean drainage rate was 19.9 ± 8.0 and 9.5±1.4 mL/min for the 20-F prototype and control (P < .001) and 63.9 ± 4.3 and 35.4 ± 3.4 mL/min for the 28-F prototype and control (P = .006), respectively, with complete drainage achieved in all trials. In the particulate model, mean drainage rate was 24.5 ± 9.7 and 12.0 ± 12.5 mL/min for the 28-F prototype and control (P = .003), respectively, with 69.0% versus 41.1% total drainage achieved over 24 minutes (P = .029). In the hematoma model, mean drainage rate was 22.7 ± 4.6 and 4.8 ± 4.3 mL/min for the 28-F prototype and control (P = .022), respectively, with 80.3% versus 20.1% drainage achieved over 15 minutes (P = .003). Particulate and hematoma 20-F prototypes and conventional trials failed due to immediate occlusion. CONCLUSIONS: The proposed dual-lumen drainage catheter with irrigation of a dedicated flush lumen improved evacuation of complex fluid collections in vitro.

A sub-1V, microwatt power-consumption iontronic pressure sensor based on organic electrochemical transistors.

Wearable and implantable pressure sensors are in great demand for personalized health monitoring. Pressure sensors with low operation voltage and low power-consumption are desired for energy-saving devices. Organic iontronic devices, such as organic electrochemical transistors (OECTs), have demonstrated great potential for low power-consumption bioelectronic sensing applications. The ability to conduct both electrons and ions, in addition to their low-operation voltage has enabled the widespread use of OECTs in different biosensing fields. However, despite these merits, OECTs have not been demonstrated for pressure sensing applications. This is because most OECTs are gated with aqueous electrolyte, which fails to respond to external pressure. Here, a low power-consumption iontronic pressure sensor is presented based on an OECT, in which an ionic hydrogel is used as a solid gating medium. The resultant iontronic device operated at voltages less than 1 V, with a power-consumption between ~ 101-103 µW, while maintaining a tunable sensitivity between 1 ~ 10 kPa-1. This work places OECTs on the frontline for developing low power-consumption iontronic pressure sensors and for biosensing applications.