Engineering Hydrogels for Modulation of Dendritic Cell Function.

Dendritic cells (DCs), the most potent antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs encounter numerous microenvironments with different biophysical properties, such as stiffness and viscoelasticity. Considering the emerging importance of mechanical cues for DC function, it is essential to understand the impacts of these cues on DC function in a physiological or pathological context. Engineered hydrogels have gained interest for the exploration of the impacts of biophysical matrix cues on DC functions, owing to their extracellular-matrix-mimetic properties, such as high water content, a sponge-like pore structure, and tunable mechanical properties. In this review, the introduction of gelation mechanisms of hydrogels is first summarized. Then, recent advances in the substantial effects of developing hydrogels on DC function are highlighted, and the potential molecular mechanisms are subsequently discussed. Finally, persisting questions and future perspectives are presented.

Isoliquiritigenin Nanoemulsion Preparation by Combined Sonication and Phase-Inversion Composition Method: In Vitro Anticancer Activities.

Isoliquiritigenin (ILQ) has a number of biological activities such as antitumor and anti-inflammatory effects. However, biomedical applications of ILQ are impeded by its poor aqueous solubility. Therefore, in this research, we prepared a novel ILQ-loaded nanoemulsion, i.e., ILQ-NE, which consisted of Labrafil® M 1944 CS (oil), Cremophor® EL (surfactant), ILQ, and phosphate-buffered saline, by employing a combined sonication (high-energy) and phase-inversion composition (low-energy) method (denoted as the SPIC method). The ILQ-NE increased the ILQ solubility ~1000 times more than its intrinsic solubility. It contained spherical droplets with a mean diameter of 44.10 ± 0.28 nm and a narrow size distribution. The ILQ loading capacity was 4%. The droplet size of ILQ-NE remained unchanged during storage at 4 °C for 56 days. Nanoemulsion encapsulation effectively prevented ILQ from degradation under ultraviolet light irradiation, and enhanced the ILQ in vitro release rate. In addition, ILQ-NE showed higher cellular uptake and superior cytotoxicity to 4T1 cancer cells compared with free ILQ formulations. In conclusion, ILQ-NE may facilitate the biomedical application of ILQ, and the SPIC method presents an attractive avenue for bridging the merits and eliminating the shortcomings of traditional high-energy methods and low-energy methods.

Shape-Recoverable Macroporous Nanocomposite Hydrogels Created via Ice Templating Polymerization for Noncompressible Wound Hemorrhage.

Uncontrolled hemorrhage resulting from severe trauma or surgical operations remains a challenge. It is highly important to develop functional materials to treat noncompressible wound bleeding. In this work, a shape-recoverable macroporous nanocomposite hydrogel was facilely created through ice templating polymerization. The covalently cross-linked gelatin networks provide a robust framework, while the Laponite nanoclay disperses into the three-dimensional matrix, enabling mechanical reinforcement and hemostatic functions. The resultant macroporous nanocomposite hydrogel possesses an inherent interconnected macroporous structure and rapid deformation recovery. In vitro assessments indicate that the hydrogel displays good cytocompatibility and a low hemolysis ratio. The hydrogel shows a higher coagulation potential and more erythrocyte adhesion compared to the commercial gauze and gelatin sponge. The noncompressible liver hemorrhage models also confirm its promising hemostasis performance. This strategy of combining a nano-enabled solution with ice templating polymerization displays great potential to develop appealing absorbable macroporous biomaterials for rapid hemostasis.

3D printed double-network alginate hydrogels containing polyphosphate for bioenergetics and bone regeneration.

Low mechanical strength, poor processability, and low bioactivity of hydrogels limit their application in bone tissue engineering severely. Herein, a new 3D-printable, osteoinductive, and bioenergetic-active double-network (DN) hydrogel containing sodium alginate (SA), poly (ethylene glycol) diacrylate (PEGDA), and sodium polyphosphate (PolyP) was developed via a two-step method. The synergy of the covalent cross-linking network and the ionic cross-linking network improves the mechanical properties of the hydrogel. And the pre-gel with Ca2+ has better 3D printing performance to print complex tissue engineering scaffolds than common hydrogels. In addition, the incorporation of PolyP into DN hydrogel matrix significantly improves the bioactivity of hydrogels. The bioenergetic effect of PolyP improves adenosine triphosphate content of cells significantly to promote cell activities such as migration. The in vitro osseointegration investigation suggests that the orthophosphate monomer units, which are degradation fragments of PolyP, provide enough phosphoric acid units for the formation of calcium phosphate and accelerate the osteogenic differentiation of cells greatly. Therefore, the proposed printable, bioenergetic-active, osteoinductive DN hydrogel is potential to solve the problems of complex tissue engineering scaffolds and be applied in energy-crucial bone tissue regeneration.

Water promotes the formation of fibril bridging in antler bone illuminated by in situ AFM testing.

Water, as one of the main components of bone, has a significant impact on the mechanical properties of bone. However, the micro-/nanoscale toughening mechanism induced by water in bone remains at only the theoretical level with static observations, and further research is still needed. In this study, a new in situ mechanical test combined with atomic force microscopy (AFM) was used to track the micro-/nanocrack propagation of hydrated and dehydrated antler bones in situ to explore the influence of water on the micro-/nanomechanical behavior of bone. In hydrated bone, observations of the crack tip region revealed major uncracked ligament bridging, and the conversion of mineralized collagen fibrils (MCFs) from bridging to breaking is clearly seen in real time. In dehydrated bone, multiple uncracked ligament bridges can be observed, but they are quickly broken by cracks, and the MCFs tend to break directly instead of forming fibril bridges. These experimental results indicate that the hydrated interface promotes slippage between collagen and the mineral phase and slippage between MCFs, while the dehydrated interface causes MCFs to fracture directly under lower strain. The platform we built provides new insights for studying the mechanism of toughening of the components in bones.

Ordered Fibril Arrays in Osteons Promote the Multidirectional Nanodeflection of Cracks: In Situ AFM Imaging.

The high fracture resistance of cortical bone is not completely understood across its complex hierarchical structure, especially on micro- and nanolevels. Here, a novel in situ bending test combined with atomic force microscopy (AFM) is utilized to assess the micro-/nanoscale failure behavior of cortical bone under the external load. Unlike the smoother crack path in the transverse direction, the multilevel composite material model endows the longitudinal direction to show multilevel Y-shaped cracks with more failure interfaces for enhancing the fracture resistance. In the lamellae, the nanocracks originating from the interfibrillar nanointerface deflect multidirectionally at certain angles related to the periodic ordered arrangement of the mineralized collagen fibril (MCF) arrays. The ordered MCF arrays in the lamellae may use the nanodeflection of the dendritic nanocracks to adjust the direction of the crack tip, which subsequently reaches the interlamellae to sharply deflect and finally form a zigzag path. This work provides an insight into the relationship between the structure and the function of bone at a multilevel under load, specifically the role of the ordered MCF arrays in the lamellar structure.

Three-Dimensional Printed Hydrogels with High Elasticity, High Toughness, and Ionic Conductivity for Multifunctional Applications.

Hydrogels have drawn extensive attention due to their unique physical and biological properties. However, the relatively low mechanical strength and poor processability of hydrogels limit their applications. Especially, the emerging 3D printing technology for nontoxic hydrogels requires proper formability and controllable mechanical behaviors. In this study, a new strategy to construct a novel double-network biocompatible hydrogel from poly(ethylene glycol) diacrylate (PEGDA) and short-chain chitosan (CS) via ionic-covalent cross-linking is by a two-step method involving UV curing followed by immersion in an anionic solution. The CS-based ionic network and PEGDA-based covalent network as well as the hydrogen bonds between them jointly induce excellent mechanical properties, which can be regulated by changing the PEGDA/CS content and ionic cross-linking time. Compared with conventional hydrogels, this mechanically optimized hydrogel exhibits a superior elastic modulus (3.84 ± 0.4 MPa), higher tensile strength (7.23 ± 0.2 MPa), and higher tensile strain (162 ± 7%). Notably, its excellent printing capability through the citrate anionic solution adjustment enables 3D printing with precision, flexibility, and a complex inner structure by extrusion in air at room temperature. In addition, a number of citrate ions existed in the ionic network, giving the hydrogels good electrical conductivity. Therefore, this printable, conductive, and tough hydrogel exhibits potential for vascular engineering, cartilage tissue engineering, and wearable device applications.

Investigation of nanoscale failure behaviour of cortical bone under stress by AFM.

The contribution of nanostructures of bone to the macroscale mechanical properties has received much attention, but most of nano-toughening mechanisms have remained in the theoretical stage or at static experimental observation. Our study shows that the medullary surface of the bovine femur provides a smooth natural surface ideal for observing nanostructures in bone. Mechanical loading is applied using an in situ mechanical device and the nanomechanical behaviours of the specimens are in situ recorded and imaged using an atomic force microscope (AFM). By the in situ observation of nanomechanical behaviours under stress, the existing nano-toughening mechanisms, such as fibril slippage and fibril bridging, are confirmed. Before the micro failure stage, mineralized collagen fibrils are strained with the increase of stress, followed by pre-separation (or slippage) due to stress concentration, resulting in cracked nanoscale interfaces. When micro-failure occurs (i.e. crack initiation), the nano-bridging mechanism contributes to resisting the formation of nanometre crack interface, the propagation of crack tip and the failure of crack bridging. Our study provides direct evidence for the connection between bridging-type mechanisms at different scale, which are composed of the corresponding bone structures at each level. Through the in situ observation of the microscopic failure in bone, some visual information are offered on the interaction between nanomechanical behaviours and nanostructures.