Organ‐on‐a‐Chip Systems: Microengineering to Biomimic Living Systems

“Organ‐on‐a‐chip” systems integrate microengineering, microfluidic technologies, and biomimetic principles to create key aspects of living organs faithfully, including critical microarchitecture, spatiotemporal cell–cell interactions, and extracellular microenvironments. This creative platform and its multiorgan integration recapitulating organ‐level structures and functions can bring unprecedented benefits to a diversity of applications, such as developing human in vitro models for healthy or diseased organs, enabling the investigation of fundamental mechanisms in disease etiology and organogenesis, benefiting drug development in toxicity screening and target discovery, and potentially serving as replacements for animal testing. Recent advances in novel designs and examples for developing organ‐on‐a‐chip platforms are reviewed. The potential for using this emerging technology in understanding human physiology including mechanical, chemical, and electrical signals with precise spatiotemporal controls are discussed. The current challenges and future directions that need to be pursued for these proof‐of‐concept studies are also be highlighted.     

Scaffold‐Free Liver‐On‐A‐Chip with Multiscale Organotypic Cultures

The considerable advances that have been made in the development of organotypic cultures have failed to overcome the challenges of expressing tissue‐specific functions and complexities, especially for organs that require multitasking and complex biological processes, such as the liver. Primary liver cells are ideal biological building blocks for functional organotypic reconstruction, but are limited by their rapid loss of physiological integrity in vitro. Here the concept of lattice growth used in material science is applied to develop a tissue incubator, which provides physiological cues and controls the 3D assembly of primary cells. The cues include a biological growing template, spatial coculture, biomimetic radial flow, and circulation in a scaffold‐free condition. The feasibility of recapitulating a multiscale physiological structural hierarchy, complex drug clearance, and zonal physiology from the cell to tissue level in long‐term cultured liver‐on‐a‐chip is demonstrated. These methods are promising for future applications in pharmacodynamics and personal medicine.     

Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration

Cancer is one of the leading causes of death worldwide, despite the large efforts to improve the understanding of cancer biology and development of treatments. The attempts to improve cancer treatment are limited by the complexity of the local milieu in which cancer cells exist. The tumor microenvironment (TME) consists of a diverse population of tumor cells and stromal cells with immune constituents, microvasculature, extracellular matrix components, and gradients of oxygen, nutrients, and growth factors. The TME is not recapitulated in traditional models used in cancer investigation, limiting the translation of preliminary findings to clinical practice. Advances in 3D cell culture, tissue engineering, and microfluidics have led to the development of “cancer‐on‐a‐chip” platforms that expand the ability to model the TME in vitro and allow for high‐throughput analysis. The advances in the development of cancer‐on‐a‐chip platforms, implications for drug development, challenges to leveraging this technology for improved cancer treatment, and future integration with artificial intelligence for improved predictive drug screening models are discussed.     

Reversible Cavitation‐Induced Junctional Opening in an Artificial Endothelial Layer

Targeting pharmaceuticals through the endothelial barrier is crucial for drug delivery. In this context, cavitation‐assisted permeation shows promise for effective and reversible opening of intercellular junctions. A vessel‐on‐a‐chip is exploited to investigate and quantify the effect of ultrasound‐excited microbubbles—stable cavitation—on endothelial integrity. In the vessel‐on‐a‐chip, the endothelial cells form a complete lumen under physiological shear stress, resulting in intercellular junctions that exhibit barrier functionality. Immunofluorescence microscopy is exploited to monitor vascular integrity following vascular endothelial cadherin staining. It is shown that microbubbles amplify the ultrasound effect, leading to the formation of interendothelial gaps that cause barrier permeabilization. The total gap area significantly increases with pressure amplitude compared to the control. Gap opening is fully reversible with gap area distribution returning to the control levels 45 min after insonication. The proposed integrated platform allows for precise and repeatable in vitro measurements of cavitation‐enhanced endothelium permeability and shows potential for validating irradiation protocols for in vivo applications.     

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

Significant advances in materials, microscale technology, and stem cell biology have enabled the construction of 3D tissues and organs, which will ultimately lead to more effective diagnostics and therapy. Organoids and organs‐on‐a‐chip (OOC), evolved from developmental biology and bioengineering principles, have emerged as major technological breakthrough and distinct model systems to revolutionize biomedical research and drug discovery by recapitulating the key structural and functional complexity of human organs in vitro. There is growing interest in the development of functional biomaterials, especially hydrogels, for utilization in these promising systems to build more physiologically relevant 3D tissues with defined properties. The remarkable properties of defined hydrogels as proper extracellular matrix that can instruct cellular behaviors are presented. The recent trend where functional hydrogels are integrated into organoids and OOC systems for the construction of 3D tissue models is highlighted. Future opportunities and perspectives in the development of advanced hydrogels toward accelerating organoids and OOC research in biomedical applications are also discussed.     

Human‐on‐Leaf‐Chip: A Biomimetic Vascular System Integrated with Chamber‐Specific Organs

The vascular network is a central component of the organ‐on‐a‐chip system to build a 3D physiological microenvironment with controlled physical and biochemical variables. Inspired by ubiquitous biological systems such as leaf venation and circulatory systems, a fabrication strategy is devised to develop a biomimetic vascular system integrated with freely designed chambers, which function as niches for chamber‐specific vascularized organs. As a proof of concept, a human‐on‐leaf‐chip system with biomimetic multiscale vasculature systems connecting the self‐assembled 3D vasculatures in chambers is fabricated, mimicking the in vivo complex architectures of the human cardiovascular system connecting vascularized organs. Besides, two types of vascularized organs are built independently within the two halves of the system to verify its feasibility for conducting comparative experiments for organ‐specific metastasis studies in a single chip. Successful culturing of human hepatoma G2 cells (HepG2s) and mesenchymal stem cells (MSCs) with human umbilical vein endothelial cells (HUVECs) shows good vasculature formation, and organ‐specific metastasis is simulated through perfusion of pancreatic cancer cells and shows distinct cancer encapsulation by MSCs, which is absent in HepG2s. Given good culture efficacy, study design flexibility, and ease of modification, these results show that the bioinspired human‐on‐leaf‐chip possesses great potential in comparative and metastasis studies while retaining organ‐to‐organ crosstalk.     

Biomechanical Strain Exacerbates Inflammation on a Progeria‐on‐a‐Chip Model

Organ‐on‐a‐chip platforms seek to recapitulate the complex microenvironment of human organs using miniaturized microfluidic devices. Besides modeling healthy organs, these devices have been used to model diseases, yielding new insights into pathophysiology. Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disease showing accelerated vascular aging, leading to the death of patients due to cardiovascular diseases. HGPS targets primarily vascular cells, which reside in mechanically active tissues. Here, a progeria‐on‐a‐chip model is developed and the effects of biomechanical strain are examined in the context of vascular aging and disease. Physiological strain induces a contractile phenotype in primary smooth muscle cells (SMCs), while a pathological strain induces a hypertensive phenotype similar to that of angiotensin II treatment. Interestingly, SMCs derived from human induced pluripotent stem cells of HGPS donors (HGPS iPS‐SMCs), but not from healthy donors, show an exacerbated inflammatory response to strain. In particular, increased levels of inflammation markers as well as DNA damage are observed. Pharmacological intervention reverses the strain‐induced damage by shifting gene expression profile away from inflammation. The progeria‐on‐a‐chip is a relevant platform to study biomechanics in vascular biology, particularly in the setting of vascular disease and aging, while simultaneously facilitating the discovery of new drugs and/or therapeutic targets.     

Plasticizing Silk Protein for On‐Skin Stretchable Electrodes

Soft and stretchable electronic devices are important in wearable and implantable applications because of the high skin conformability. Due to the natural biocompatibility and biodegradability, silk protein is one of the ideal platforms for wearable electronic devices. However, the realization of skin‐conformable electronic devices based on silk has been limited by the mechanical mismatch with skin, and the difficulty in integrating stretchable electronics. Here, silk protein is used as the substrate for soft and stretchable on‐skin electronics. The original high Young's modulus (5–12 GPa) and low stretchability (<20%) are tuned into 0.1–2 MPa and > 400%, respectively. This plasticization is realized by the addition of CaCl₂ and ambient hydration, whose mechanism is further investigated by molecular dynamics simulations. Moreover, highly stretchable (>100%) electrodes are obtained by the thin‐film metallization and the formation of wrinkled structures after ambient hydration. Finally, the plasticized silk electrodes, with the high electrical performance and skin conformability, achieve on‐skin electrophysiological recording comparable to that by commercial gel electrodes. The proposed skin‐conformable electronics based on biomaterials will pave the way for the harmonized integration of electronics into human.     

A Spontaneous 3D Bone‐On‐a‐Chip for Bone Metastasis Study of Breast Cancer Cells

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone‐on‐a‐chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co‐culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone‐on‐a‐chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis.     

In vitro models to estimate drug penetration through the compromised stratum corneum barrier

Objectives: The phospholipid vesicle-based permeation assay (PVPA) is a recently established in vitro stratum corneum model to estimate the permeability of intact and healthy skin. The aim here was to further evolve this model to mimic the stratum corneum in a compromised skin barrier by reducing the barrier functions in a controlled manner. Methods: To mimic compromised skin barriers, PVPA barriers were prepared with explicitly defined reduced barrier function and compared with literature data from both human and animal skin with compromised barrier properties. Caffeine, diclofenac sodium, chloramphenicol and the hydrophilic marker calcein were tested to compare the PVPA models with established models. Results and discussions: The established PVPA models mimicking the stratum corneum in healthy skin showed good correlation with biological barriers by ranking drugs similar to those ranked by the pig ear skin model and were comparable to literature data on permeation through healthy human skin. The PVPA models provided reproducible and consistent results with a distinction between the barriers mimicking compromised and healthy skin. The trends in increasing drug permeation with an increasing degree of compromised barriers for the model drugs were similar to the literature data from other in vivo and in vitro models. Conclusions: The PVPA models have the potential to provide permeation predictions when investigating drugs or cosmeceuticals intended for various compromised skin conditions and can thus possibly reduce the time and cost of testing as well as the use of animal testing in the early development of drug candidates, drugs and cosmeceuticals.     

Tough and Water‐Insensitive Self‐Healing Elastomer for Robust Electronic Skin

An electronic (e‐) skin is expected to experience significant wear and tear over time. Therefore, self‐healing stretchable materials that are simultaneously soft and with high fracture energy, that is high tolerance of damage or small cracks without propagating, are essential requirements for the realization of robust e‐skin. However, previously reported elastomers and especially self‐healing polymers are mostly viscoelastic and lack high mechanical toughness. Here, a new class of polymeric material crosslinked through rationally designed multistrength hydrogen bonding interactions is reported. The resultant supramolecular network in polymer film realizes exceptional mechanical properties such as notch‐insensitive high stretchability (1200%), high toughness of 12 000 J m^?2, and autonomous self‐healing even in artificial sweat. The tough self‐healing materials enable the wafer‐scale fabrication of robust and stretchable self‐healing e‐skin devices, which will provide new directions for future soft robotics and skin prosthetics.     

Microfluidic Surface‐Enhanced Raman Scattering Sensors Based on Nanopillar Forests Realized by an Oxygen‐Plasma‐Stripping‐of‐Photoresist Technique

A novel surface‐enhanced Raman scattering (SERS) sensor is developed for real‐time and highly repeatable detection of trace chemical and biological indicators. The sensor consists of a polydimethylsiloxane (PDMS) microchannel cap and a nanopillar forest‐based open SERS‐active substrate. The nanopillar forests are fabricated based on a new oxygen‐plasma‐stripping‐of‐photoresist technique. The enhancement factor (EF) of the SERS‐active substrate reaches 6.06 × 10⁶, and the EF of the SERS sensor is about 4 times lower due to the influence of the PDMS cap. However, the sensor shows much higher measurement repeatability than the open substrate, and it reduces the sample preparation time from several hours to a few minutes, which makes the device more reliable and facile for trace chemical and biological analysis.     

Art‐on‐a‐Chip: Preserving Microfluidic Chips for Visualization and Permanent Display

“After a certain high level of technical skill is achieved, science and art tend to coalesce in aesthetics, plasticity, and form. The greatest scientists are always artists as well.” said Albert Einstein. Currently, photographic images bridge the gap between microfluidic/lab‐on‐a‐chip devices and art. However, the microfluidic chip itself should be a form of art. Here, novel vibrant epoxy dyes are presented in combination with a simple process to fill and preserve microfluidic chips, to produce microfluidic art or art‐on‐a‐chip. In addition, this process can be used to produce epoxy dye patterned substrates that preserve the geometry of the microfluidic channels—height within 10% of the mold master. This simple approach for preserving microfluidic chips with vibrant, colorful, and long‐lasting epoxy dyes creates microfluidic chips that can easily be visualized and photographed repeatedly, for at least 11 years, and hence enabling researchers to showcase their microfluidic chips to potential graduate students, investors, and collaborators.     

A Bioinspired Mineral Hydrogel as a Self‐Healable,Mechanically Adaptable Ionic Skin for Highly Sensitive Pressure Sensing

In the past two decades, artificial skin‐like materials have received increasing research interests for their broad applications in artificial intelligence, wearable devices, and soft robotics. However, profound challenges remain in terms of imitating human skin because of its unique combination of mechanical and sensory properties. In this work, a bioinspired mineral hydrogel is developed to fabricate a novel type of mechanically adaptable ionic skin sensor. Due to its unique viscoelastic properties, the hydrogel‐based capacitive sensor is compliant, self‐healable, and can sense subtle pressure changes, such as a gentle finger touch, human motion, or even small water droplets. It might not only show great potential in applications such as artificial intelligence, human/machine interactions, personal healthcare, and wearable devices, but also promote the development of next‐generation mechanically adaptable intelligent skin‐like devices.     

Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor‐On‐A‐Chip

Cancer remains the leading cause of death worldwide despite the enormous efforts that are made in the development of cancer biology and anticancer therapeutic treatment. Furthermore, recent studies in oncology have focused on the complex cancer metastatic process as metastatic disease contributes to more than 90% of tumor‐related death. In the metastatic process, isolation and analysis of circulating tumor cells (CTCs) play a vital role in diagnosis and prognosis of cancer patients at an early stage. To obtain relevant information on cancer metastasis and progression from CTCs, reliable approaches are required for CTC detection and isolation. Additionally, experimental platforms mimicking the tumor microenvironment in vitro give a better understanding of the metastatic microenvironment and antimetastatic drugs' screening. With the advancement of microfabrication and rapid prototyping, microfluidic techniques are now increasingly being exploited to study cancer metastasis as they allow precise control of fluids in small volume and rapid sample processing at relatively low cost and with high sensitivity. Recent advancements in microfluidic platforms utilized in various methods for CTCs' isolation and tumor models recapitulating the metastatic microenvironment (tumor‐on‐a‐chip) are comprehensively reviewed. Future perspectives on microfluidics for cancer metastasis are proposed.     

Breathable Nanowood Biofilms as Guiding Layer for Green On‐Skin Electronics

Thin‐film electronics are urged to be directly laminated onto human skin for reliable, sensitive biosensing together with feedback transdermal therapy, their self‐power supply using the thermoelectric and moisture‐induced‐electric effects also has gained great attention (skin and on‐skin electronics (On‐skinE) themselves are energy storehouses). However, “thin‐film” On‐skinE 1) cannot install “bulky” heatsinks or sweat transport channels, but the output power of thermoelectric generator and moisture‐induced‐electric generator relies on the temperature difference (?T ) across generator and the ambient humidity (AH), respectively; 2) lack a routing and accumulation of sweat for biosensing, lack targeted delivery of drugs for precise transdermal therapy; and 3) need insulation between the heat‐generating unit and heat‐sensitive unit. Here, two breathable nanowood biofilms are demonstrated, which can help insulate between units and guide the heat and sweat to another in‐plane direction. The transparent biofilms achieve record‐high transport_///transport_⊥ (//: along cellulose nanofiber alignment direction, ⊥: perpendicular direction) of heat (925%) and sweat (338%), winning applications emphasizing on ?T/AH‐dependent output power and “reliable” biosensing. The porous biofilms are competent in applications where “sensitive” biosensing (transporting_// sweat up to 11.25 mm s^?1 at the 1st second), “insulating” between units, and “targeted” delivery of saline‐soluble drugs are of uppermost priority.     

Biotinylated Photopolymers for 3D‐Printed Unibody Lab‐on‐a‐Chip Optical Platforms

The present work reports the first demonstration of straightforward fabrication of monolithic unibody lab‐on‐a‐chip (ULOCs) integrating bioactive micrometric 3D scaffolds by means of multimaterial stereolithography (SL). To this end, a novel biotin‐conjugated photopolymer is successfully synthesized and optimally formulated to achieve high‐performance SL‐printing resolution, as demonstrated by the SL‐fabrication of biotinylated structures smaller than 100 µm. By optimizing a multimaterial single‐run SL‐based 3D‐printing process, such biotinylated microstructures are incorporated within perfusion microchambers whose excellent optical transparency enables real‐time optical microscopy analyses. Standard biotin‐binding assays confirm the existence of biotin‐heads on the surfaces of the embedded 3D microstructures and allow to demonstrate that the biofunctionality of biotin is not altered during the SL‐printing, thus making it exploitable for further conjugation with other biomolecules. As a step forward, an in‐line optical detection system is designed, prototyped via SL‐printing and serially connected to the perfusion microchambers through customized world‐to‐chip connectors. Such detection system is successfully employed to optically analyze the solution flowing out of the microchambers, thus enabling indirect quantification of the concentration of target interacting biomolecules. The successful application of this novel biofunctional photopolymer as SL‐material enables to greatly extend the versatility of SL to directly fabricate ULOCs with intrinsic biofunctionality.     

Stable High‐Index Faceted Pt Skin on Zigzag‐Like PtFe Nanowires Enhances Oxygen Reduction Catalysis

Selectively exposing active surfaces and judiciously tuning the near‐surface composition of electrode materials represent two prominent means of promoting electrocatalytic performance. Here, a new class of Pt₃Fe zigzag‐like nanowires (Pt‐skin Pt₃Fe z‐NWs) with stable high‐index facets (HIFs) and nanosegregated Pt‐skin structure is reported, which are capable of substantially boosting electrocatalysis in fuel cells. These unique structural features endow the Pt‐skin Pt₃Fe z‐NWs with a mass activity of 2.11 A mg^?1 and a specifc activity of 4.34 mA cm^?2 for the oxygen reduction reaction (ORR) at 0.9 V versus reversible hydrogen electrode, which are the highest in all reported PtFe‐based ORR catalysts. Density function theory calculations reveal a combination of exposed HIFs and formation of Pt‐skin structure, leading to an optimal oxygen adsorption energy due to the ligand and strain effects, which is responsible for the much enhanced ORR activities. In contrast to previously reported HIFs‐based catalysts, the Pt‐skin Pt₃Fe z‐NWs maintain ultrahigh durability with little activity decay and negligible structure transformation after 50 000 potential cycles. Overcoming a key technical barrier in electrocatalysis, this work successfully extends the nanosegregated Pt‐skin structure to nanocatalysts with HIFs, heralding the exciting prospects of high‐effcient Pt‐based catalysts in fuel cells.     

Addressable Microfluidic Polymer Chip for DNA‐Directed Immobilization of Oligonucleotide‐Tagged Compounds

A microfluidic polymer chip for the self‐assembly of DNA conjugates through DNA‐directed immobilization is developed. The chip is fabricated from two parts, one of which contains a microfluidic channel produced from poly(dimethylsiloxane) (PDMS) by replica‐casting technique using a mold prepared by photolithographic techniques. The microfluidic part is sealed by covalent bonding with a chemically activated glass slide containing a DNA oligonucleotide microarray. The dimension of the PDMS–glass microfluidic chip is equivalent to standard microscope slides (76 × 26 mm²). The DNA microarray surface inside the microfluidic channels is configured through conventional spotting, and the resulting DNA patches can be conveniently addressed with compounds containing complementary DNA tags. To demonstrate the utility of the addressable surface within the microfluidic channel, DNA‐directed immobilization (DDI) of DNA‐modified gold nanoparticles (AuNPs) and DNA‐conjugates of the enzymes glucose oxidase (GOx) and horseradish peroxidase (HRP) are carried out. DDI of AuNPs is used to demonstrate site selectivity and reversibility of the surface‐modification process. In the case of the DNA–enzyme conjugates, the patterned assembly of the two enzymes allows the establishment and investigation of the coupled reaction of GOx and HRP, with particular emphasis on surface coverage and lateral flow rates. The results demonstrate that this addressable chip is well suited for the generation of fluidically coupled multi‐enzyme microreactors.