Absorption Of Small Molecules Research Articles

Nanoporous, Gas Permeable PEGDA Ink for 3D Printing Organ‐on‐a‐Chip Devices

AbstractPolydimethylsiloxane (PDMS), commonly used in organ‐on‐a‐chip (OoC) systems, faces limitations in replicating complex geometries, hindering its effectiveness in creating 3D OoC models. In contrast, poly(ethylene glycol)diacrylate (PEGDA‐250), favored for its fabrication ease and resistance to small molecule absorption, is increasingly used for 3D printing microfluidic devices. However, applications in cell culture have been limited due to poor cell adhesion. Here, a nanoporous PEGDA ink (P‐PEGDA) is introduced to enhance cell adhesion. P‐PEGDA is formulated with a porogen, photopolymerized, followed by the porogen removal. Utilizing P‐PEGDA, complex microstructures, and membranes as thin as 27 µm are 3D‐printed. Porogen concentrations from 10 to 30% are tested yielding constructs with increasing porosity and oxygen permeability surpassing PDMS, without compromising printing resolution. Tests across four cell lines show >80% cell viability, with a notable 77‐fold increase in MDA‐MB‐231 cell coverage on the porous scaffolds. Finally, an OoC model comprising a gyroid scaffold with a central opening filled with a cancer spheroid is introduced. This setup, after a 14 days co‐culture, demonstrates significant endothelial sprouting and integration within the spheroid. The P‐PEGDA formulation is suitable for high‐resolution 3D printing of constructs for 3D cell culture and OoC owing to its printability, gas permeability, biocompatibility, and cell adhesion.

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments.

Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000-fold between polymers with polydimethyl siloxane (PDMS) being most absorptive, whereas polytetrafluoroethylene (PTFE) and thiol-ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations, whereas isogenic cultures in PDMS devices are resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability.

Scalable Processing of Cyclic Olefin Copolymer (COC) Microfluidic Biochips.

Microfluidics evolved with the appearance of polydimethylsiloxane (PDMS), an elastomer with a short processing time and the possibility for replication on a micrometric scale. Despite the many advantages of PDMS, there are well-known drawbacks, such as the hydrophobic surface, the absorption of small molecules, the low stiffness, relatively high cost, and the difficulty of scaling up the fabrication process for industrial production, creating a need for alternative materials. One option is the use of stiffer thermoplastics, such as the cyclic olefin copolymer (COC), which can be mass produced, have lower cost and possess excellent properties. In this work, a method to fabricate COC microfluidic structures was developed. The work was divided into process optimization and evaluation of material properties for application in microfluidics. In the processing step, moulding, sealing, and liquid handling aspects were developed and optimized. The resulting COC devices were evaluated from the point of view of molecular diffusion, burst pressure, temperature resistance, and susceptibility to surface treatments and these results were compared to PDMS devices. Lastly, a target DNA hybridization assay was performed showing the potential of the COC-based microfluidic device to be used in biosensing and Lab-on-a-Chip applications.

Parylene-C Coating Protects Resin-3D-Printed Devices from Material Erosion and Prevents Cytotoxicity toward Primary Cells.

Resin 3D printing is attractive for the rapid fabrication of microscale cell culture devices, but common resin materials are unstable and cytotoxic under culture conditions. Strategies such as leaching or overcuring are insufficient to protect sensitive primary cells such as white blood cells. Here, we evaluated the effectiveness of using a parylene C coating of commercially available clear resins to prevent cytotoxic leaching, degradation of microfluidic devices, and absorption of small molecules. We found that parylene C significantly improved both the cytocompatibility with primary murine white blood cells and the material integrity of prints while maintaining the favorable optical qualities held by clear resins.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood. To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures. This framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity. Our modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Ectopic stem cell niches sustain rainbow trout (Oncorhynchus mykiss) intestine absorptive capacity when challenged with a plant protein-rich diet

To develop more sustainable feed formulations, it is important to assess in detail their effect on gut function and health. We previously described the specific organization of the epithelial and stromal components of the intestinal stem cell niche (ISCN), in rainbow trout (RT) under actual farming conditions. In the present work, we used our previous observation, for performing a comparative analysis between a control diet (CF) and an experimental vegetable-based diet (CV) under a new perspective. We correlated diet-induced changes of the morphology and the absorptive capability of the RT mucosa with modifications of the ISCN. Histological analysis confirmed that CV diet caused a mucosa remodeling, characterized by the generation of accessory branches sprouting from the middle of the proximal intestine folds, determining a significant increase of the luminal surface. The newly-formed structures showed positivity for PepT1, Sglt-1, and Fabp2 indicating their active role in small molecule absorption. However, the cells lining the base of the new branches expressed both epithelial (sox9) and stromal (pdgfrα and foxl1) stem cell markers, rather than the expected markers of fully differentiated cells. Our results suggest that a nutritional challenge results in the formation of an ectopic ISNC at the middle of the intestinal folds that sustains the formation of functional collateral branches, presumably to compensate for the reduced intestinal absorption. Overall, these data highlight, for the first time, the plasticity of the ISCN and its possible role in compensating intestinal functions in response to challenging conditions.

Nasal epithelial cell culture fluorescence recovery after photobleaching predicts cystic fibrosis therapeutic response.

Human nasal epithelial (HNE) cells can be sampled noninvasively and cultured to provide a model of the airway epithelium that reflects cystic fibrosis (CF) pathophysiology. We hypothesised that in vitro measures of HNE cell physiology would correlate directly with in vivo measures of lung physiology and therapeutic response, providing a framework for using HNE cells for therapeutic development and precision medicine. We sampled nasal cells from participants with CF (CF group, n=26), healthy controls (HC group, n=14) and single CF transmembrane conductance regulator (CFTR) mutation carrier parents of the CF group (CR group, n=16). Participants underwent lung physiology and sweat chloride testing, and nuclear imaging-based measurement of mucociliary clearance (MCC) and small-molecule absorption (ABS). CF participants completed a second imaging day that included hypertonic saline (HS) inhalation to assess therapeutic response in terms of MCC. HNE measurements included Ussing chamber electrophysiology, small-molecule and liquid absorption rates, and particle diffusion rates through the HNE airway surface liquid (ASL) measured using fluorescence recovery after photobleaching (FRAP). Long FRAP diffusion times were associated with increased MCC response to HS in CF. This implies a strong relationship between inherent factors affecting ASL mucin concentration and therapeutic response to a hydrating therapy. MCC decreased with age in the CR group, which had a larger range of ages than the other two groups. Likely this indicates a general age-related effect that may be accentuated in this group. Measures of lung ABS correlated with sweat chloride in both the HC and CF groups, indicating that CFTR function drives this measure of paracellular small-molecule probe absorption. Our results demonstrate the utility of HNE cultures for assessing therapeutic response for hydrating therapies. In vitro measurements of FRAP were particularly useful for predicting response and for characterising important properties of ASL mucus that were ultimately reflected in lung physiology.

An Overview on Nasal Drug Delivery System

Nasal drug delivery has got a great deal of attention as a convenient, reliable and potential method for the systemic administration of drugs. It is specially for those molecules which are ineffective orally and only effective if given by injection. The nasal route of drug delivery has advantages over the other alternative systems of non-invasive drug administration. Nasal route is advantageous for the drugs which are unstable on oral administration as they are much degraded in GIT or else metabolized by first pass effect in liver. Nasal route is alternative to parenteral therapy and as well helpful for long term therapy. Nasal mucosa is greatly vascularised as well as mainly permeable giving fast absorption and onset of action. Nasal route is non invasive, extensively used for the local treatment might also be used for systemic therapy as drug directly goes in systemic circulation. Nasal route gives excellent absorption of small molecules, than that of large molecules can be augmented by absorption promoters. The present review presents information pertaining to nasal drug delivery system such as advantages, limitations, anatomy of nose, mechanism of drug absorption, barriers to drug absorption, factors influencing nasal drug absorption, strategies to improve nasal absorption, excipients used in nasal formulations, nasal formulations and their evaluation.

RNA-Seq unveiled section-specific host response to lack of gut microbiota in mouse intestine

To identify host responses induced by commensal microbiota in intestine, transcriptomes of four sections of the intestine were compared between germ-free (GF) mice and conventional (CV) controls using RNA-Seq. Cuffdiff revealed that jejunum had the highest number of differentially expressed genes (over 2000) between CV and GF mice, followed by large intestine (LI), duodenum, and ileum. Gene set association analysis identified section-specific alterations in pathways associated with the absence of commensal microbiota. For example, in GF mice, cytochrome P450 (Cyp)-mediated xenobiotic metabolism was preferably down-regulated in duodenum and ileum, whereas intermediary metabolism pathways such as protein digestion and amino acid metabolism were preferably up-regulated in duodenum, jejunum, and LI. In GF mice, carboxypeptidase A1 (Cpa1), which is important for protein digestion, was the top most up-regulated gene within the entire transcriptome in duodenum (53-fold) and LI (142-fold). Conversely, fatty acid binding protein 6 (Fabp6/Ibabp), which is important for bile acid intestinal reabsorption, was the top most down-regulated gene in jejunum (358-fold), and the drug-metabolizing enzyme Cyp1a1 was the top most down-regulated gene in ileum (40-fold). Section-specific host transcriptomic response to the absence of intestinal microbiota was also observed for other important physiological pathways such as cell junction, the absorption of small molecules, bile acid homeostasis, and immune response. In conclusion, the present study has revealed section-specific host gene transcriptional alterations in GF mice, highlighting the importance of intestinal microbiota in facilitating the physiological and drug responses of the host intestine.

Brain Targeting Through Intranasal Route: An Overview

Brain targeting has always been challenging due to the presence of physiological barriers by Changing the integrity of these barriers, so as to allow the toxic substances, bacteria and viruses into the brain, Which may severely damage the central nervous system .This problem can be reduced by delivering drugs through the intra nasal route, which by passes the blood brain barrier and reaches into the brain. Nasal route is a non-invasive type, widely used for the local treatment as well as used for systemic therapy as drug delivery directly goes in to systemic circulation. Nasal route provides good absorption of small molecules compared to that of large molecules, absorption of small molecules and large molecules can be increased by absorption promoters. Different drug delivery devices are developed for nasal administration like liquids, semi-solid and solid formulation are consider to deliver the drugs to treat most of the CNS diseases (i.e. Parkinson’s, Alzheimer’s disease) because it requires specific targeting of drugs to the brain. This review highlighted the challenges, approaches for brain targeting and various drug delivery systems developed with different drugs targeting to brain through nasal administration.

Facile Patterning of Thermoplastic Elastomers and Robust Bonding to Glass and Thermoplastics for Microfluidic Cell Culture and Organ-on-Chip.

The emergence and spread of microfluidics over the last decades relied almost exclusively on the elastomer polydimethylsiloxane (PDMS). The main reason for the success of PDMS in the field of microfluidic research is its suitability for rapid prototyping and simple bonding methods. PDMS allows for precise microstructuring by replica molding and bonding to different substrates through various established strategies. However, large-scale production and commercialization efforts are hindered by the low scalability of PDMS-based chip fabrication and high material costs. Furthermore, fundamental limitations of PDMS, such as small molecule absorption and high water evaporation, have resulted in a shift toward PDMS-free systems. Thermoplastic elastomers (TPE) are a promising alternative, combining properties from both thermoplastic materials and elastomers. Here, we present a rapid and scalable fabrication method for microfluidic systems based on a polycarbonate (PC) and TPE hybrid material. Microstructured PC/TPE-hybrid modules are generated by hot embossing precise features into the TPE while simultaneously fusing the flexible TPE to a rigid thermoplastic layer through thermal fusion bonding. Compared to TPE alone, the resulting, more rigid composite material improves device handling while maintaining the key advantages of TPE. In a fast and simple process, the PC/TPE-hybrid can be bonded to several types of thermoplastics as well as glass substrates. The resulting bond strength withstands at least 7.5 bar of applied pressure, even after seven days of exposure to a high-temperature and humid environment, which makes the PC/TPE-hybrid suitable for most microfluidic applications. Furthermore, we demonstrate that the PC/TPE-hybrid features low absorption of small molecules while being biocompatible, making it a suitable material for microfluidic biotechnological applications.

Lung on a Chip Development from Off-Stoichiometry Thiol-Ene Polymer.

Current in vitro models have significant limitations for new respiratory disease research and rapid drug repurposing. Lung on a chip (LOAC) technology offers a potential solution to these problems. However, these devices typically are fabricated from polydimethylsiloxane (PDMS), which has small hydrophobic molecule absorption, which hinders the application of this technology in drug repurposing for respiratory diseases. Off-stoichiometry thiol–ene (OSTE) is a promising alternative material class to PDMS. Therefore, this study aimed to test OSTE as an alternative material for LOAC prototype development and compare it to PDMS. We tested OSTE material for light transmission, small molecule absorption, inhibition of enzymatic reactions, membrane particle, and fluorescent dye absorption. Next, we microfabricated LOAC devices from PDMS and OSTE, functionalized with human umbilical vein endothelial cell (HUVEC) and A549 cell lines, and analyzed them with immunofluorescence. We demonstrated that compared to PDMS, OSTE has similar absorption of membrane particles and effect on enzymatic reactions, significantly lower small molecule absorption, and lower light transmission. Consequently, the immunofluorescence of OSTE LOAC was significantly impaired by OSTE optical properties. In conclusion, OSTE is a promising material for LOAC, but optical issues should be addressed in future LOAC prototypes to benefit from the material properties.

Design of Porous Membranes by Liquid Gating Technology

ConspectusPorous membranes are playing paramount roles in the areas of wastewater treatment, chemical analysis, energy storage and conversion, flexible devices, and biomedical engineering. Despite their significance in the above fields, the performances of the porous membrane will be weakened due to the inevitable membrane fouling. Solid surfaces or pores of the membranes are easily contaminated or even clogged due to the absorption of small molecules or the accumulation of fine particles, which lower the flux of fluid transport over time, reduce the separation efficiency, shorten the lifetime of the membranes, and increase the operational costs. In addition, the defects in membranes also hinder their applications to some extent. The above-mentioned limitations all arise from the intrinsic properties of the solid surfaces of the membranes. To solve these challenges, liquid gating technology was proposed, which utilizes the capillary-stabilized functional liquid as a pressure-driven, reversible, and reconfigurable gate to fill and seal the pores on demand. Using liquid gating technology, multiphase transportation in the membrane can be modulated with exceptional antifouling and energy-saving manners due to the defect-free molecular-smooth liquid interface. Moreover, the further responsive interface design accelerated the development of liquid gating membranes and their practical applications to a great extent. In recent years, the concept of the liquid gating membrane has become a reality through developing various porous membranes by the rational selection and design of the two essential parts of the composite membranes: the solid porous matrix and the gating liquid. These membranes expand the basic scientific issues of the traditional membranes from the solid–liquid/gas interface to the solid–liquid–liquid/gas interface and bring more possibilities for the applications of porous membranes. With properties and advantages of antifouling, anticorrosion, enhanced transparency, energy-saving, and stability, these porous membranes have shown various applications in multiphase separation, biomedical catheters, chemical detection, mobile valves, microscale flow control, etc.In this Account, we provide a systematic review of our group’s recent progresses in the design and applications of porous membranes with liquid gating technology. First, we give a comprehensive introduction to the liquid gating technology, followed by further details on how to design porous membranes through liquid gating technology and properties and advantages of the porous membranes. Second, we discuss the applications of these porous membranes in the fields of multiphase separation, biomedical catheters, chemical detection, mobile valves, and microscale flow control. Third, we conclude the Account by describing the current challenges and future directions of the field.

Modular Microphysiological System for Modeling of Biologic Barrier Function.

Microphysiological systems, also known as organs-on-chips, are microfluidic devices designed to model human physiology in vitro. Polydimethylsiloxane (PDMS) is the most widely used material for organs-on-chips due to established microfabrication methods, and properties that make it suitable for biological applications such as low cytotoxicity, optical transparency, gas permeability. However, absorption of small molecules and leaching of uncrosslinked oligomers might hinder the adoption of PDMS-based organs-on-chips for drug discovery assays. Here, we have engineered a modular, PDMS-free microphysiological system that is capable of recapitulating biologic barrier functions commonly demonstrated in PDMS-based devices. Our microphysiological system is comprised of a microfluidic chip to house cell cultures and pneumatic microfluidic pumps to drive flow with programmable pressure and shear stress. The modular architecture and programmable pumps enabled us to model multiple in vivo microenvironments. First, we demonstrate the ability to generate cyclic strain on the culture membrane and establish a model of the alveolar air-liquid interface. Next, we utilized three-dimensional finite element analysis modeling to characterize the fluid dynamics within the device and develop a model of the pressure-driven filtration that occurs at the glomerular filtration barrier. Finally, we demonstrate that our model can be used to recapitulate sphingolipid induced kidney injury. Together, our results demonstrate that a multifunctional and modular microphysiological system can be deployed without the use of PDMS. Further, the bio-inert plastic used in our microfluidic device is amenable to various established, high-throughput manufacturing techniques, such as injection molding. As a result, the development plastic organs-on-chips provides an avenue to meet the increasing demand for organ-on-chip technology.

CARACTERIZACIÓN, DIGESTIBILIDAD Y EFECTO PREBIOTICO DEL EXTRACTO DEL FRUTO DE Stenocereus queretaroensis F.A.C. WEBER BUXBAUM

La digestibilidad es la facilidad con la que los alimentos se convierten en el sistema digestivo en sustancias útiles para la nutrición; ésta comprende la hidrólisis de moléculas complejas y la absorción de moléculas pequeñas en el intestino. La microbiota es fundamental en estos procesos y el mal funcionamiento de estos microorganismos está asociado con enfermedades metabólicas. El objetivo de este estudio fue caracterizar y evaluar la digestibilidad y el efecto prebiótico del extracto de fruto de Stenocereus queretaroensis, ya que se desconocen su valor nutricional y funcionalidad. El extracto se obtuvo del fruto a 4 °C usando un extractor de jugo; posteriormente, se filtró y liofilizó; además, se determinó su valor y calidad nutricional parcial mediante análisis fisicoquímicos y proximales. Asimismo, se establecieron técnicas para evaluar la digestibilidad oral, gástrica e intestinal y para evaluar el efecto prebiótico. El extracto mostró un color rojo (L* = 17.21 ± 0.1, a* = 38.61 ± 0.1, b* = 10.60 ± 0.2), con un pH de 3.78 ± 0.1, sin grasa cruda y 0.77 ± 0.0 % (p/p) de fibra cruda, 1.36 ± 0.0 % de proteína, 88.82 ± 0.8 % de extracto libre de nitrógeno y efecto prebiótico para Bacillus coagulans, Lactobacillus sporogenes y L. delbrueckii.

Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes

Free energy calculations are essential to unveil mechanisms at the atomic scale such as binding of small solutes and their translocation across cell membranes, eventually producing cellular absorption. Melatonin regulates biological rhythms and is directly related to carcinogenesis and neurodegenerative disorders. Free energy landscapes obtained from well-tempered metadynamics simulations precisely describe the characteristics of melatonin binding to specific sites in the membrane and reveal the role of cholesterol in free energy barrier crossing. A specific molecular torsional angle and the distance between melatonin and the center of the membrane along the normal to the membrane Z-axis have been considered as suitable reaction coordinates. Free energy barriers between two particular orientations of the molecular structure (folded and extended) have been found to be of about 18 kJ/mol for z-distances of about 1–2 nm. The ability of cholesterol to expel melatonin out of the internal regions of the membrane towards the interface and the external solvent is explained from a free energy perspective. The calculations reported here offer detailed free energy landscapes of melatonin embedded in model cell membranes and reveal microscopic information on its transition between free energy minima, including the location of relevant transition states, and provide clues on the role of cholesterol in the cellular absorption of small molecules.

Injectable Therapeutic Organoids Using Sacrificial Hydrogels

SummaryOrganoids are becoming widespread in drug-screening technologies but have been used sparingly for cell therapy as current approaches for producing self-organized cell clusters lack scalability or reproducibility in size and cellular organization. We introduce a method of using hydrogels as sacrificial scaffolds, which allow cells to form self-organized clusters followed by gentle release, resulting in highly reproducible multicellular structures on a large scale. We demonstrated this strategy for endothelial cells and mesenchymal stem cells to self-organize into blood-vessel units, which were injected into mice, and rapidly formed perfusing vasculature. Moreover, in a mouse model of peripheral artery disease, intramuscular injections of blood-vessel units resulted in rapid restoration of vascular perfusion within seven days. As cell therapy transforms into a new class of therapeutic modality, this simple method—by making use of the dynamic nature of hydrogels—could offer high yields of self-organized multicellular aggregates with reproducible sizes and cellular architectures.

Plug-and-Play In Vitro Metastasis System toward Recapitulating the Metastatic Cascade

Microfluidic-based tumor models that mimic tumor culture environment have been developed to understand the cancer metastasis mechanism and discover effective antimetastatic drugs. These models successfully recapitulated key steps of metastatic cascades, yet still limited to few metastatic steps, operation difficulty, and small molecule absorption. In this study, we developed a metastasis system made of biocompatible and drug resistance plastics to recapitulate each metastasis stage in three-dimensional (3D) mono- and co-cultures formats, enabling the investigation of the metastatic responses of cancer cells (A549-GFP). The plug-and-play feature enhances the efficiency of the experimental setup and avoids initial culture failures. The results demonstrate that cancer cells tended to proliferate and migrate with circulating flow and intravasated across the porous membrane after a period of 3 d when they were treated with transforming growth factor-beta 1 (TGF-β1) or co-cultured with human pulmonary microvascular endothelial cells (HPMECs). The cells were also observed to detach and migrate into the circulating flow after a period of 20 d, indicating that they transformed into circulating tumor cells for the next metastasis stage. We envision this metastasis system can provide novel insights that would aid in fully understanding the entire mechanism of tumor invasion.

A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia.

Cystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, these results were used to inform a quantitative systems pharmacology model of airway epithelium describing electrically and chemically driven transcellular ionic transport, contributions of both convective and diffusive paracellular solute transport, and osmotically driven transepithelial water dynamics. Model predictions showed CF cultures, relative to non-CF ones, have increased apical and basolateral water permeabilities, and increase paracellular permeability and transepithelial chemical driving force for a radiolabeled tracer used to track small molecule absorption. These results provide a computational platform to better understand and probe the mechanisms behind the liquid hyperabsorption and small molecule retention profiles observed in the CF airway.