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.
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.
Transdermal drug delivery patches based on hydrogels are widely used for the transdermal delivery of diverse drugs. However, most hydrogels do not exhibit adequate adhesiveness to skin surface. ...Herein, tissue adhesive hydrogels consisting of polyacrylamide/polydopamine (PAM/PDA) hydrogels embedded with extra‐large pore mesoporous silica nanoparticles (XL‐MSNs) are proposed based on the synergy of cohesive and adhesive properties. The incorporation of XL‐MSNs leads to enhanced strength and adhesiveness to skin tissue due to an increased cohesive property derived from molecular interactions between XL‐MSNs and polymer chains. The application of XL‐MSNs to the hydrogel–skin tissue interface leads to a further enhanced adhesiveness due to the adhesive gluing role of XL‐MSNs on the interface. The optimized condition enables a 4.9‐fold increase in adhesion energy on the porcine skin tissue, compared to the control PAM/PDA patch. Strong adhesion is achieved immediately after the hydrogel patch is attached onto the skin as well as the surfaces of other organs. Finally, transdermal drug delivery through porcine skin is demonstrated by using the hydrogel patch, with a model drug loaded in the XL‐MSNs embedded in the patch. These observations indicate a simple but highly effective strategy for preparing a highly adhesive hydrogel patch for transdermal drug delivery.
The incorporation of extra‐large pore mesoporous silica nanoparticles in adhesive polyacrylamide/polydopamine hydrogels and the additional application of the mesoporous silica nanoparticles on the hydrogel–tissue interface lead to a significant enhancement of the strength and adhesiveness of the hydrogel. The rapid adhesion and sustained drug delivery through the skin allow a highly adhesive hydrogel patch for transdermal drug delivery.
Gram-negative bacteria actively secrete outer membrane vesicles, spherical nano-meter-sized proteolipids enriched with outer membrane proteins, to the surroundings. Outer membrane vesicles have ...gained wide interests as non-living complex vaccines or delivery vehicles. However, no study has used outer membrane vesicles in treating cancer thus far. Here we investigate the potential of bacterial outer membrane vesicles as therapeutic agents to treat cancer via immunotherapy. Our results show remarkable capability of bacterial outer membrane vesicles to effectively induce long-term antitumor immune responses that can fully eradicate established tumors without notable adverse effects. Moreover, systematically administered bacterial outer membrane vesicles specifically target and accumulate in the tumor tissue, and subsequently induce the production of antitumor cytokines CXCL10 and interferon-γ. This antitumor effect is interferon-γ dependent, as interferon-γ-deficient mice could not induce such outer membrane vesicle-mediated immune response. Together, our results herein demonstrate the potential of bacterial outer membrane vesicles as effective immunotherapeutic agent that can treat various cancers without apparent adverse effects.Bacterial outer membrane vesicles (OMVs) contain immunogens but no study has yet examined their potential in treating cancer. Here, the authors demonstrate that OMVs can suppress established tumours and prevent tumour metastasis by an interferon-γ mediated antitumor response.
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.
Skeletal muscle has an inherent capacity for spontaneous regeneration. However, recovery after severe injuries such as volumetric muscle loss (VML) is limited. There is therefore a need to develop ...interventions to induce functional skeletal muscle restoration. One suggested approach includes tissue‐engineered muscle constructs. Tissue‐engineering treatments have so far been impeded by the lack of reliable cell sources and the challenges in engineering of suitable tissue scaffolds. To address these challenges, muscle extracellular matrix (MEM) and induced skeletal myogenic progenitor cells (iMPCs) are integrated within thermally drawn fiber based microchannel scaffolds. The microchannel fibers decorated with MEM enhance differentiation and maturation of iMPCs. Furthermore, engraftment of these bioengineered hybrid muscle constructs induce de novo muscle regeneration accompanied with microvessel and neuromuscular junction formation in a VML mouse model, ultimately leading to functional recovery of muscle activity.
A bioengineered skeletal muscle construct is generated by culturing induced skeletal myogenic progenitor cells in a thermally drawn polycaprolactone porous fiber scaffold modified with decellularized muscle extracellular matrix. The hybrid composite fiber shows favorable mechanical and biochemical signals for muscle reprogramming and maturation. The bioengineered muscle construct repairs volumetric muscle loss injury via de novo muscle regeneration and functional restoration.
•Carbon dose and contact time affected micropollutant adsorption to activated carbon.•Hydrophilics better fit to linear, and hydrophobics better to Freundlich isotherm.•Adsorption of hydrophilic ...micropollutant was significantly affected by pH.•DOM in surface water competed with micropollutants in the adsorption to activated carbon.•Low temperature decreased the adsorption of hydrophobic micropollutants.
In this study, we investigated adsorption characteristics of nine selected micropollutants (six pharmaceuticals, two pesticides, and one endocrine disruptor) in water using an activated carbon. The effects of carbon dosage, contact time, pH, DOM (dissolved organic matter), and temperature on the adsorption removal of micropollutants were examined. Increasing carbon dosage and contact time enhanced the removal of micropollutants. Sorption coefficients of hydrophilic compounds (caffeine, acetaminophen, sulfamethoxazole, and sulfamethazine) fit a linear isotherm and hydrophobic compounds (naproxen, diclofenac, 2, 4-D, triclocarban, and atrazine) fit a Freundlich isotherm. The removal of hydrophobic pollutants and caffeine were independent of pH changes, but acetaminophen, sulfamethazine, and sulfamethoxazole were adsorbed by mainly electrostatic interaction with activated carbon and so were affected by pH. The decrease in adsorption removal in surface water samples was observed and this decrease was more significant for hydrophobic than hydrophilic compounds. The decline in the adsorption capacity in surface water samples is caused by the competitive inhibition of DOM with micropollutants onto activated carbon. Low temperature (5°C) also decreased the adsorption removal of micropollutants, and affected hydrophobic compounds more than hydrophilic compounds. The results obtained in this study can be applied to optimize the adsorption capacities of micropollutants using activated carbon in water treatment process.
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.
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.
Batteries and supercapacitors (SC) complement one another; a battery has a relatively high energy density but a low power density, whereas an SC has a relatively high power density but a low energy ...density. In order to offset their opposing limitations, an active battery/SC hybrid energy storage system (HESS) using a dc/dc converter has been proposed. The major problem concerning an active HESS is in how to control the current flow in order to achieve two objectives: the minimization of the magnitude/fluctuation of the current flowing in and out of the battery and the energy loss seen by the SCs. This problem has not been analytically investigated for an optimal solution regarding these two goals. In this paper, we present an optimal energy management scheme for active HESS. In order to obtain the optimal solution, we formulate the problem as an optimization problem concerning these two objectives. Observing that the feasibility and optimality of the solution critically depends on the boundary parameters of the problem, we present an algorithm that effectively adjusts the parameter values. The proposed algorithm is based on the multiplicative-increase- additive-decrease principle, which guarantees a feasible optimal solution. Through MATLAB simulations, we demonstrate that the proposed scheme can optimally minimize the magnitude/fluctuation of the battery current and the SC energy loss.
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