In Situ Self-Cross-Linkable, Long-Term Stable Hyaluronic Acid Filler by Gallol Autoxidation for Tissue Augmentation and Wrinkle Correction

Copyright © 2019 American Chemical Society.Injectable fillers mainly aim to augment tissue volume and correct wrinkles in cosmetic and plastic reconstructions. However, the development of long-lasting, injectable fillers with minimal complications of pain, toxicity, and displacement has been challenging because of the absence of reliable cross-linking chemistry. Here, we report a novel cross-linker-free injectable hydrogel formulated by autoxidation as a highly biocompatible, easily injectable, and long-term volumetrically stable filler agent. Self-cross-linkable hyaluronic acid (SC-HA) with gallol moieties could form a hydrogel via autoxidation of gallols in vivo without additional cross-linking agents. The gelation of SC-HA in situ after injection is accelerated by the self-production of oxygen species and endogenous peroxidase in vivo. The SC-HA filler does not require a high injection force, thus minimizing pain, bleeding, and tissue damage-associated complications. In addition, improved tissue adhesiveness of the SC-HA hydrogel by oxidized gallols (shear strength; 2 kPa) prevented displacement of the filler constructs from the injection site. The SC-HA filler retained its mechanical properties in vivo (600-700 Pa) for wrinkle correction and volumetric augmentation up to 1 year after injection. Overall, the performance of the SC-HA hydrogel as an injectable dermal filler was superior to that of commercially available, chemically cross-linked biphasic HA filler composites in terms of injectability, tissue adhesiveness, and long-term volumetric augmentation. Our injectable HA hydrogel with no need of cross-linkers provides a long-lasting filler that has clinical utility for cosmetic applications11sciescopu

A serotonin-modified hyaluronic acid hydrogel for multifunctional hemostatic adhesives inspired by a platelet coagulation mediator

© 2019 The Royal Society of Chemistry.Bleeding control is very important during operations and surgical treatments of wounds and traumatic injuries. This need has led to development and practical uses of various hemostatic agents. However, the currently available hemostatic agents have several limitations related to biocompatibility and hemostatic performance due to the presence of cytotoxic and immunogenic components and the individual differences in the blood coagulation system. In this study, a hydrogel system inspired by a blood clotting mediator in platelets was developed as a new class of hemostatic adhesive with improved performance and multi-functionality. The proposed hydrogel system was prepared using serotonin-conjugated hyaluronic acid, both of which are highly biocompatible as they are natural components of the body. Serotonin facilitates hemostasis by acting as a blood clotting mediator in platelets and acts as a crosslinker to form adhesive hydrogels. The serotonin-conjugated hyaluronic acid hydrogel exhibited significantly improved hemostatic capability in vivo with normal and hemophilic injuries compared with a commercially available fibrin-based hemostatic agent and prevented abnormal tissue adhesion after hemostasis. This hydrogel system, inspired by the platelet clotting mechanism, is a novel hemostatic adhesive that overcomes several limitations of existing hemostatic agents and could substantially improve bleeding control, thereby improving outcomes of surgical procedures11sciescopu

Endoscopically injectable and self-crosslinkable hydrogel-mediated stem cell transplantation for alleviating esophageal stricture after endoscopic submucosal dissection

Esophageal stricture after extensive endoscopic submucosal dissection impairs the quality of life of patients with superficial esophageal carcinoma. Beyond the limitations of conventional treatments including endoscopic balloon dilatation and the application of oral/topical corticosteroids, several cell therapies have been recently attempted. However, such methods are still limited in clinical situations and existing setups, and the efficacies are less in some cases since the transplanted cells hardly remain at the resection site for a long time due to swallowing and peristalsis of the esophagus. Thus, a cell transplantation platform directly applicable with clinically established equipment and enabling stable retention of transplanted cells can be a promising therapeutic option for better clinical outcomes. Inspired by ascidians that rapidly self-regenerate, this study demonstrates endoscopically injectable and self-crosslinkable hyaluronate that allows both endoscopic injection in a liquid state and self-crosslinking as an in situ-forming scaffold for stem cell therapy. The pre-gel solution may compatibly be applied with endoscopic tubes and needles of small diameters, based on the improved injectability compared to the previously reported endoscopically injectable hydrogel system. The hydrogel can be formed via self-crosslinking under in vivo oxidative environment, while also exhibiting superior biocompatibility. Finally, the mixture containing adipose-derived stem cells and the hydrogel can significantly alleviate esophageal stricture after endoscopic submucosal dissection (75% of circumference, 5 cm in length) in a porcine model through paracrine effects of the stem cell in the hydrogel, which modulate regenerative processes. The stricture rates on Day 21 were 79.5% ± 2.0%, 62.8% ± 1.7%, and 37.9% ± 2.9% in the control, stem cell only, and stem cell-hydrogel groups, respectively (p < 0.05). Therefore, this endoscopically injectable hydrogel-based therapeutic cell delivery system can serve as a promising platform for cell therapies in various clinically relevant situations. © 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.11Nsciescopu

Immediately Activating Hemostatic Cellulose Sealants for Uncontrolled Hemorrhage

© 2022 Elsevier LtdThe control of bleeding is one of the most important processes in surgical treatments and wound healing, and the development of effective hemostatic agents is urgently required. An ideal hemostatic agent should be immediately activated when exposed to bleeding to reduce blood loss as soon as possible and should be user-friendly for urgent situations. To meet these demands, we functionalized carboxymethyl cellulose (CMC) with two different phenolic moieties, catechol (CA) and pyrogallol (PG), and then formulated each CMC derivative into adhesive hydrogels with high hemostatic ability. These hemostatic platforms exhibited sturdy modulus (CMC-CA: 0.55 ± 0.08 kPa, CMC-PG: 1.37 ± 0.24 kPa), wet-tissue adhesiveness (CMC-CA: 2.19 ± 0.53 kPa, CMC-PG: 3.13 ± 0.25 kPa), and rapid crosslinking within seconds for wound closure. We transformed the CMC hydrogels into a patch design, resulting in 16∼19-fold increase in elastic modulus and 3∼4-fold increase in adhesiveness, which can completely seal the wound for more efficient hemostatic action. The adhesive CMC patches exhibited superior hemostatic capability to fibrin glue as a wound sealant by rapidly stopping bleeding in mouse liver hemorrhage. This study demonstrated that bio-inspired polyphenolic CMC hydrogels produce a highly effective, instantly working hemostatic agent.11Nsciescopu

Ascidian-Inspired Fast-Forming Hydrogel System for Versatile Biomedical Applications: Pyrogallol Chemistry for Dual Modes of Crosslinking Mechanism

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. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinhe

Ferritin Nanoshuttle for Long-Lasting Self-Healing of Phenolic Hydrogels

Herein,we highlight a novel finding that ferritin can play a crucialrole in the "self-healing lifetime" of soft phenolicmaterials. Ferritin interacts with a catechol-functionalized polymerto form a self-healable and adhesive hydrogel bidirectionally by providingand retrieving Fe3+. As a result of its unique role asa nanoshuttle to store and release iron, ferritin significantly increasesthe self-healing lifetime of the hydrogel compared with that affordedby catechol-Fe3+ coordination through direct Fe3+ addition without ferritin. Ferritin also induces stableoxidative coupling between catechol moieties following metal coordination,which contributes to double cross-linking networks of catechol-catecholadducts and catechol-Fe3+ coordination. Thus, ferritin-mediatedcross-linking can provide phenolic hydrogels with the advantages ofhydrogels prepared by both metal coordination and oxidative coupling,thereby overcoming the limitations of the current cross-linking methodsof phenolic hydrogels and broadening their versatility in biomedicalapplications.11Nsciescopu

pH-Universal Catechol-Amine Chemistry for Versatile Hyaluronic Acid Bioadhesives

Catechol, a major mussel-inspired underwater adhesive moiety, has been used to develop functional adhesive hydrogels for biomedical applications. However, oxidative catechol chemistry for interpolymer crosslinking and adhesion is exclusively effective under alkaline conditions, with limited applications in non-alkaline conditions. To overcome this limitation, pH-universal catechol-amine chemistry to recapitulate naturally occurring biochemical events induced by pH variation in the mussel foot is suggested. Aldehyde moieties are introduced to hyaluronic acid (HA) by partial oxidation, which enables dual-mode catechol tethering to the HA via both stable amide and reactive secondary amine bonds. Because of the presence of additional reactive amine groups, the resultant aldehyde-modified HA conjugated with catechol (AH-CA) is effectively crosslinked in acidic and neutral pH conditions. The AH-CA hydrogel exhibits not only fast gelation via active crosslinking regardless of pH conditions, but also strong adhesion and excellent biocompatibility. The hydrogel enables rapid and robust wound sealing and hemostasis in neutral and alkaline conditions. The hydrogel also mediates effective therapeutic stem cell and drug delivery even in dynamic and harsh environments, such as a motile heart and acidic stomach. Therefore, the AH-CA hydrogel can serve as a versatile biomaterial in a wide range of pH conditions in vivo.11Nsciescopu

Mechanically-reinforced and highly adhesive decellularized tissue-derived hydrogel for efficient tissue repair

© 2021 Elsevier B.V.Hydrogels derived from decellularized tissue (DT) have demonstrated huge potential in regenerative medicine. However, the hydrogel resulting from a thermally-induced crosslinking process via the self-assembly of collagen fibrils in DT exhibits weak mechanical properties. This restricts its application in tissue regeneration that requires strong mechanical properties and structural integrity of the hydrogel constructs. To overcome the aforementioned challenges of the present DT-derived hydrogels, we developed a DT hydrogel equipped with oxidative crosslinking chemistry by conjugating catechol moieties to the extracellular matrix in DT. The catechol-modified DT (DT-CA) constructed hydrogel instantly upon oxidation via catechol–catechol adducts, exhibiting 10 times stronger mechanical properties compared to that of the unmodified DT hydrogel. The oxidative crosslinking also increased the adhesiveness and physical integrity of the DT hydrogel, allowing for the shaping of scaffolds without using any supportive material, which could not be accomplished with conventional DT hydrogels. DT-CA hydrogel demonstrated an enhanced osteogenic differentiation of human stem cells and accelerated formation of new bones in a mouse model of the critical-sized calvarial defect. In addition, the patch type of DT-CA facilitated wound healing by mediating efficient topical delivery of growth factors. Similarly, other phenolic adhesive moiety (pyrogallol) could be introduced to improve DT hydrogel for promoting wound regeneration. Collectively, the results of this study support the applicability of mechanically-reinforced, adhesive DT hydrogel for effective tissue regeneration.11Nsciescopu

Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids

© 2022, The Author(s).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.11Nsciescopu

In situ Diagnosis and Simultaneous Treatment of Cardiac Diseases using a Single-device Platform

The in situ diagnosis of cardiac activities with simultaneous therapeutic electrical stimulation of the heart is key to preventing cardiac arrhythmia. Here, we present an unconventional single-device platform that enables in situ monitoring even in a wet condition and control of beating heart motions without interferences to the recording signal. This platform consists of the active-matrix array of pressure-sensitive transistors for detecting cardiac beatings, biocompatible, low-impedance electrodes for cardiac stimulations, and an alginate-based hydrogel adhesive for attaching this platform conformally to the epicardium. In contrast to conventional electrophysiological sensing using electrodes, the pressure-sensitive transistors measured mechanophysiological characteristics by monitoring the spatiotemporal distributions of cardiac pressures during heart beating motions. In vivo tests show mechanophysiological readings having good correlation with electrocardiography and negligible interference with the electrical artifacts caused during cardiac stimulations. This platform can therapeutically synchronize the rhythm of abnormal heartbeats through efficient pacing of cardiac arrhythmia.11Nsciescopu