Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for ...brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.
Hydrogels have been applied to improve stem cell therapy and drug delivery, but current hydrogel‐based delivery methods are inefficient in clinical settings due to difficulty in handling and ...treatment processes, and low off‐the‐shelf availability. To overcome these limitations, an adhesive hyaluronic acid (HA) hydrogel patch is developed that acts as a ready‐to‐use tissue tape for therapeutic application. The HA hydrogel patches functionalized with phenolic moieties (e.g., catechol, pyrogallol) exhibit stronger tissue adhesiveness, greater elastic modulus, and increased off‐the‐shelf availability, compared with their bulk solution gel form. With this strategy, stem cells are efficiently engrafted onto beating ischemic hearts without injection, resulting in enhanced angiogenesis in ischemic regions and improving cardiac functions. HA hydrogel patches facilitate the in vivo engraftment of stem cell–derived organoids. The off‐the‐shelf availability of the hydrogel patch is also demonstrated as a drug‐loaded ready‐made tissue tape for topical drug delivery to promote wound healing. Importantly, the applicability of the cross‐linker‐free HA patch is validated for therapeutic cell and drug delivery. The study suggests that bioinspired phenolic adhesive hydrogel patches can provide an innovative method for simple but highly effective cell and drug delivery, increasing the off‐the‐shelf availability—a critically important component for translation to clinical settings.
Tissue tape hyaluronic acid (HA) hydrogel patches with catechol or pyrogallol modification exhibit significantly improved physical, mechanical, and adhesive properties over the HA solution hydrogel form. The phenolic HA hydrogel patches are ready‐to‐use for stem cell therapy and therapeutic drug delivery, increasing off‐the‐shelf availability and enabling successful therapeutic applications even without cross‐linking agents.
Matrigel, a mouse tumor extracellular matrix protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and ...regenerative medicine due to its tumor-derived origin, batch-to-batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal tissue-derived extracellular matrix hydrogels are suitable substitutes for Matrigel in gastrointestinal organoid culture. We found that the development and function of gastric or intestinal organoids grown in tissue extracellular matrix hydrogels are comparable or often superior to those in Matrigel. In addition, gastrointestinal extracellular matrix hydrogels enabled long-term subculture and transplantation of organoids by providing gastrointestinal tissue-mimetic microenvironments. Tissue-specific and age-related extracellular matrix profiles that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that extracellular matrix hydrogels derived from decellularized gastrointestinal tissues are effective alternatives to the current gold standard, Matrigel, and produce organoids suitable for gastrointestinal disease modeling, drug development, and tissue regeneration.
Induced hepatic (iHep) cells generated by direct reprogramming have been proposed as cell sources for drug screening and regenerative medicine. However, the practical use of a 3D hepatic tissue ...culture comprised of iHep cells for drug screening and toxicology testing has not been demonstrated. In this study, a 3D vascularized liver organoid composed of iHep cells and a decellularized liver extracellular matrix (LEM) cultured in a microfluidic system is demonstrated. iHep cells are generated by transfection with polymer nanoparticles and plasmids expressing hepatic transcription factors. The iHep cells are cocultured with endothelial cells in the 3D LEM hydrogel in a microfluidic‐based cell culture device with a continuous dynamic flow of media. The resultant 3D vascularized liver organoids maintained under this physiologically relevant culture microenvironment exhibit improved hepatic functionalities, metabolic activity, biosynthetic activity, and drug responses. Finally, the feasibility of using the iHep‐based 3D liver organoid as a high‐throughput drug screening platform, as well as its use in a multiorgan model comprised of multiple internal organoids is confirmed. The study suggests that a combined strategy of direct reprogramming, matrix engineering, and microfluidics can be used to develop a highly functional, standardized, drug screening, and toxicological analysis platform.
A combined strategy of direct reprogramming, matrix engineering, and microfluidics is used to generate 3D vascularized liver organoids for a drug screening platform. Under the continuous flow of media, the 3D vascularized liver organoids show improved hepatic functionalities and drug responses. The feasibility for a high‐throughput drug screening and an integrated drug testing comprised of multiple organoids is also demonstrated.
Exploitation of unique biochemical and biophysical properties of marine organisms has led to the development of functional biomaterials for various biomedical applications. Recently, ascidians have ...received great attention, owing to their extraordinary properties such as strong underwater adhesion and rapid self‐regeneration. Specific polypeptides containing 3,4,5‐trihydroxyphenylalanine (TOPA) in the blood cells of ascidians are associated with such intrinsic properties generated through complex oxidative processes. In this study, a bioinspired hydrogel platform is developed, demonstrating versatile applicability for tissue engineering and drug delivery, by conjugating pyrogallol (PG) moiety resembling ascidian TOPA to hyaluronic acid (HA). The HA–PG conjugate can be rapidly crosslinked by dual modes of oxidative mechanisms using an oxidant or pH control, resulting in hydrogels with different mechanical and physical characteristics. The versatile utility of HA–PG hydrogels formed via different crosslinking mechanisms is tested for different biomedical platforms, including microparticles for sustained drug delivery and tissue adhesive for noninvasive cell transplantation. With extraordinarily fast and different routes of PG oxidation, ascidian‐inspired HA–PG hydrogel system may provide a promising biomaterial platform for a wide range of biomedical applications.
Ascidian‐inspired, fast‐forming hyaluronic acid (HA) hydrogel systems are developed for versatile biomedical applications by dual modes of pyrogallol (PG)‐based oxidative crosslinking chemistry. HA–PG hydrogels prepared by oxidant or pH control exhibit different physical, mechanical, and degradation properties, allowing differential applications, i.e., either microparticles or tissue adhesives. Each HA–PG format is successfully tested for growth factor delivery for therapeutic angiogenesis and noninvasive cell therapy, respectively.
The recent emergence of organoid technology has attracted great attention in gastroenterology because the gastrointestinal (GI) tract can be recapitulated in vitro using organoids, enabling disease ...modeling and mechanistic studies. However, to more precisely emulate the GI microenvironment in vivo, several neighboring cell types and types of microbiota need to be integrated into GI organoids. This article reviews the recent progress made in elucidating the crosstalk between GI organoids and components of their microenvironment. We outline the effects of stromal cells (such as fibroblasts, neural cells, immune cells, and vascular cells) on the gastric and intestinal epithelia of organoids. Because of the important roles that microbiota play in the physiology and function of the GI tract, we also highlight interactions between organoids and commensal, symbiotic, and pathogenic microorganisms and viruses. GI organoid models that contain niche components will provide new insight into gastroenterological pathophysiology and disease mechanisms.
Abstract
Oral disease is one of the most common conditions worldwide, negatively affecting general health, reducing the quality of life, and often developing into systemic illness. However, the ...design of therapeutic agents for oral diseases is challenging due to various unique features of the oral cavity, including its wet and dynamic environment and curved shape. Herein, the development of highly biocompatible mucoadhesive functional hydrogels for oral applications is reported, generated by introducing bio‐inspired phenolic moieties into a pectin polymer. Pyrogallol‐functionalized pectin (Pec‐PG) can be crosslinked in situ via autoxidation without chemical agents and readily fabricated as various formulations. Sprayable Pec‐PG hydrogel exhibits strong mucoadhesion and outstanding hydration ability ex vivo and in vivo, thus displaying significant potential as a novel saliva substitute for dry mouth. The authors further show that topical application of mucoadhesive Pec‐PG patches pre‐loaded with corticosteroid significantly promotes the repair of diabetic oral ulcer tissue via prolonged drug release, free radical scavenging, and physical barrier effects. Moreover, similar applications for oral ulcer treatment using a pectin hydrogel modified with catechol (Pec‐CA), another phenolic moiety are demonstrated. Together, these findings suggest that mucoadhesive phenolic pectin derivatives can provide highly biocompatible, convenient, and effective hydrogel platforms for treating oral diseases.
Exoskeletons of insects formed by sclerotization processes exhibit superstrong properties in moduli. Here, it is demonstrated that mimicking the sclerotization process using phenol and polyamine ...molecules unexpectedly results in a 100% ecofriendly, biocompatible waterborne superglue. Oxygen presented in air and dissolved in water acts as an initiator producing phenolic radical/quinone for superglue curing. Despite synthesis‐free uses of water, phenol, and polyamine, its adhesion strength is comparable to commercial epoxy glue showing >6 MPa in lap shear strength. The phenol‐amine superglue bonds to various substrates including ceramics, woods, fabrics, plastics, metals, and importantly biological tissues. Due to strong adhesion, the superglue effectively seals wounds within a few seconds, and, due to its waterborne nature, no harmful respiratory effect is observed because of any release of volatile organic compounds. The easy, cost‐effective preparation of the phenol‐amine superglue can revolutionize varieties of industrial, biomedical, daily life processes.
A phenol/polyamine superglue (PPS) inspired by insect‐cuticle‐inspired chemistry is reported. PPS is 100% waterborne superglue with unprecedented strong adhesion (≈6 MPa) comparable to industrial epoxy glues. The key chemistry in PPS is silica‐agglomerate‐mediated phenolic oxidation and entanglement network formations. Besides the adhesion, PPS exhibits superior biocompatibility without emitting volatile organic compounds.
Although power conversion efficiency (PCE) of state‐of‐the‐art perovskite solar cells has already exceeded 20%, photo‐ and/or moisture instability of organolead halide perovskite have prevented ...further commercialization. In particular, the underlying weak interaction of organic cations with surrounding iodides due to eight equivalent orientations of the organic cation along the body diagonals in unit cell and chemically non‐inertness of organic cation result in photo‐ and moisture instability of organometal halide perovskite. Here, a perovskite light absorber incorporating organic–inorganic hybrid cation in the A‐site of 3D APbI3 structure with enhanced photo‐ and moisture stability is reported. A partial substitution of Cs+ for HC(NH2)2+ in HC(NH2)2PbI3 perovskite is found to substantially improve photo‐ and moisture stability along with photovoltaic performance. When 10% of HC(NH2)2+ is replaced by Cs+, photo‐ and moisture stability of perovskite film are significantly improved, which is attributed to the enhanced interaction between HC(NH2)2+ and iodide due to contraction of cubo‐octahedral volume. Moreover, trap density is reduced by one order of magnitude upon incorporation of Cs+, which is responsible for the increased open‐circuit voltage and fill factor, eventually leading to enhancement of average PCE from 14.9% to 16.5%.
FA0.9Cs0.1PbI3 with improved moisture‐ and photostability is developed. Incorporation of 10% of Cs cation in the FA cation sites improves photovoltaic performance as well as photo‐ and moisture stability. Property–structure correlation plays important role in improving the stability of perovskite solar cells.
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