Enhanced osteogenic differentiation in 3D hydrogel scaffold via macrophage mitochondrial transfer.

To assess the efficacy of a novel 3D biomimetic hydrogel scaffold with immunomodulatory properties in promoting fracture healing. Immunomodulatory scaffolds were used in cell experiments, osteotomy mice treatment, and single-cell transcriptomic sequencing. In vitro, fluorescence tracing examined macrophage mitochondrial transfer and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Scaffold efficacy was assessed through alkaline phosphatase (ALP), Alizarin Red S (ARS) staining, and in vivo experiments. The scaffold demonstrated excellent biocompatibility and antioxidant-immune regulation. Single-cell sequencing revealed a shift in macrophage distribution towards the M2 phenotype. In vitro experiments showed that macrophage mitochondria promoted BMSCs' osteogenic differentiation. In vivo experiments confirmed accelerated fracture healing. The GAD/Ag-pIO scaffold enhances osteogenic differentiation and fracture healing through immunomodulation and promotion of macrophage mitochondrial transfer.

Effects of cell adhesion motif, fiber stiffness, and cyclic strain on tenocyte gene expression in a tendon mimetic fiber composite hydrogel.

We recently developed a fiber composite consisting of tenocytes seeded onto discontinuous fibers embedded within a hydrogel, designed to mimic physiological tendon micromechanics of tension and shear. This study examined if cell adhesion peptide (DGEA or YRGDS), fiber modulus (50 or 1300 kPa) and/or cyclic strain (5% strain, 1 Hz) influenced bovine tenocyte gene expression. Ten genes were analyzed and none were sensitive to peptide or fiber modulus in the absence of cyclic tensile strain. Genes associated with tendon (SCX and TNMD), collagens (COL1A1, COL3A1, COL11A1), and matrix remodelling (MMP1, MMP2, and TIMP3) were insensitive to cyclic strain. Contrarily, cyclic strain up-regulated IL6 by 30-fold and MMP3 by 10-fold in soft YRGDS fibers. IL6 expression in soft YRGDS fibers was 5.7 and 3.3-fold greater than in soft DGEA fibers and stiff RGD fibers, respectively, under cyclic strain. Our findings suggest that changes in the surrounding matrix can influence catabolic genes in tenocytes when cultured in a complex strain environment mimicking that of tendon, while having minimal effects on tendon and homeostatic genes.

Biomimetic Hydrogel Containing Copper Sulfide Nanoparticles and Deferoxamine for Photothermal Therapy of Infected Diabetic Wounds.

Inducing cell migration from the edges to the center of a wound, promoting angiogenesis, and controlling bacterial infection are very important for diabetic wound healing. Incorporating growth factors and antibiotics into hydrogels for wound dressing is considered a potential strategy to meet these requirements. However, some present drawbacks greatly slow down their development toward application, such as the short half-life and high price of growth factors, low antibiotic efficiency against drug-resistant bacteria, insufficient ability of hydrogels to promote cell migration, etc. Deferoxamine (DFO) can upregulate the expression of HIF-1α, thus stimulating the secretion of angiogenesis-related endogenous growth factors. Copper sulfide (CuS) nanoparticles possess excellent antibacterial performance combined with photothermal therapy (PTT). Herein, DFO and CuS nanoparticles are incorporated into a biomimetic hydrogel, which mimics the structure and function of the extracellular matrix (ECM), abbreviated as DFO/CuS-ECMgel. This biomimetic hydrogel is expected to be able to promote cell adhesion and migration, be degraded by cell-secreted matrix metalloproteinases (MMPs), and then release DFO and CuS nanoparticles at the wound site to exert their therapeutic effects. As a result, the three crucial requirements for diabetic wound healing, "beneficial for cell adhesion and migration, promoting angiogenesis, effectively killing drug-resistant bacteria," can be achieved simultaneously.

Biomimetic Hydrogels Promote Pseudoislet Formation to Improve Glycemic Control in Diabetic Mice.

Islet or ß-cell transplantation is currently considered to be the ideal treatment for diabetes, and three-dimensional (3D) bioprinting of a bionic pancreas with physiological stiffness is considered to be promising for the encapsulation and transplantation of ß-cells. In this study, a 5%GelMA/2%AlgMA hybrid hydrogel with pancreatic physiological stiffness was constructed and used for ß-cell encapsulation, 3D bioprinting, and in vivo transplantation to evaluate glycemic control in diabetic mice. The hybrid hydrogel had good cytocompatibility and could induce insulin-producing cells (IPCs) to form pseudoislet structures and improve insulin secretion. Furthermore, we validated the importance of betacellulin (BTC) in IPCs differentiation and confirmed that IPCs self-regulation was achieved by altering the nuclear and cytoplasmic distributions of BTC expression. In vivo transplantation of diabetic mice quickly restored blood glucose levels. In the future, 3D bioprinting of ß-cells using biomimetic hydrogels will provide a promising platform for clinical islet transplantation for the treatment of diabetes.

Collagen-based hydrogels induce stem cell chondrogenesis and hyaline cartilage regeneration: an in vivo study.

Injectable, self-crosslinking collagen-based hydrogels are beneficial for chondrocytes to secrete matrix, positioning them as promising candidates for cartilage tissue engineering. However, previous studies lacked insight into the ability of cell-free collagen-based hydrogels to regenerate hyaline cartilage defect. Therefore, this study aimed to evaluate the potential of collagen-based hydrogels (Col and ColHA) to induce chondrogenic differentiation of stem cells and in situ hyaline cartilage regeneration. Both Col and ColHA hydrogels self-crosslinked in situ and exhibited similar physical properties. In vitro experiments showed they supported the survival, adhesion, spreading, and proliferation of bone marrow stem cells (BMSCs). Moreover, both hydrogels induced ectopic differentiation of BMSCs into chondrocytes when implanted subcutaneously into the back of nude mice. ColHA hydrogel notably enhanced type II collagen secretion. The results of repairing cartilage defects in situ revealed both hydrogels facilitated hyaline cartilage regeneration and maintained cartilage phenotype without exogenous BMSCs. Hydrogels encapsulating BMSCs expedited cartilage repair, and ColHA/BMSC constructs showed better mechanical properties, suggesting their potential for cartilage repair applications. This study implies that collagen-based hydrogels are good candidates for hyaline cartilage regeneration.

Developing a Biomimetic 3D Neointimal Layer as a Prothrombotic Substrate for a Humanized In Vitro Model of Atherothrombosis.

Acute cardiovascular events result from clots caused by the rupture and erosion of atherosclerotic plaques. This paper aimed to produce a functional biomimetic hydrogel of the neointimal layer of the atherosclerotic plaque that can support thrombogenesis upon exposure to human blood. A biomimetic hydrogel of the neointima was produced by culturing THP-1-derived foam cells within 3D collagen hydrogels in the presence or absence of atorvastatin. Prothrombin time and platelet aggregation onset were measured after exposure of the neointimal models to platelet-poor plasma and washed platelet suspensions prepared from blood of healthy, medication-free volunteers. Activity of the extrinsic coagulation pathway was measured using the fluorogenic substrate SN-17. Foam cell formation was observed following preincubation of the neointimal biomimetic hydrogels with oxidized LDL, and this was inhibited by pretreatment with atorvastatin. The neointimal biomimetic hydrogel was able to trigger platelet aggregation and blood coagulation upon exposure to human blood products. Atorvastatin pretreatment of the neointimal biomimetic layer significantly reduced its pro-aggregatory and pro-coagulant properties. In the future, this 3D neointimal biomimetic hydrogel can be incorporated as an additional layer within our current thrombus-on-a-chip model to permit the study of atherosclerosis development and the screening of anti-thrombotic drugs as an alternative to current animal models.

Biomimetic Mechanically Robust Chiroptical Hydrogel Enabled by Hierarchical Bouligand Structure Engineering.

Natural bouligand structures enable crustacean exoskeletons and fruits to strike a combination of exceptional mechanical robustness and brilliant chiroptical properties owing to multiscale structural hierarchy. However, integrating such a high strength-stiffness-toughness combination and photonic functionalities into synthetic hydrogels still remains a grand challenge. In this work, we report a simple yet general biomimetic strategy to construct an ultrarobust chiroptical hydrogel by closely mimicking the natural bouligand structure at multilength scale. The hierarchical structural engineering of long-range ordered cellulose nanocrystals' bouligand structure, well-defined poly(vinyl alcohol) nanocrystalline domains, and dynamic interfacial interaction synergistically contributes to the integration of high strength (23.3 MPa), superior modulus (264 MPa), and high toughness (54.7 MJ m-3), as well as extraordinary impact resistance, which far exceed their natural counterparts and synthetic photonic hydrogels. More importantly, seamless chiroptical and solvent-responsive patterns with high resolution can also be scalably integrated into the hydrogel by localized manipulation of the photonic band, while maintaining good ionic conductivity. Such exceptional mechanical-photonic combination holds tremendous potential for applications in wearable sensors, encryption, displays, and soft robotics.

Facile Formation of Multifunctional Biomimetic Hydrogel Fibers for Sensing Applications.

To face the challenges in preparing hydrogel fibers with complex structures and functions, this study utilized a microfluidic coaxial co-extrusion technique to successfully form functional hydrogel fibers through rapid ionic crosslinking. Functional hydrogel fibers with complex structures, including linear fibers, core-shell structure fibers, embedded helical channels, hollow tubes, and necklaces, were generated by adjusting the composition of internal and external phases. The characteristic parameters of the hydrogel fibers (inner and outer diameter, helix generation position, pitch, etc.) were achieved by adjusting the flow rate of the internal and external phases. As biocompatible materials, hydrogel fibers were endowed with electrical conductivity, temperature sensitivity, mechanical enhancement, and freeze resistance, allowing for their use as temperature sensors for human respiratory monitoring and other biomimetic application developments. The hydrogel fibers had a conductivity of up to 22.71 S/m, a response time to respiration of 37 ms, a recovery time of 1.956 s, and could improve the strength of respiration; the tensile strength at break up to 8.081 MPa, elongation at break up to 159%, and temperature coefficient of resistance (TCR) up to -13.080% °C-1 were better than the existing related research.

Biomimetic hydrogels with mesoscale collagen architecture for patient-derived tumor organoids culture.

Patient-derived tumor organoids (PDTOs) shows great potential as a preclinical model. However, the current methods for establishing PDTOs primarily focus on modulating local properties, such as sub-micrometer topographies. Nevertheless, they neglect to capture the global millimeter or intermediate mesoscale architecture that have been demonstrated to influence tumor response to therapeutic treatment and tumor progression. In this study, we present a rapid technique for generating collagen bundles with an average length of 90 ± 27 µm and a mean diameter of 5 ± 1.5 µm from tumor tissue debris that underwent mechanical agitation following enzymatic digestion. The collagen bundles were subsequently utilized for the fabrication of biomimetic hydrogels, incorporating microbial transglutaminase (mTG) crosslinked gelatin. These biomimetic hydrogels, referred to as MC-gel, were specifically designed for patient-derived tumor organoids. The lung cancer organoids cultured in MC-gel exhibited larger diameters and higher cell viability compared to those cultured in gels lacking the mesoscale collagen bundle; moreover, their irregular morphology more closely resembled that observed in vivo. The MC-gel-based lung cancer organoids effectively replicated the histology and mutational landscapes observed in the original donor patient's tumor tissue. Additionally, these lung cancer organoids showed a remarkable similarity in their gene expression and drug response across different matrices. This recently developed model holds great potential for investigating the occurrence, progression, metastasis, and management of tumors, thereby offering opportunities for personalized medicine and customized treatment options.

Biomimetic Hydrogel Applications and Challenges in Bone, Cartilage, and Nerve Repair.

Tissue engineering and regenerative medicine is a highly sought-after field for researchers aiming to compensate and repair defective tissues. However, the design and development of suitable scaffold materials with bioactivity for application in tissue repair and regeneration has been a great challenge. In recent years, biomimetic hydrogels have shown great possibilities for use in tissue engineering, where they can tune mechanical properties and biological properties through functional chemical modifications. Also, biomimetic hydrogels provide three-dimensional (3D) network spatial structures that can imitate normal tissue microenvironments and integrate cells, scaffolds, and bioactive substances for tissue repair and regeneration. Despite the growing interest in various hydrogels for biomedical use in previous decades, there are still many aspects of biomimetic hydrogels that need to be understood for biomedical and clinical trial applications. This review systematically describes the preparation of biomimetic hydrogels and their characteristics, and it details the use of biomimetic hydrogels in bone, cartilage, and nerve tissue repair. In addition, this review outlines the application of biomimetic hydrogels in bone, cartilage, and neural tissues regarding drug delivery. In particular, the advantages and shortcomings of biomimetic hydrogels in biomaterial tissue engineering are highlighted, and future research directions are proposed.

Crosslinking strategies for biomimetic hydrogels in bone tissue engineering.

Bone tissue engineering has become a popular area of study for making biomimetic hydrogels to treat bone diseases. In this work, we looked at biocompatible hydrogels that can be injected into bone defects that require the smallest possible surgery. Mineral ions can be attached to polymer chains to make useful hydrogels that help bones heal faster. These ions are very important for the balance of the body. In the chemically-triggered sector, advanced hydrogels cross-linked by different molecular agents have many advantages, such as being selective, able to form gels, and having mechanical properties that can be modified. In addition, different photo-initiators can be used to make photo cross linkable hydrogels react quickly and moderately under certain light bands. Enzyme-triggered hydrogels are another type of hydrogel that can be used to repair bone tissue because they are biocompatible and gel quickly. We also look at some of the important factors mentioned above that could change how well bone tissue engineering works as a therapy. Finally, this review summarizes the problems that still need to be solved to make clinically relevant hydrogels.

Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition.

Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti-invasive agents that are also selectively cytotoxic toward TSC2-/- cells. The anti-invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Genotype-selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue-engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study.

Extracellular magnetic labeling of biomimetic hydrogel-induced human mesenchymal stem cell spheroids with ferumoxytol for MRI tracking.

Labeling of mesenchymal stem cells (MSCs) with superparamagnetic iron oxide nanoparticles (SPIONs) has emerged as a potential method for magnetic resonance imaging (MRI) tracking of transplanted cells in tissue repair studies and clinical trials. Labeling of MSCs using clinically approved SPIONs (ferumoxytol) requires the use of transfection reagents or magnetic field, which largely limits their clinical application. To overcome this obstacle, we established a novel and highly effective method for magnetic labeling of MSC spheroids using ferumoxytol. Unlike conventional methods, ferumoxytol labeling was done in the formation of a mechanically tunable biomimetic hydrogel-induced MSC spheroids. Moreover, the labeled MSC spheroids exhibited strong MRI T2 signals and good biosafety. Strikingly, the encapsulated ferumoxytol was localized in the extracellular matrix (ECM) of the spheroids instead of the cytoplasm, minimizing the cytotoxicity of ferumoxytol and maintaining the viability and stemness properties of biomimetic hydrogel-induced MSC spheroids. This demonstrates the potential of this method for post-transplantation MRI tracking in the clinic.

Remote control of the recruitment and capture of endogenous stem cells by ultrasound for in situ repair of bone defects.

Stem cell-based tissue engineering has provided a promising platform for repairing of bone defects. However, the use of exogenous bone marrow mesenchymal stem cells (BMSCs) still faces many challenges such as limited sources and potential risks. It is important to develop new approach to effectively recruit endogenous BMSCs and capture them for in situ bone regeneration. Here, we designed an acoustically responsive scaffold (ARS) and embedded it into SDF-1/BMP-2 loaded hydrogel to obtain biomimetic hydrogel scaffold complexes (BSC). The SDF-1/BMP-2 cytokines can be released on demand from the BSC implanted into the defected bone via pulsed ultrasound (p-US) irradiation at optimized acoustic parameters, recruiting the endogenous BMSCs to the bone defected or BSC site. Accompanied by the daily p-US irradiation for 14 days, the alginate hydrogel was degraded, resulting in the exposure of ARS to these recruited host stem cells. Then another set of sinusoidal continuous wave ultrasound (s-US) irradiation was applied to excite the ARS intrinsic resonance, forming highly localized acoustic field around its surface and generating enhanced acoustic trapping force, by which these recruited endogenous stem cells would be captured on the scaffold, greatly promoting them to adhesively grow for in situ bone tissue regeneration. Our study provides a novel and effective strategy for in situ bone defect repairing through acoustically manipulating endogenous BMSCs.

A universal post-treatment strategy for biomimetic composite hydrogel with anisotropic topological structure and wide range of adjustable mechanical properties.

The development of biomimetic materials with anisotropic topological structure and wide range of adjustable mechanical properties is central to tissue engineering fields. In this work, on the basis of a stiff/stretchable dually crosslinked hydrogel, we paid more attention to the synergistic contribution of the confined drying and re-swelling (CDR) effect and Hofmeister effect to its micro structures, polymer aggregation states and mechanical strength. Specifically, by changing the pre-strains of the CDR procedure and the soaking time during the salting-out procedure, the arrangement structure orientation, chain-entanglement density, and supramolecular interaction strength within the polymer can be adjusted by changing the processing sequence of the two procedures, so that to obtain anisotropic biomimetic hydrogels with adjustable mechanical properties in a wide range. Thus, this engineered anisotropic polymer can mimic the natural tissues' mechanical properties in regeneration. Moreover and importantly, these anisotropic hydrogels exhibit prominent self-recovery properties. In summary, with the integration of molecular and structural engineering approaches, this study presents a universal strategy for developing anisotropic hydrogels, which could be widely used as biomimetic substitutes with anisotropic features in tissue regeneration.

Piezoelectric Effect of Antibacterial Biomimetic Hydrogel Promotes Osteochondral Defect Repair.

The lack of vascular tissue and the low metabolism and biological activity of mature chondrocytes lead to the low regeneration ability of articular cartilage. People try to solve this problem through various methods, but the effect is not very ideal. Inspired by the piezoelectric effect of collagen in cartilage tissue, this work focused on the design of a biomimetic hydrogel by introducing piezoelectric materials and silver nanowires into hydrogel to endow them with piezoelectric and antibacterial properties to promote tissue regeneration. Additionally, the mechanical and swelling properties of the material were adjusted to match natural articular cartilage. Based on bionic principles, a double-layer piezoelectric hydrogel was prepared and applied for the repair of osteochondral defects. An enhanced repair effect of osteochondral defects has been seen, which has demonstrated potential values for future application in bionics principle- and piezoelectric effect-based osteochondral tissue engineering. Furthermore, piezoelectric effect-induced degradation was observed. These results fully indicated the positive effect of the piezoelectric effect on promoting the regeneration of osteochondral tissue and in vivo degradation of materials.

Biomimetic hydrogel scaffolds via enzymatic reaction for cartilage tissue engineering.

OBJECTIVE: We aimed to evaluate cytocompatibility of hyaluronic acid (HA) and gelatin (Gela) conjugation with phenolic groups (Phs) via enzyme-mediated crosslinking. Phenolic moieties were substituted on the backbone of HA (HA-Ph) and Gela (Gela-Ph) and subsequently were subjected for horseradish peroxidase crosslinking in the presence of H2O2 as an electron donor to create a stable hybrid microenvironment for cellular behavior and cartilage tissue engineering. RESULTS: Successful synthesis of biopolymers confirmed by NRM and UV-Vis spectrophotometry. The physical characteristic of hydrogels including mechanical properties and water contact angle of hydrogels enhanced with addition of Gela-Ph in HA-based hydrogel. The Gela-Ph showed longest gelation time and highest degradation rate. The cellular studies showed cells did not attach to HA-Ph hydrogel. While, proper cell attachment and proliferation observed on blend hydrogel surface compared with the neat hydrogels which interpret by the existence of cell-adhesive motifs of utilized Gela-Ph in this hydrogel. The encapsulated cells in HA-Ph hydrogel were spheroid and just maintained their viability. Hydrogels containing Gela-Ph, the cells were spindle shape with high degrees of cytoplasmic extension. Overall, the results suggest that hybrid biomimetic hydrogel can provide a superior biological microenvironment for chondrocytes in 3D cartilage tissue engineering.

High-Sensitivity Flexible Sensor Based on Biomimetic Strain-Stiffening Hydrogel.

Recently, flexible wearable and implantable electronic devices have attracted enormous interest in biomedical applications. However, current bioelectronic systems have not solved the problem of mechanical mismatch of tissue-electrode interfaces. Therefore, the biomimetic hydrogel with tissue-like mechanical properties is highly desirable for flexible electronic devices. Herein, we propose a strategy to fabricate a biomimetic hydrogel with strain-stiffening property via regional chain entanglements. The strain-stiffening property of the biomimetic hydrogel is realized by embedding highly swollen poly(acrylate sodium) microgels to act as the microregions of dense entanglement in the soft polyacrylamide matrix. In addition, poly(acrylate sodium) microgels can release Na+ ions, endowing hydrogel with electrical signals to serve as strain sensors for detecting different human movements. The resultant sensors own a low Young's modulus (22.61-112.45 kPa), high nominal tensile strength (0.99 MPa), and high sensitivity with a gauge factor up to 6.77 at strain of 300%. Based on its simple manufacture process, well mechanical matching suitability, and high sensitivity, the as-prepared sensor might have great potential for a wide range of large-scale applications such as wearable and implantable electronic devices.

Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering.

Bone tissue engineering has emerged as a significant research area that provides promising novel tools for the preparation of biomimetic hydrogels applied in bone-related diseases (e.g., bone defects, cartilage damage, osteoarthritis, etc.). Herein, thermal sensitive polymers (e.g., PNIPAAm, Soluplus, etc.) were introduced into main chains to fabricate biomimetic hydrogels with injectability and compatibility for those bone defect need minimally invasive surgery. Mineral ions (e.g., calcium, copper, zinc, and magnesium), as an indispensable role in maintaining the balance of the organism, were linked with polymer chains to form functional hydrogels for accelerating bone regeneration. In the chemically triggered hydrogel section, advanced hydrogels crosslinked by different molecular agents (e.g., genipin, dopamine, caffeic acid, and tannic acid) possess many advantages, including extensive selectivity, rapid gel-forming capacity and tunable mechanical property. Additionally, photo crosslinking hydrogel with rapid response and mild condition can be triggered by different photoinitiators (e.g., I2959, LAP, eosin Y, riboflavin, etc.) under specific wavelength of light. Moreover, enzyme triggered hydrogels were also utilized in the tissue regeneration due to its rapid gel-forming capacity and excellent biocompatibility. Particularly, some key factors that can determine the therapy effect for bone tissue engineering were also mentioned. Finally, brief summaries and remaining issues on how to properly design clinical-oriented hydrogels were provided in this review.

Ion-responsive chitosan hydrogel actuator inspired by carrotwood seed pod.

Inspired by the gradient hygroscopic structure of carrotwood seed pod, patterned anisotropic structure was created in polysaccharide hydrogel by an anodic electrical writing process. Locally released Fe2+ was oxidized to Fe3+ and chelated with chitosan chains in the written area, resulting in a gradient structure in the hydrogel. The asymmetrical stress generated by the different swelling of the gradient structure enables the hydrogel to bend autonomously. The hydrogel shows opposite bending in deionized water and NaCl solution. The physicochemical properties of the hydrogel are characterized by tensile test, SEM, EDS, XRD, TGA, DTG and FT-IR. SEM and EDS show that the written hydrogel has a structural gradient and a concentration gradient of Fe3+ vertically. Moreover, anodic electrical writing increases the flexibility of chitosan hydrogel due to decreased crystallinity. This controllable electrical writing technique is convenient to create patterned anisotropic structure and provide a novel design concept for natural hydrogel actuators.