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.

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 highthroughput 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.

Triboelectric nanogenerators (TENGs) can be an effective cell reprogramming platform for producing functional neuronal cells for therapeutic applications. Triboelectric stimulation accelerates nonviral direct conversion of functional induced neuronal cells from fibroblasts, increases the conversion efficiency, and induces highly matured neuronal phenotypes with improved electrophysiological functionalities. TENG devices may also be used for biomedical in vivo reprogramming.

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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.

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.

Naturally derived nanovesicles secreted from various cell types and found in body fluids can provide effective platforms for the delivery of various cargoes because of their intrinsic ability to be internalized for intercellular signal transmission and membrane recycling. In this study, the versatility of bioengineered extracellular membranous nanovesicles as potent carriers of small‐interfering RNAs (siRNAs) for stem cell engineering and in vivo delivery has been explored. Here, exosomes have been engineered, one of the cell‐derived vesicle types, to overexpress exosomal proteins fused with cell‐adhesion or cell‐penetrating peptides for enhanced intracellular gene transfer. To devise a more effective delivery system with potential for mass production, a new siRNA delivery system has also been developed by artificially inducing the outward budding of plasma membrane nanovesicles. Those nanovesicles have been engineered by overexpressing E‐cadherin to facilitate siRNA delivery to human stem cells with resistance to intracellular gene transfer. Both types of engineered nanovesicles deliver siRNAs to human stem cells for lineage specification with negligible cytotoxicity. The nanovesicles are efficient in delivering siRNA in vivo, suggesting feasibility for gene therapy. Cell‐derived, bioengineered nanovesicles used for siRNA delivery can provide functional platforms enabling effective stem cell therapeutics and in vivo gene therapy.

Organoid culture is a fast-emerging technology in the biological and biomedical research fields, garnering interest due to its unique features of self-organization from diverse types of stem cells and close resemblance to organs in the human body. This innovative in vitro model system presents the possibility of significant advances in the understanding of human development and disease mechanisms as well as in the discovery of novel diagnostics and therapeutics. Here, the authors review several types of tissue-specific organoids and discuss the most recent studies on the biomedical application of organoids. Finally, the challenges and prospects of organoids as an in vitro model system are laid out.