Heterogeneous Hydrogel Research Articles

3D printed heterogeneous hybrid hydrogel scaffolds for sequential tumor photothermal-chemotherapy and wound healing.

Surgical resection remains the mainstay of melanoma treatment. However, due to the difficulties in controlling tumor recurrence and wound healing simultaneously, high postoperative recurrence rates and wound reconstruction remain the most significant challenges. As a result, a heterogeneous hybrid hydrogel scaffold was designed in this work to achieve sequential photothermal therapy and chemotherapy for melanoma recurrence inhibition and wound healing. A 3D printing platform was used to create a SA-GG@PDA hybrid hydrogel scaffold, which was prepared from a hybrid bioink consisting of sodium alginate (SA), gellan gum (GG), and polydopamine nanoparticles (PDA NPs). The printability, biocompatibility, and mechanical qualities of the hybrid bioink were all satisfactory. PDA NPs were generated in situ in the hybrid bioink, providing superior photothermal effects to the scaffold. After coating with a thermosensitive gelatin hydrogel loaded with the chemotherapeutic drug doxorubicin (DOX), the heterogeneous hydrogel scaffold could accelerate drug release under photothermal triggering and achieve photothermal-chemotherapy to suppress tumor cell proliferation and recurrence after surgical resection. Subsequently, the printed porous hybrid hydrogel scaffold enhanced HUVEC proliferation and migration, as well as tissue ingrowth, promoting wound healing following surgery. In the same mouse model, the sequential treatment with the heterogeneous SA-GG@PDA + DOX hydrogel scaffold was tested. The fabrication of the heterogeneous SA-GG@PDA + DOX hydrogel scaffold with multifunctional capabilities seemed to be a potential technique for preventing tumor recurrence and promoting wound healing following surgery.

Fabrication of heterogeneous chemical patterns on stretchable hydrogels using single-photon lithography.

Curved hydrogel surfaces bearing chemical patterns are highly desirable in various applications, including artificial blood vessels, wearable electronics, and soft robotics. However, previous studies on the fabrication of chemical patterns on hydrogels employed two-photon lithography, which is still not widely accessible to most laboratories. This work demonstrates a new patterning technique for fabricating curved hydrogels with chemical patterns on their surfaces without two-photon microscopy. In this work, we show that exposing hydrogels in fluorophore solutions to single photons via confocal microscopy enables the patterning of fluorophores on hydrogels. By applying this technique to highly stretchable hydrogels, we demonstrate three applications: (1) improving pattern resolution by fabricating patterns on stretched hydrogels and then returning the hydrogels to their initial, unstretched length; (2) modifying the local stretchability of hydrogels at a microscale resolution; and (3) fabricating perfusable microchannels with chemical patterns by winding chemically patterned hydrogels around a template, embedding the hydrogels in a second hydrogel, and then removing the template. The patterning method demonstrated in this work may facilitate a better mimicking of the physicochemical properties of organs in tissue engineering and may be used to make hydrogel robots with specific chemical functionalities.

In Situ Evaluation of the Polymer Concentration Distribution of Microphase-Separated Polyelectrolyte Hydrogels by the Microelectrode Technique

The heterogeneous structure that exists in virtually all hydrogels has a significant influence on the resulting strength and toughness. While the internal structure has been observed with electron microscopy, it is difficult to measure the in situ local polymer concentration in the native swollen state. In this study, a modified microelectrode technique (MET) was employed to measure the Donnan potential of a heterogeneous hydrogel with a phase-separated structure. With this method, we succeeded in observing quantitative in situ polymer concentrations ranging from 10.2 μmol/L to several hundred mmol/L. From the obtained concentration profiles, we could successfully evaluate the internal phase-separated structure with a resolution of less than 0.8 μm. Using MET, we could estimate the average activity coefficient of the hydrogel, and we found a difference in concentration between the dense and sparse phases. We demonstrate that MET is a powerful method that can locally and quantitatively measure the polyelectrolyte concentration distribution within hydrogels. Furthermore, this method can be applied to cells and organs in vivo due to their similarities with polyelectrolytes. Enabling the in situ determination of the internal structures of biomaterials could have important implications toward the characterization of damaged and diseased tissues on the local scale.

On Harvesting and Handling of Porcine Jejunal Mucus: A Few Tricks of the Trade

As a heterogeneous hydrogel, mucus has evolved into a formidable physiological barrier protecting the human body from external pathogens and toxic molecules. With mucin as its primary solid component, the viscoelasticity of mucus remains dynamic and dependent upon a plethora of factors, including pathological state, food intake, and infection. Current nanomedicine research strives toward developing nanoformulations that can permeate through the mucus barrier and release the encapsulated cargo of drug molecules at the vicinity of epithelial lining or be directly absorbed into the bloodstream. However, it is difficult to mimic mucus in vitro while the ex vivo models remain inadequate or incompatible with many established microscopic platforms. The UCD School of Veterinary Medicine has a rich legacy of working with porcine gut mucus as an experimental model, while some interesting and innovative ideas were developed by researchers here to address these challenges. This article presents a snapshot of those ideas and life hacks that the author wishes to share with the nanomedicine research community.

Introducing Hyaluronic Acid into Supramolecular Polymers and Hydrogels.

The use of supramolecular polymers to construct functional biomaterials is gaining more attention due to the tunable dynamic behavior and fibrous structures of supramolecular polymers, which resemble those found in natural systems, such as the extracellular matrix. Nevertheless, to obtain a biomaterial capable of mimicking native systems, complex biomolecules should be incorporated, as they allow one to achieve essential biological processes. In this study, supramolecular polymers based on water-soluble benzene-1,3,5-tricarboxamides (BTAs) were assembled in the presence of hyaluronic acid (HA) both in solution and hydrogel states. The coassembly of BTAs bearing tetra(ethylene glycol) at the periphery (BTA-OEG4) and HA at different ratios showed strong interactions between the two components that led to the formation of short fibers and heterogeneous hydrogels. BTAs were further covalently linked to HA (HA-BTA), resulting in a polymer that was unable to assemble into fibers or form hydrogels due to the high hydrophilicity of HA. However, coassembly of HA-BTA with BTA-OEG4 resulted in the formation of long fibers, similar to those formed by BTA-OEG4 alone, and hydrogels were produced with tunable stiffness ranging from 250 to 700 Pa, which is 10-fold higher than that of hydrogels assembled with only BTA-OEG4. Further coassembly of BTA-OEG4 fibers with other polysaccharides showed that except for dextran, all polysaccharides studied interacted with BTA-OEG4 fibers. The possibility of incorporating polysaccharides into BTA-based materials paves the way for the creation of dynamic complex biomaterials.

Injectable thiol-ene hydrogel of galactoglucomannan and cellulose nanocrystals in delivery of therapeutic inorganic ions with embedded bioactive glass nanoparticles

We propose an injectable nanocomposite hydrogel that is photo-curable via light-induced thiol-ene addition between methacrylate modified O-acetyl-galactoglucomannan (GGMMA) and thiolated cellulose nanocrystal (CNC-SH). Compared to free-radical chain polymerization, the orthogonal step-growth of thiol-ene addition allows a less heterogeneous hydrogel network and more rapid crosslinking kinetics. CNC-SH reinforced the GGMMA hydrogel as both a nanofiller and a crosslinker to GGMMA resulting in an interpenetrating network via thiol-ene addition. Importantly, the mechanical stiffness of the GGMMA/CNC-SH hydrogel is mainly determined by the stoichiometric ratio between the thiol groups on CNC-SH and the methacrylate groups in GGMMA. Meanwhile, the bioactive glass nanoparticle (BaGNP)-laden hydrogels of GGMMA/CNC-SH showed a sustained release of therapeutic ions in simulated body fluid in vitro, which extended the bioactive function of hydrogel matrix. Furthermore, the suitability of the GGMMA/CNC-SH formulation as biomaterial resin to fabricate digitally designed hydrogel constructs via digital light processing (DLP) lithography printing was evaluated.

Research Progress in the Multilayer Hydrogels.

Hydrogels have been widely used in many fields including biomedicine and water treatment. Significant achievements have been made in these fields due to the extraordinary properties of hydrogels, such as facile processability and tissue similarity. However, based on the in-depth study of the microstructures of hydrogels, as a result of the enhancement of biomedical requirements in drug delivery, cell encapsulation, cartilage regeneration, and other aspects, it is challenge for conventional homogeneous hydrogels to simultaneously meet different needs. Fortunately, heterogeneous multilayer hydrogels have emerged and become an important branch of hydrogels research. In this review, their main preparation processes and mechanisms as well as their composites from different resources and methods, are introduced. Moreover, the more recent achievements and potential applications are also highlighted, and their future development prospects are clarified and briefly discussed.

Novel nano heterogeneous structure hydrogels with mechanically robust, extensive stretching and highly swelling

Stimuli-responsive hydrogels that can change their properties as a result of external stimuli have shown great promise in various applications, but it is still a great challenge to simultaneously provide hydrogels with excellent mechanical properties and significant response. Herein, we propose a facile synthesis of smart PAAm based hydrogels with highly elastic and swellable by introducing the activated nanoparticles into the hydrogel networks. Due to the heterogeneous microporous structure of the hydrogels, this material demonstrates the highly elastic property to withstand slicing and high level of compression and deformations, as well as significant swelling ratio (~5500%). Moreover, photonic hydrogel elastomers are fabricated by incorporating monodispersed SiO2@PS microspheres within this hydrogel elastomer matrix. The as formed materials possess structural color and the highly elasticity enables their good mechanochromic capability. Our strategy is a straightforward way to design smart hydrogels whose response and mechanical properties can be tuned through the judicious choice of the polymerization time and content of activated nanogel, extending the potential application of hydrogels.

Multilayered and heterogeneous hydrogel construct printing system with crosslinking aerosol

Microextrusion bioprinting has been used to recreate the complex architecture and composition of a physiological system through the quick and accurate handling of various biomaterials. However, existing techniques are limited in precisely fabricating complex constructs, including multilayers and heterogeneous patterns with distinct regions, because the extruded bioink spreads rapidly upon contact with the substrate and is partially mixed with subsequently printed bioinks. This issue leads to difficulties in accurately and stably constructing multi-material structures with clear interfaces for prolonged printing before gelation. To fabricate multilayered and heterogeneous constructs, a bioprinting system should be able to continuously extrude various biomaterials and simultaneously crosslink the extruded bioink to stabilize the printed construct. In this study, a multiple-bioink printing system was developed by integrating a multibarrel nozzle for extruding multiple bioinks with a nebulizer for simultaneous crosslinking. The crosslinking aerosol sprayed from the nebulizer was able to gelate the various hydrogel bioinks as they were extruded through the multibarrel nozzle. Such aerosol-based crosslinking improved printing resolution and stability. The developed bioprinting system showed the possibility of recapitulating the physiological complex architecture such as a cancer microenvironment with well-defined interfaces between regions of different mechanical properties and cellular compositions. Using the integrated bioprinting system, a multilayered and heterogeneous construct was printed with four bioinks, including three types of cells (breast cancer cells, stromal cells, and vascular endothelial cells). The printed biological model was characterized by analyzing cancer cell migration and vascular network formation. The developed multiple-bioink printing system is expected to be highly efficient in recapitulating complex tissues and their environments with compartmentalized regions.

Liquid Stratification and Diffusion‐Induced Anisotropic Hydrogel Actuators with Excellent Thermosensitivity and Programmable Functionality

Smart hydrogel actuators with programmable anisotropic structures present fascinating prospects considering their distinctive shape transformation and controllable environmental responsiveness under external stimuli. However, the design of anisotropic hydrogels with simple and universal fabrication and programmable functionality is challenging for their valuable applications in smart actuators and soft robots. Herein, a simple, green, and devisable strategy is proposed to construct a heterogeneous porous hydrogel system by the different liquid diffusion (such as amyl alcohol, water, and ethanol) into a monomeric precursor solution of thermosensitive hydrogels. The well‐defined micro/nanoporous gradient and patterned structures related to selective liquid stratification and interfacial diffusion favor the fast response and accurate programmable deformation of hydrogels under temperature stimuli. Inspiringly, this simple diffusion‐driven tactic can be perfectly applicable for different responsive hydrogels with programmable multifunctionality by adding functional nanomaterials into the diffusible liquid. This green, general, and facile diffusion‐driven strategy provides significant guidance for fabricating environmentally responsive hydrogels with tailorable functionality for their multipurpose applications in drug delivery, bioengineering, smart actuators, and soft robots.

Soft-fiber-reinforced tough and fatigue resistant hydrogels

Soft-fiber-reinforced tough and fatigue resistant hydrogels

Fabricating hydrogels to mimic biological tissues of complex shapes and high fatigue resistance

<h2>Summary</h2> Biological tissues, such as heart valves and vocal cords, function through complex shapes and high fatigue resistance. Achieving both attributes with synthetic materials is hitherto an unmet challenge. Here we meet this challenge with hydrogels of heterogeneous structures. We fabricate a three-dimensional hydrogel skeleton by stereolithography and a hydrogel matrix by cast. Both the skeleton and matrix are elastic and stretchable, but the skeleton is much stiffer than the matrix, and their polymer networks entangle topologically. When such a hydrogel is stretched, the compliance of the matrix deconcentrates stress in the skeleton and amplifies fatigue resistance. We fabricate a homogeneous hydrogel and a heterogeneous hydrogel, each in the shape of a human heart valve. Subject to cyclic pressure, the former fractures in ∼560 cycles but the latter is intact after 50,000 cycles. Soft materials of complex shapes and high fatigue resistance open broad opportunities for applications.

Heterogeneous Hydrogel Structures with Spatiotemporal Reconfigurability using Addressable and Tunable Voxels.

Stimuli-responsive hydrogels can sense environmental cues and change their volume accordingly without the need for additional sensors or actuators. This enables a significant reduction in the size and complexity of resulting devices. However, since the responsive volume change of hydrogels is typically uniform, their robotic applications requiring localized and time-varying deformations have been challenging to realize. Here, using addressable and tunable hydrogel building blocks-referred to as soft voxel actuators (SVAs)-heterogeneous hydrogel structures with programmable spatiotemporal deformations are presented. SVAs are produced using a mixed-solvent photopolymerization method, utilizing a fast reaction speed and the cononsolvency property of poly(N-isopropylacrylamide) (PNIPAAm) to produce highly interconnected hydrogel pore structures, resulting in tunable swelling ratio, swelling rate, and Young's modulus in a simple, one-step casting process that is compatible with mass production of SVA units. By designing the location and swelling properties of each voxel and by activating embedded Joule heaters in the voxels, spatiotemporal deformations are achieved, which enables heterogeneous hydrogel structures to manipulate objects, avoid obstacles, generate traveling waves, and morph to different shapes. Together, these innovations pave the way toward tunable, untethered, and high-degree-of-freedom hydrogel robots that can adapt and respond to changing conditions in unstructuredenvironments.

Heterogenous hydrogel mimicking the osteochondral ECM applied to tissue regeneration.

Inspired by the intricate extracellular matrix (ECM) of natural cartilage and subchondral bone, a heterogenous bilayer hydrogel scaffold is fabricated. Gelatin methacrylate (GelMA) and acryloyl glucosamine (AGA) serve as the main components in the upper layer, mimicking the chondral ECM. Meanwhile, vinylphosphonic acid (VPA) as a non-collagen protein analogue is incorporated into the bottom layer to induce the in situ biomineralization of calcium phosphate. The two heterogenous layers are effectively sutured together by the inter-diffusion between the upper and bottom layer hydrogels, together with chelation between the calcium ions and alginate added to separate layers. The interfacial bonding between the two different layers was thoroughly investigated via rheological measurements. The incorporation of AGA promotes chondrocytes to produce collagen type II and glycosaminoglycans and upregulates the expression of chondrogenesis-related genes. In addition, the minerals induced by VPA facilitate the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). In vivo evaluation confirms the biocompatibility of the scaffold with minor inflammation and confirms the best repair ability of the bilayer hydrogel. This cell-free, cost-effective and efficient hydrogel shows great potential for osteochondral repair and inspires the design of other tissue-engineering scaffolds.

Microscopic local stiffening in a supramolecular hydrogel network expedites stem cell mechanosensing in 3D and bone regeneration.

Dynamic hydrogels cross-linked by weak and reversible physical interactions enhance the 3-dimensional (3D) spreading and mechanosensing abilities of encapsulated cells in a matrix. However, the highly dynamic nature of these physical cross-links also results in low mechanical stiffness in the hydrogel network and high tether compliance of the cell adhesion motifs attached to the network. The resulting low force feedback of the soft hydrogel network impedes the efficient activation of mechanotransduction signalling in the encapsulated cells. Herein, we demonstrate that the chemical incorporation of acryloyl nanoparticle-based cross-linkers creates regionally stiff network structures in the dynamic supramolecular hydrogels without compromising the dynamic properties of the cell-adaptable inter-nanoparticle hydrogel network. The obtained dynamic hydrogels with a heterogeneous hydrogel network topology expedite the development of adhesion structures, 3D spreading, and mechanosensing of the encapsulated stem cells, as evidenced by the upregulated expression of key biomarkers such as vinculin, FAK, and YAP. This enhanced spreading and mechanotransduction promotes the osteogenic differentiation of the encapsulated stem cells. In contrast, doping with physically entrapped nanoparticles or molecular cross-linkers (PEGDA) cannot locally reinforce the dynamic hydrogel network and therefore fails to facilitate cell mechanosensing or differentiation in the 3D hydrogels. We further show that the dynamic hydrogels with a locally stiffened network promote the in situ regeneration of bone defects in an animal model. Our findings provide valuable insights into the design of the supramolecular dynamic hydrogels with biomimetic hierarchical biomechanical structures as the optimized carrier material for stem cell-based therapies.

Heterogeneous multi-compartmental DNA hydrogel particles prepared via microfluidic assembly for lymphocyte-inspired precision medicine.

Lymphocytes play a vital role in immunosurveillance through sensing biomolecules and eliminating targeted invaders. Compared with conventional therapies that depend on drug loading, lymphocytes are advantageous as they are able to ensure self-regulated therapeutics. Here, novel multi-compartmental DNA hydrogel particles were synthesized using a microfluidic assembly for intelligent cancer treatment via the logic-based control of siRNA release without external stimulation. The sensing sequence (D1) was compartmentalized from the treatment sequence (D2) with the use of core-shell DNA hydrogel particles. When D1 detects a cancer-associated biomarker, miRNA-21, a sequence cascade is triggered to release siRNA from D2, effectively eliminating the targeted cancer cells via lymphocyte-inspired precision medicine.

Hierarchical and heterogeneous hydrogel system as a promising strategy for diversified interfacial tissue regeneration.

Despite breakthroughs in tissue engineering, a tremendous problem still lies in repairing the interfacial tissue which connects soft tissue to hard tissue, particularly cartilage-bone, tendon/ligament-bone, and cementum-ligament-bone interfaces. The challenge comes from the complicated biophysical and biochemical characteristics of interfacial tissues, involving a graded variation of chemical components, structures, and mechanical properties as well as a heterogeneous cell distribution from the soft end to the hard end. Accordingly, significant progress has been made in the design of hierarchical and heterogeneous hydrogel systems in order to solve this problem. Advanced programmable technologies, such as 3D printing and microfluidic platforms, have shown potential in constructing templates or scaffolds with tissue-specific characteristics. The structural specialty of the three aforementioned interfacial tissues is summarized in this review. Then the text concentrates on how to utilize different scale hydrogels (from chemical variation, nanoscale, microscale to cellular regulation) to fabricate gradient constructions for regenerating interfacial tissues, together with in vitro and in vivo outcomes. In particular, the fabrication of continuous gradients is highlighted in this review. Promisingly, the versatile designs involved in fabricating hierarchical and heterogeneous hydrogel systems are predicted to tackle the unsolved problems, and this interfacial tissue engineering methodology is expected to expand its use in therapeutic applications.

Quantifying the equilibrium swelling responses and swelling-induced snap-through of heterogeneous spherical hydrogels

We employ the finite deformation theory to analyze the inhomogeneous large deformation of a heterogeneous spherical hydrogel subjected to chemo-mechanical loadings. The heterogeneous spherical hydrogel is composed of two concentric spherical hydrogel layers with different material properties. The Gent model is employed for the free energy function of the polymer stretching part in order to tackle the effect of the limiting chain extensibility. The heterogeneous spherical hydrogel is assumed to be perfectly bonded at the interface and is traction free at the external surface. At the internal surface, two boundary conditions are considered: one is internally fixed and the other is internally pressurized. Numerical examples are performed to describe the nonlinear behaviors of a heterogeneous spherical hydrogel when subjected to the swelling and mechanical loadings. For internally fixed case, numerical results show that the limiting chain extensibility and the initial swelling ratio have significant effect on the actuation deformation of a heterogeneous spherical hydrogel. For internally pressurized case, we find that the swelling-induced snap-through instability can be triggered under specified conditions. It is shown that the chemo-mechanical behaviors of the heterogeneous spherical hydrogels can be adjusted by tuning the material properties and the initial swelling ratios.

Bioinspired Hydrogels with Muscle-Like Structure for AIEgen-Guided Selective Self-Healing

Living systems, including human beings, animals, and plants, display the power to self-heal spontaneously after being damaged. The self-healing is usually selective, which means that the healing ef...

Grayscale surface patterning using electrophoretic motion through a heterogeneous hydrogel material.

Chemical surface patterning can be an incredibly powerful tool in a variety of applications, as it enables precise spatial control over surface properties. But the equipment required to create functional surface patterns-especially "grayscale" patterns where independent control over species placement and density are needed-is often expensive and inaccessible. In this work, we leveraged equipment and methods readily available to many research labs, namely 3D printing and electroblotting, to generate controlled grayscale surface patterns. Three-dimensional-printed molds were used to cast polyacrylamide hydrogels with regions of variable polymer density; regions of low polymer density within the hydrogels served as reservoirs for proteins that were later driven onto a target surface using electrophoresis. This mechanism was used to deposit grayscale patterns of fluorescently labeled proteins, and the fluorescent intensity of these patterns was measured and compared to a theoretical analysis of the deposition mechanism.