Cell tumbling enhances stem cell differentiation in hydrogels via nuclear mechanotransduction.

Cells can deform their local niche in three dimensions via whole-cell movements such as spreading, migration or volume expansion. These behaviours, occurring over hours to days, influence long-term cell fates including differentiation. Here we report a whole-cell movement that occurs in sliding hydrogels at the minutes timescale, termed cell tumbling, characterized by three-dimensional cell dynamics and hydrogel deformation elicited by heightened seconds-to-minutes-scale cytoskeletal and nuclear activity. Studies inhibiting or promoting the cell tumbling of mesenchymal stem cells show that this behaviour enhances differentiation into chondrocytes. Further, it is associated with a decrease in global chromatin accessibility, which is required for enhanced differentiation. Cell tumbling also occurs during differentiation into other lineages and its differentiation-enhancing effects are validated in various hydrogel platforms. Our results establish that cell tumbling is an additional regulator of stem cell differentiation, mediated by rapid niche deformation and nuclear mechanotransduction.

Granular Biphasic Colloidal Hydrogels for 3D Bioprinting.

Granular hydrogels composed of hydrogel microparticles are promising candidates for 3D bioprinting due to their ability to protect encapsulated cells. However, to achieve high print fidelity, hydrogel microparticles need to jam to exhibit shear-thinning characteristics, which is crucial for 3D printing. Unfortunately, this overpacking can significantly impact cell viability, thereby negating the primary advantage of using hydrogel microparticles to shield cells from shear forces. To overcome this challenge, a novel solution: a biphasic, granular colloidal bioink designed to optimize cell viability and printing fidelity is introduced. The biphasic ink consists of cell-laden polyethylene glycol (PEG) hydrogel microparticles embedded in a continuous gelatin methacryloyl (GelMA)-nanosilicate colloidal network. Here, it is demonstrated that this biphasic bioink offers outstanding rheological properties, print fidelity, and structural stability. Furthermore, its utility for engineering complex tissues with multiple cell types and heterogeneous microenvironments is demonstrated, by incorporating ß-islet cells into the PEG microparticles and endothelial cells in the GelMA-nanosilicate colloidal network. Using this approach, it is possible to induce cell patterning, enhance vascularization, and direct cellular function. The proposed biphasic bioink holds significant potential for numerous emerging biomedical applications, including tissue engineering and disease modeling.

Dynamically Cross-Linked Granular Hydrogels for 3D Printing and Therapeutic Delivery.

Granular hydrogels have recently emerged as promising biomaterials for tissue engineering and 3D-printing applications, addressing the limitations of bulk hydrogels while exhibiting desirable properties such as injectability and high porosity. However, their structural stability can be improved with post-injection interparticle cross-linking. In this study, we developed granular hydrogels with interparticle cross-linking through reversible and dynamic covalent bonds. We fragmented photo-cross-linked bulk hydrogels to produce aldehyde or hydrazide-functionalized microgels using chondroitin sulfate. Mixing these microgels facilitated interparticle cross-linking through reversible hydrazone bonds, providing shear-thinning and self-healing properties for injectability and 3D printing. The resulting granular hydrogels displayed high mechanical stability without the need for secondary cross-linking. Furthermore, the porosity and sustained release of growth factors from these hydrogels synergistically enhanced cell recruitment. Our study highlights the potential of reversible interparticle cross-linking for designing injectable and 3D printable therapeutic delivery scaffolds using granular hydrogels. Overall, our study highlights the potential of reversible interparticle cross-linking to improve the structural stability of granular hydrogels, making them an effective biomaterial for use in tissue engineering and 3D-printing applications.

Dynamically crosslinked thermoresponsive granular hydrogels.

Granular hydrogels are a promising biomaterial for a wide range of biomedical applications, including tissue regeneration, drug/cell delivery, and 3D printing. These granular hydrogels are created by assembling microgels through the jamming process. However, current methods for interconnecting the microgels often limit their use due to the reliance on postprocessing for crosslinking through photoinitiated reactions or enzymatic catalysis. To address this limitation, we incorporated a thiol-functionalized thermo-responsive polymer into oxidized hyaluronic acid microgel assemblies. The rapid exchange rate of thiol-aldehyde dynamic covalent bonds allows the microgel assembly to be shear-thinning and self-healing, with the phase transition behavior of the thermo-responsive polymer serving as secondary crosslinking to stabilize the granular hydrogels network at body temperature. This two-stage crosslinking system provides excellent injectability and shape stability, while maintaining mechanical integrity. In addition, the aldehyde groups of the microgels act as covalent binding sites for sustained drug release. These granular hydrogels can be used as scaffolds for cell delivery and encapsulation, and can be 3D printed without the need for post-printing processing to maintain mechanical stability. Overall, our work introduces thermo-responsive granular hydrogels with promising potential for various biomedical applications.

Nano-bio interactions of 2D molybdenum disulfide.

Two-dimensional (2D) molybdenum disulfide (MoS2) is an ultrathin nanomaterial with a high degree of anisotropy, surface-to-volume ratio, chemical functionality and mechanical strength. These properties together enable MoS2 to emerge as a potent nanomaterial for diverse biomedical applications including drug delivery, regenerative medicine, biosensing and bioelectronics. Thus, understanding the interactions of MoS2 with its biological interface becomes indispensable. These interactions, referred to as "nano-bio" interactions, play a key role in determining the biocompatibility and the pathways through which the nanomaterial influences molecular, cellular and biological function. Herein, we provide a critical overview of the nano-bio interactions of MoS2 and emphasize on how these interactions dictate its biomedical applications including intracellular trafficking, biodistribution and biodegradation. Also, a critical evaluation of the interactions of MoS2 with proteins and specific cell types such as immune cells and progenitor/stem cells is illustrated which governs the short-term and long-term compatibility of MoS2-based biomedical devices.

Light-Triggered In Situ Gelation of Hydrogels using 2D Molybdenum Disulfide (MoS2 ) Nanoassemblies as Crosslink Epicenter.

Light-responsive biomaterials are an emerging class of materials used for developing noninvasive, noncontact, precise, and controllable biomedical devices. Long-wavelength near-infrared (NIR) radiation is an attractive light source for in situ gelation due to its higher penetration depth and minimum side effects. The conventional approach to obtain crosslinked biomaterials relies heavily on the use of a photoinitiator by generating reactive species when exposed to short-wavelength radiation, which is detrimental to surrounding cells and tissue. Here, a new class of NIR-triggered in situ gelation system based on defect-rich 2D molybdenum disulfide (MoS2 ) nanoassemblies and thiol-functionalized thermoresponsive polymer in the absence of a photoinitiator is introduced. Exposure to NIR radiation activates the dynamic polymer-nanomaterials interactions by leveraging the photothermal characteristics of MoS2 and intrinsic phase transition ability of the thermoresponsive polymer. Specifically, upon NIR exposure, MoS2 acts as a crosslink epicenter by connecting with multiple polymeric chains via defect-driven click chemistry. As a proof-of-concept, the utility of NIR-triggered in situ gelation is demonstrated in vitro and in vivo. Additionally, the crosslinked gel exhibits the potential for NIR light-responsive release of encapsulated therapeutics. These light-responsive biomaterials have strong potential for a range of biomedical applications, including artificial muscle, smart actuators, 3D/4D printing, regenerative medicine, and therapeutic delivery.

Light-Responsive Inorganic Biomaterials for Biomedical Applications.

Light-responsive inorganic biomaterials are an emerging class of materials used for developing noninvasive, noncontact, precise, and controllable medical devices in a wide range of biomedical applications, including photothermal therapy, photodynamic therapy, drug delivery, and regenerative medicine. Herein, a range of biomaterials is discussed, including carbon-based nanomaterials, gold nanoparticles, graphite carbon nitride, transition metal dichalcogenides, and up-conversion nanoparticles that are used in the design of light-responsive medical devices. The importance of these light-responsive biomaterials is explored to design light-guided nanovehicle, modulate cellular behavior, as well as regulate extracellular microenvironments. Additionally, future perspectives on the clinical use of light-responsive biomaterials are highlighted.

Characterization of a Sandwich PLGA-Gallic Acid-PLGA Coating on Mg Alloy ZK60 for Bioresorbable Coronary Artery Stents.

Absorbable magnesium stents have become alternatives for treating restenosis owing to their better mechanical properties than those of bioabsorbable polymer stents. However, without modification, magnesium alloys cannot provide the proper degradation rate required to match the vascular reform speed. Gallic acid is a phenolic acid with attractive biological functions, including anti-inflammation, promotion of endothelial cell proliferation, and inhibition of smooth muscle cell growth. Thus, in the present work, a small-molecule eluting coating is designed using a sandwich-like configuration with a gallic acid layer enclosed between poly (d,l-lactide-co-glycolide) layers. This coating was deposited on ZK60 substrate, a magnesium alloy that is used to fabricate bioresorbable coronary artery stents. Electrochemical analysis showed that the corrosion rate of the specimen was ~2000 times lower than that of the bare counterpart. The released gallic acid molecules from sandwich coating inhibit oxidation by capturing free radicals, selectively promote the proliferation of endothelial cells, and inhibit smooth muscle cell growth. In a cell migration assay, sandwich coating delayed wound closure in smooth muscle cells. The sandwich coating not only improved the corrosion resistance but also promoted endothelialization, and it thus has great potential for the development of functional vascular stents that prevent late-stent restenosis.

Phenolic Modified Ceramic Coating on Biodegradable Mg Alloy: The Improved Corrosion Resistance and Osteoblast-Like Cell Activity.

Magnesium alloys have great potential for developing orthopedic implants due to their biodegradability and mechanical properties, but the rapid corrosion rate of the currently-available alloys limits their clinical applications. To increase the corrosion resistance of the substrate, a protective ceramic coating is constructed by a micro-arc oxidation (MAO) process on ZK60 magnesium alloy. The porous ceramic coating is mainly composed of magnesium oxide and magnesium silicate, and the results from cell cultures show it can stimulate osteoblastic cell growth and proliferation. Moreover, gallic acid, a phenolic compound, was successfully introduced onto the MAO coating by grafting on hydrated oxide and chelating with magnesium ions. The gallic acid and rough surface of MAO altered the cell attachment behavior, making it difficult for fibroblasts to adhere to the MAO coating. The viability tests showed that gallic acid could suppress fibroblast growth and stimulate osteoblastic cell proliferation. Overall, the porous MAO coating combined with gallic acid offered a novel strategy for increasing osteocompatibility.