Electrically conductive hyaluronic acid (HA) hydrogels incorporated with single-walled carbon nanotubes (CNTs) and/or polypyrrole (PPy) were developed to promote differentiation of human neural stem/progenitor cells (hNSPCs). The CNT and PPy nanocomposites, which do not easily disperse in aqueous phases, dispersed well and were efficiently incorporated into catechol-functionalized HA (HA-CA) hydrogels by the oxidative catechol chemistry used for hydrogel cross-linking. The prepared electroconductive HA hydrogels provided dynamic, electrically conductive three-dimensional (3D) extracellular matrix environments that were biocompatible with hNSPCs. The HA-CA hydrogels containing CNT and/or PPy significantly promoted neuronal differentiation of human fetal neural stem cells (hfNSCs) and human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) with improved electrophysiological functionality when compared to differentiation of these cells in a bare HA-CA hydrogel without electroconductive motifs. Calcium channel expression was upregulated, depolarization was activated, and intracellular calcium influx was increased in hNSPCs that were differentiated in 3D electroconductive HA-CA hydrogels; these data suggest a potential mechanism for stem cell neurogenesis. Overall, our bioinspired, electroconductive HA hydrogels provide a promising cell-culture platform and tissue-engineering scaffold to improve neuronal regeneration.

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.

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.

Chondroitin sulfate (CS), the main component of cartilage extracellular matrix, has attracted attention as a biomaterial for cartilage tissue engineering. However, current CS hydrogel systems still have limitations for application in successful cartilage tissue engineering owing to their unsuitable degradation kinetics, insufficient mechanical similarity, and lack of integration with the native cartilage tissue. In this study, using mussel adhesive-inspired catechol chemistry, we developed a functional CS hydrogel that exhibits tunable physical and mechanical properties as well as excellent tissue adhesion for efficient integration with native tissues. Various properties of the developed catechol-functionalized CS (CS-CA) hydrogel, including swelling, degradation, mechanical properties, and adhesiveness, could be tailored by varying the conjugation ratio of the catechol group to the CS backbone and the concentration of the CS-CA conjugates. CS-CA hydrogels exhibited significantly increased modulus (∼10 kPa) and superior adhesive properties (∼3 N) over conventional CS hydrogels (∼hundreds Pa and ∼0.05 N). In addition, CS-CA hydrogels incorporating decellularized cartilage tissue dice promoted the chondrogenic differentiation of human adipose-derived mesenchymal stem cells by providing a cartilage-like microenvironment. Finally, the transplantation of autologous cartilage dice using tissue-adhesive CS-CA hydrogels enhanced cartilage integration with host tissue and neo-cartilage formation owing to favorable physical, mechanical, and biological properties for cartilage formation. In conclusion, our study demonstrated the potential utility of the CS-CA hydrogel system in cartilage tissue reconstruction.

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 applications.