Methacrylated Chondroitin Sulfate Research Articles

Multifunctional magnetic-responsive hydrogels to engineer tendon-to-bone interface

Photocrosslinkable magnetic hydrogels are attracting great interest for tissue engineering strategies due to their versatility and multifunctionality, including their remote controllability ex vivo, thus enabling engineering complex tissue interfaces. This study reports the development of a photocrosslinkable magnetic responsive hydrogel made of methacrylated chondroitin sulfate (MA-CS) enriched with platelet lysate (PL) with tunable features, envisioning their application in tendon-to-bone interface. MA-CS coated iron-based magnetic nanoparticles were incorporated to provide magnetic responsiveness to the hydrogel. Osteogenically differentiated adipose-derived stem cells and/or tendon-derived cells were encapsulated within the hydrogel, proliferating and expressing bone- and tendon-related markers. External magnetic field (EMF) application modulated the swelling, degradation and release of PL-derived growth factors, and impacted both cell morphology and the expression and synthesis of tendon- and bone-like matrix with a more evident effect in co-cultures. Overall, the developed magnetic responsive hydrogel represents a potential cell carrier system for interfacial tissue engineering with EMF-controlled properties.

Tough, Semisynthetic Hydrogels for Adipose Derived Stem Cell Delivery for Chondral Defect Repair.

Cell-based therapies have great potential to regenerate and repair injured articular cartilage, and a range of synthetic and natural polymer-based hydrogels have been used in combination with stem cells and growth factors for this purpose. Although the hydrogel scaffolds developed to date possess many favorable characteristics, achieving the required mechanical properties has remained a challenge. A hydrogel system with tunable mechanical properties, composed of a mixture of natural and synthetic polymers, and its use for the encapsulation of adipose derived stem/stromal cells (ASCs) is described. Solutions of methacrylated chondroitin sulfate (MCS) are mixed with solutions of acrylate-poly(trimethylene carbonate)-b-poly(ethylene glycol)-b-poly(trimethylene carbonate)-acrylate (PEG-(PTMC-A)2 ) in phosphate buffered saline and crosslinked via thermally initiated free radical polymerization. The hydrogel compressive equilibrium moduli and toughness are readily tailored by varying the concentration of the pre-polymers, as well as the molecular weight of the PEG used to prepare the PEG-(PTMC-A)2 . Two peptide sequences, GVOGEA and GGGGRGDS, are individually conjugated to the MCS to facilitate cell binding. The presence of the peptide ligands yields high ASC viability and long term metabolic activity following encapsulation in hydrogels prepared using the thermal initiator system. Overall, these hydrogels show promise as a minimally invasive ASC delivery strategy for chondral defect repair.

Gelatin-based extracellular matrix cryogels for cartilage tissue engineering

Abstract In this study, gelatin-based cryogels were fabricated by mixing methacrylated gelatin (GelMA) with methacrylated hyaluronic acid (MeHA) or methacrylated chondroitin sulfate (MeCS) for cartilage tissue engineering. In vitro revealed that MeCS incorporated gelatin-based cryogel (G-MeCS) showed significant cartilaginous tissue stimulation. Furthermore, the cell-laden gelatin-based ECM cryogels were implanted into mouse subcutaneous tissue for 6 weeks and displayed uniform distribution of cells with normal phenotype maintenance. Finally, when these cryogels were implanted into osteochondral defect of New Zealand white rabbit, full integration with host tissue and increased cellularity were observed with G-MeCS cryogel.

A Synthetic Thermosensitive Hydrogel for Cartilage Bioprinting and Its Biofunctionalization with Polysaccharides.

Hydrogels based on triblock copolymers of polyethylene glycol and partially methacrylated poly[N-(2-hydroxypropyl) methacrylamide mono/dilactate] make up an attractive class of biomaterials because of their biodegradability, cytocompatibility, and tunable thermoresponsive and mechanical properties. If these properties are fine-tuned, the hydrogels can be three-dimensionally bioprinted, to generate, for instance, constructs for cartilage repair. This study investigated whether hydrogels based on the polymer mentioned above with a 10% degree of methacrylation (M10P10) support cartilage formation by chondrocytes and whether the incorporation of methacrylated chondroitin sulfate (CSMA) or methacrylated hyaluronic acid (HAMA) can improve the mechanical properties, long-term stability, and printability. Chondrocyte-laden M10P10 hydrogels were cultured for 42 days to evaluate chondrogenesis. M10P10 hydrogels with or without polysaccharides were evaluated for their mechanical properties (before and after UV photo-cross-linking), degradation kinetics, and printability. Extensive cartilage matrix production occurred in M10P10 hydrogels, highlighting their potential for cartilage repair strategies. The incorporation of polysaccharides increased the storage modulus of polymer mixtures and decreased the degradation kinetics in cross-linked hydrogels. Addition of HAMA to M10P10 hydrogels improved printability and resulted in three-dimensional constructs with excellent cell viability. Hence, this novel combination of M10P10 with HAMA forms an interesting class of hydrogels for cartilage bioprinting.

Extracellular matrix-based cryogels for cartilage tissue engineering

In this study, we investigated various highly porous extracellular matrix (ECM)-based cryogels for cartilage tissue engineering. For the fabrication of ECM-based cryogels, either methacrylated chondroitin sulfate (MeCS) or methacrylated hyaluronic acid (MeHA) were cross-linked along with poly (ethylene glycol) diacrylates (PEGDA) via free radical polymerization under freezing conditions. This procedure induces ice crystallization (used as a porogen) prior polymer crosslinking in which, after complete cryopolymerization, a thawing process transforms the ice crystals into a unique interconnected macroporous structure within ECM-cryogels. The developed ECM-cryogels exhibited an average macroporosity of 75% and supported the infiltration of chondrocyteds. When rabbit chondrocytes were cultured on ECM-cryogels, MeCS-based cryogels stimulated aggrecan gene expression and GAG accumulation, whereas MeHA-based cryogels stimulated type II collagen gene expression and collagen accumulation. These results demonstrate that design of ECM-based cryogels can play an important role in promoting specific ECM proteins secretion for cartilage tissue engineering.

A thermo-responsive and photo-polymerizable chondroitin sulfate-based hydrogel for 3D printing applications

The aim of this study was to design a hydrogel system based on methacrylated chondroitin sulfate (CSMA) and a thermo-sensitive poly(N-(2-hydroxypropyl) methacrylamide-mono/dilactate)-polyethylene glycol triblock copolymer (M15P10) as a suitable material for additive manufacturing of scaffolds. CSMA was synthesized by reaction of chondroitin sulfate with glycidyl methacrylate (GMA) in dimethylsulfoxide at 50°C and its degree of methacrylation was tunable up to 48.5%, by changing reaction time and GMA feed. Unlike polymer solutions composed of CSMA alone (20% w/w), mixtures based on 2% w/w of CSMA and 18% of M15P10 showed strain-softening, thermo-sensitive and shear-thinning properties more pronounced than those found for polymer solutions based on M15P10 alone. Additionally, they displayed a yield stress of 19.2±7.0Pa. The 3D printing of this hydrogel resulted in the generation of constructs with tailorable porosity and good handling properties. Finally, embedded chondrogenic cells remained viable and proliferating over a culture period of 6days. The hydrogel described herein represents a promising biomaterial for cartilage 3D printing applications.

Chondrocyte Generation of Cartilage-Like Tissue Following Photoencapsulation in Methacrylated Polysaccharide Solution Blends.

Chondrocyte-seeded, photo-cross-linked hydrogels prepared from solutions containing 50% mass fractions of methacrylated glycol chitosan or methacrylated hyaluronic acid (MHA) with methacrylated chondroitin sulfate (MCS) are cultured in vitro under static conditions over 35 d to assess their suitability for load-bearing soft tissue repair. The photo-cross-linked hydrogels have initial equilibrium moduli between 100 and 300 kPa, but only the MHAMCS hydrogels retain an approximately constant modulus (264 ± 5 kPa) throughout the culture period. Visually, the seeded chondrocytes in the MHAMCS hydrogels are well distributed with an apparent constant viability in culture. Multicellular aggregates are surrounded by cartilaginous matrix, which contain aggrecan and collagen II. Thus, co-cross-linked MCS and MHA hydrogels may be suited for use in an articular cartilage or nucleus pulposus repair applications.

Structurally Versatile Glycosaminoglycan Hydrogels for Biomedical Applications

SummaryDespite widespread use of hydrogels in biomedical devices, low moduli and brittleness of hydrogels has hindered applications with load bearing requirements. In this study, different molecular network design strategies (homopolymer, copolymer, and double network) were used to control the arrangement of macromers to tune the mechanical properties of glycosaminoglycan (GAG)‐based hydrogels. The resulting changes in swelling ratio, crosslink density, and fracture properties of the gels were then investigated. It was hypothesized that increasing the number of polymerizable groups on the macromers methacrylated chondroitin sulfate (MCS) or methacrylated hyaluronic acid (MHA) and using oligo(ethylene glycol diacrylate) s to copolymerize with can improve the crosslinking by increasing the effectiveness of polymerization through the kinetic chains. By increasing the degree of methacrylation of MCS from 24 to 34 mol%, the swelling ratio q and the crosslink density ρx of 13 wt% MCS gel was changed from 210 to 44 g/g and from 230 to 740 mol/m3, respectively. Despite improved ρx and tuned q, the fracture strain of the homo‐ and copolymer gels remained fairly low (<25%), likely due to the highly extended conformation of glycosaminoglycans, and the microheterogeneity induced by the kinetic chains. However, using a DN double network design (with PAAm), the fracture strain and toughness of the gels were greatly improved as the fracture strain of 15 wt% MCS‐PAAm DN increased more than 3 times, from 15 to 55%. The versatile physical and favorable biological properties of GAG‐based hydrogels make them promising materials for many biomedical applications.

Biodegradable CSMA/PECA/Graphene Porous Hybrid Scaffold for Cartilage Tissue Engineering.

Owing to the limited repair capacity of articular cartilage, it is essential to develop tissue-engineered cartilage for patients suffering from joint disease and trauma. Herein, we prepared a novel hybrid scaffold composed of methacrylated chondroitin sulfate (CSMA), poly(ethylene glycol) methyl ether-ε-caprolactone-acryloyl chloride (MPEG-PCL-AC, PECA was used as abbreviation for MPEG-PCL-AC) and graphene oxide (GO) and evaluated its potential application in cartilage tissue engineering. To mimic the natural extracellular matrix (ECM) of cartilage, the scaffold had an adequate pore size, porosity, swelling ability, compression modulus and conductivity. Cartilage cells contacted with the scaffold remained viable and showed growth potential. Furthermore, CSMA/PECA/GO scaffold was biocompatible and had a favorable degradation rate. In the cartilage tissue repair of rabbit, Micro-CT and histology observation showed the group of CSMA/PECA/GO scaffold with cellular supplementation had better chondrocyte morphology, integration, continuous subchondral bone, and much thicker newly formed cartilage compared with scaffold group and control group. Our results show that the CSMA/PECA/GO hybrid porous scaffold can be applied in articular cartilage tissue engineering and may have great potential to in other types of tissue engineering applications.

Biopolymer-based functional inks for the preparation of artificial cartilage via bioprinting technology

We present bioinks based on biopolymers from the native extracellular matrix, namely gelatin and chondroitin sulfate, which are suitable for bioprinting technology applying living mammalian cells. The bioinks can be crosslinked due to chemical modification of the biopolymers with methacrylic functions. Such insoluble hydrogels with tunable physico-chemical propertie are able to closely mimic the native extracellular matrix of biological tissues (ECM). Highly methacrylated gelatin (GM10) resulted in solutions with low viscosities (e.g. 15 wt%: 6.7 ± 1.0 mPa s at 37 °C) within the inkjet-printable range and crosslinked hydrogels with high mechanical strength. Less methacrylated gelatin (GM2) was proper for preparation of soft hydrogels and highly viscous bioinks for pneumatic dispensing technology (e.g. 15 wt%: 39.3 ± 3.6 mPa s at 37 °C). By additional acetylation of GM2 (GM2A8) the solution viscosity could be significantly lowered (e.g. 15 wt%: η = 5.2 ± 0.5 mPa s, 37 °C) and, thus, inkjet-printable bioinks with low crosslinking capacity were also gained. Consequently, a versatile bioink system for bioprinting technology was created. by adjustable twofold modification of gelatin with photochemically reactive and inert groups. Introduction of an additional methacrylated component of the ECM, methacrylated chondroitin sulfate (CSM), further tuned the chemical and physical properties of bioink and hydrogels. GM(A)-CSM hybrid hydrogels possessed for example significantly higher swellability than pure GM(A) hydrogels of the same mass fraction. CSM also influenced bioink viscosity: For unmodified gelatin and gelatin with low degree of modification CSM induced a decrease in bioink viscosity (e.g. 15 wt% GM2: 39.3 ± 3.6 mPa s versus 14 wt% GM2 + 1 wt% CSM: 32.9 ± 6.5 mPa s). In contrast to this, addition of CSM to bioinks made of gelatins with high degree of modification, GM2A8 or GM10, induced an increase in solution viscosity (e.g. 15 wt% GM2A8: 5.2 ± 0.5 mPa s versus 14 wt% GM2A8 + 1 wt% CSM: 6.5 ± 1.0 mPa s). The developed bioinks were proven to be suitable for bioprinting with viable mammalian cells, in this case porcine articular chondrocytes, and for fabrication of tissue models with intrinsic structure. Thus, biomaterials presented in this study can be used for biofabrication of artificial three-dimensional tissues with biomimetic organization, such as articular cartilage with its hierarchical structure.

Chondroitin Sulfate Microparticles Modulate Transforming Growth Factor-β1-Induced Chondrogenesis of Human Mesenchymal Stem Cell Spheroids

Mesenchymal stem cells (MSCs) have been previously explored as a part of cell-based therapies for the repair of damaged cartilage. Current MSC chondrogenic differentiation strategies employ large pellets; however, we have developed a technique to form small MSC aggregates (500-1,000 cells) that can reduce transport barriers while maintaining a multicellular structure analogous to cartilaginous condensations. The objective of this study was to examine the effects of incorporating chondroitin sulfate methacrylate (CSMA) microparticles (MPs) within small MSC spheroids cultured in the presence of transforming growth factor (TGF)-β₁ on chondrogenesis. Spheroids with MPs induced earlier increases in collagen II and aggrecan gene expression (chondrogenic markers) than spheroids without MPs, although no large differences in immunostaining for these matrix molecules were observed by day 21 between these groups. Collagen I and X were also detected in the extracellular matrix (ECM) of all spheroids by immunostaining. Interestingly, histology revealed that CSMA MPs clustered together near the center of the MSC spheroids and induced circumferential alignment of cells and ECM around the material core. This study demonstrates the use of CSMA materials to further examine the effects of matrix molecules on MSC phenotype as well as potentially direct differentiation in a more spatially controlled manner that better mimics the architecture of specific musculoskeletal tissues.

Tuning Mechanical Properties of Chondroitin Sulfate-Based Hydrogels Using the Double-Network Strategy

ABSTRACTThe double-network (DN) hydrogel concept developed by J.P. Gong and Y. Osada builds upon interpenetrating networks by combining brittle and ductile components to have significantly enhanced fracture properties. The generality of the DN effect was tested by creating biopolymer-based hydrogels of methacrylated chondroitin sulfate (MCS) and polyacrylamide (PAAm) and extended upon creating DNs of MCS and poly(N,N dimethyl acrylamide) (PDMAAm), verifying that DNs were not limited to the original combination of poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS)/polyacrylamide (PAAm). Further, the mechanical properties were varied by changing the monomer concentrations, cross-linker concentrations and the addition of cross-linking groups through copolymerizations of MCS and poly(ethylene glycol) diacrylate (PEGDA). Overall, this work demonstrates that a broad range of mechanical properties achievable through DN effect under tension and compression, generally independent of the swelling degree, which is fundamentally different behavior than possible with single networks.

Mimicking the Extracellular Matrix: Tuning the Mechanical Properties of Chondroitin Sulfate Hydrogels by Copolymerization with Oligo(ethylene glycol) Diacrylates

ABSTRACTChondroitin sulfate (CS) is one of the major glycosaminoglycans (GAGs) present in the connective tissue extracellular matrix (ECM) and is responsible for the regulation of cellular activities as well as providing mechanical support for the surrounding tissue. Due to presence of CS in the natural tissues including cartilage, hydrogels of CS and other GAGs have been widely used in cartilage regeneration. Due to their polyelectrolyte nature, GAG-based hydrogels are brittle and require modifications to overcome the weak mechanical properties. In this work, we showed copolymerization of methacrylated chondroitin sulfate with oligo(ethylene glycol)s improved the crosslink density of the gels from 2 to 20 times depending on the methacrylation degree of CS and length of the crosslinking monomer. Copolymerization of CS with oligo(ethylene glycol) acrylates is a method to design hydrogels with tunable swelling and mechanical properties.

Smart Stimuli Sensitive Nanogels in Cancer Drug Delivery and Imaging: A Review

Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.

Increasing Cross-Linking Efficiency of Methacrylated Chondroitin Sulfate Hydrogels by Copolymerization with Oligo(Ethylene Glycol) Diacrylates

A simple method was developed for increasing the modulus of methacrylated chondroitin sulfate (MCS) hydrogels. Photopolymerized MCS gels are relatively soft with low cross-link density, but copolymerization of MCS with 0.5 to 2.0 wt % oligo(ethylene glycol) diacrylates (OEGDA) increased the moduli over an order of magnitude. The shear modulus of gels was amplified 2–25 times by increasing the methacrylation extent and copolymerizing with higher molar mass OEGDAs (up to 700 Da). In contrast, copolymerizing MCS with oligomers of ethylene glycol dimethacrylate (OEGDMA) reduced the moduli from that of MCS alone. The cross-linking appears to occur primarily by incorporation of methacrylate groups of different MCS molecules into common kinetic chains rather than by linking different kinetic chains together by EG linking chains since monoacrylate monomers enhanced cross-linking nearly as much as the diacrylates. The difference between the copolymerization behaviors of OEGDAs vs analogous OEGDMAs was hypothesized...

A biomimetic extracellular matrix for cartilage tissue engineering centered on photocurable gelatin, hyaluronic acid and chondroitin sulfate

The development of hydrogels tailored for cartilage tissue engineering has been a research and clinical goal for over a decade. Directing cells towards a chondrogenic phenotype and promoting new matrix formation are significant challenges that must be overcome for the successful application of hydrogels in cartilage tissue therapies. Gelatin–methacrylamide (Gel-MA) hydrogels have shown promise for the repair of some tissues, but have not been extensively investigated for cartilage tissue engineering. We encapsulated human chondrocytes in Gel-MA-based hydrogels, and show that with the incorporation of small quantities of photocrosslinkable hyaluronic acid methacrylate (HA-MA), and to a lesser extent chondroitin sulfate methacrylate (CS-MA), chondrogenesis and mechanical properties can be enhanced. The addition of HA-MA to Gel-MA constructs resulted in more rounded cell morphologies, enhanced chondrogenesis as assessed by gene expression and immunofluorescence, and increased quantity and distribution of the newly synthesized extracellular matrix (ECM) throughout the construct. Consequently, while the compressive moduli of control Gel-MA constructs increased by 26kPa after 8weeks culture, constructs with HA-MA and CS-MA increased by 114kPa. The enhanced chondrogenic differentiation, distribution of ECM, and improved mechanical properties make these materials potential candidates for cartilage tissue engineering applications.

Tuning Mechanical Properties of Chondroitin Sulfate‐Based Double‐Network Hydrogels

SummaryHigh strength double‐network (DN) biopolymer‐based hydrogels were created using copolymers of methacrylated chondroitin sulfate (MCS) and poly(ethylene glycol) diacrylate (PEGDA) as the first network and polyacrylamide (PAAm) as the second network. The concentration and cross‐linking of the networks were adjusted to control the mechanical properties including the failure stress, failure strain, Young's modulus, and yielding behavior. First, we increased the cross‐linking of the first network both by increasing the MCS concentration from 13 to 20 wt% and by copolymerizing MCS with 2 to 6 wt% PEGDA. The additional cross‐linking increased the Young's modulus as much as five times, reaching 3.3 MPa, and the failure stress up as much as four times, reaching 2.9 MPa. However, this also reduced failure strain from a high of 2.9 mm/mm to a low of 0.12 mm/mm and diminished the yielding region. Changes in the concentrations of acrylamide or its cross‐linking with N,N′‐methylenebisacrylamide (BIS) in the second network had a lesser effect on the DN properties. We hypothesized that to obtain a yielding region which results in high toughness, we need to alter the cross‐linking of the first network such that the yield stress of the MCS‐PEGDA/PAAm DN does not exceed the failure stress of PAAm network. Because of the wide range of mechanical properties achieved in these DNs with limited changes in the swelling degrees, unlike conventional single‐network gels, the DN approach allows attainment of a much greater range of mechanical behavior than is possible with single networks.

The Copolymer of Poly(2‐dimethylaminoethyl methacrylate) and Methacrylated Chondroitin Sulfate with Low Cytotoxicity for Gene Delivery

Poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) is one of the most potent synthetic nonviral gene-delivery vectors because of its high transfection efficiency. However, the cytotoxicity of PDMAEMA is a major concern for its clinical applications. An anionic crosslinker is synthesized based on a natural polysaccharide, chondroitin sulfate (CS), by introducing methacrylate groups (CSMA). By systematically adjusting the substitution degree of methacrylation on CS and the weight percent of CSMA and PDMAEMA, sol-type copolymers are obtained as a gene-delivery vector. The combination of CS and PDMAEMA is expected not only to reduce the cytotoxicity of PDMAEMA, but also to facilitate better transfection efficiency than PDMAEMA because of the recognition of CS by CD44 receptors on cell surfaces. Two CSMA-modified PDMAEMA copolymers with different CSMA constituents are selected and their polyplexes prepared with plasmid DNA. The cytotoxicity and gene transfection efficiency of the polyplexes are tested and compared with those of PDMAEMA/pDNA. The copolymers of CSMA and PDMAEMA show significantly improved cell viability as compared with PDMAEMA. Their formed polyplexes with pDNA also show lower cytotoxicity than does PDMAEMA/pDNA. The transfection efficiency remarkably increases as the CSMA-modified PDMAEMA/pDNA polyplex is prepared at a weight ratio of 2.4. The internalization mechanism of CSMA-modified PDMAEMA/pDNA in HEK 293T cells is mainly based on caveolae-mediated endocytosis. However, both caveolae-mediated and CD44-mediated endocytosis mechanisms are involved in U87 cells.

Studying cell‐cell communication in co‐culture

Studying cell‐cell communication in co‐culture

Double-Network Strategy Improves Fracture Properties of Chondroitin Sulfate Networks.

A tough and ductile, ultrathin film, double-network (DN), biopolymer-based hydrogel displaying the yielding phenomenon was synthesized from methacrylated chondroitin sulfate (MCS) and polyacrylamide (PAAm). The DN of MCS/PAAm exhibited a failure stress more than 20 times greater than the single network (SN) of either MCS or PAAm and exhibited yielding stresses over 1500 kPa. In addition, the stress-strain behavior with a yielding region was also seen in a hydrogel of MCS and poly(N,N-dimethyl acrylamide) (PDMAAm). By replacing PAAm with PDMAAm, interactions known to toughen networks are removed. This demonstration supports the idea that the brittle/ductile combination is key to the DN effect over specific interactions between the networks. The MCS/PAAm and MCS/PDMAAm DN hydrogels had comparable mechanical properties to the archtypal DN hydrogels of poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS)/PAAm. In addition, these tough and ductile, biopolymer-based, double-network hydrogels demonstrated a substantial yielding region.