Bioinspired Hydrogel Research Articles

Bioinspired 3D Printable, Self-Healable, and Stretchable Hydrogels with Multiple Conductivities for Skin-like Wearable Strain Sensors

Bioinspired hydrogels have promising prospects in applications such as wearable devices, human health monitoring equipment, and soft robots due to their multifunctional sensing properties resembling natural skin. However, the preparation of intelligent hydrogels that provide feedback on multiple electronic signals simultaneously, such as human skin receptors, when stimulated by external contact pressure remains a substantial challenge. In this study, we designed a bioinspired hydrogel with multiple conductive capabilities by incorporating carbon nanotubes into a chelate of calcium ions with polyacrylic acid and sodium alginate. The bioinspired hydrogel consolidates self-healing ability, stretchability, 3D printability, and multiple conductivities. It can be fabricated as an integrated strain sensor with simultaneous piezoresistive and piezocapacitive performances, exhibiting sensitive (gauge factor of 6.29 in resistance mode and 1.25 kPa-1 in capacitance mode) responses to subtle pressure changes in the human body, such as finger flexion, knee flexion, and respiration. Furthermore, the bioinspired strain sensor sensitively and discriminatively recognizes the signatures written on it. Hence, we expect our ideas to provide inspiration for studies exploring the use of advanced hydrogels in multifunctional skin-like smart wearable devices.

Immobilization of Transglutaminase on multi-walled carbon nanotubes and its application as bioinspired hydrogel scaffolds

The chemical cross-linkers are difficult to be removed from the scaffold materials, which limit their application in tissue engineering; designing an efficient biocompatible hydrogel is though challenging is desirable. The aim of the present study was to immobilize microbial Transglutaminase (MTGase) enzyme on multi-walled carbon nanotubes (MWCNTs) for its application in hydrogel scaffolds designing. MTGase from Streptomyces mobaraensis, a non-toxic biological cross-linker, was employed for a greener approach with enhanced biochemical and structural properties. The maximum immobilization efficiency of 58% was achieved when MTGase was covalently coupled on MWCNTs. The kinetic studies showed 4.76-fold increase in catalytic efficiency and good reusability upto seven cycles. Attachment of enzyme on MWCNTs surface was studied through SEM and FTIR. The immobilized enzyme showed good cross-linking efficiency in gelatin hydrogel scaffold resulting decrease in swelling ratio of hydrogel. Our findings report for the first time the development of novel biocompatible hydrogel scaffolds with immobilized MTGase onto MWCNTS. Inevitable damage of hydrogels are incurred during their applications. To offset the damage of hydrogels, the creation of bioinspired hydrogels emulating native tissue microenvironment is highly significant. Microbial TGase holds promising future with its applicability as a cross-linker of hydrogel scaffolds in the area of tissue engineering.

Layered Hydrogel with Controllable Surface Dissociation for Durable Lubrication

Developing bioinspired hydrogel materials with extraordinary lubrication, load-bearing, and antiwear property is necessary for durable lubricious implants or devices. Despite the extensive research focus on lubrication of hydrogel materials, achieving a balance between lubrication and load-bearing for the current system is commonly difficult because of their poor mechanical property. Herein, a cartilage-inspired layered hydrogel material composed of a soft and porous top layer and a robust bottom layer is easily prepared by employing an alkali-induced network dissociation strategy. The thickness of the top soft layer increases with extending the alkali treatment time, along with differential surface and cross-sectional morphologies and mechanical property. The top soft and porous layer ensures that the surface shows extremely low friction (coefficient of friction (COF) ∼ 0.009, 3 N; COF ∼ 0.035, 20 N) against a hard steel ball contact pair, while the bottom layer acts as an excellent load-bearing function. Therefore, the layered hydrogels can achieve extraordinary wear resistance features, resulting from a combination of surface lubrication and bottom load-bearing. It is demonstrated that the method can be used to develop a layered hydrogel lubrication catheter, for which both of its inner and outer surfaces exhibit a slippery feature. The extraordinary lubricious performance of the layered hydrogels implies their potential application in the field of tissue engineering and medical devices.

Achieving High-Speed Retraction in Stretchable Hydrogels.

Hydrogels mimicking elastomeric biopolymers such as resilin, responsible for power-amplified activities in biological species necessary for locomotion, feeding, and defense have applications in soft robotics and prosthetics. Here, we report a bioinspired hydrogel synthesized through a free-radical polymerization reaction. By maintaining a balance between the hydrophilic and hydrophobic components, we obtain gels with an elastic modulus as high as 100 kPa, stretchability up to 800%, and resilience up to 98%. Such properties enable these gels to catapult projectiles. Furthermore, these gels achieve a retraction velocity of 16 m s-1 with an acceleration of 4 × 103 m s-2 when released from a stretched state, and these values are comparable to those observed in many biological species during a power amplification process. By utilizing and tuning the simple synthetic strategy used here, these gels can be used in soft robotics, prosthetics, and engineered devices where power amplification is desired.

Bioinspired Hydrogel Coating Based on Methacryloyl Gelatin Bioactivates Polypropylene Meshes for Abdominal Wall Repair.

Considering the potential of hydrogels to mimic the cellular microenvironment, methacryloyl gelatin (GelMA) and methacryloyl mucin (MuMA) were selected and compared as bioinspired coatings for commercially available polypropylene (PP) meshes for ventral hernia repair. Thin, elastic hydrated hydrogel layers were obtained through network-forming photo-polymerization, after immobilization of derivatives on the surface of the PP fibers. Fourier transform infrared spectroscopy (FTIR) proved the successful coating while the surface morphology and homogeneity were investigated by scanning electron microscopy (SEM) and micro-computed tomography (micro-CT). The stability of the hydrogel layers was evaluated through biodynamic tests performed on the coated meshes for seven days, followed by inspection of surface morphology through SEM and micro-CT. Taking into account that platelet-rich plasma (PRP) may improve healing due to its high concentration of growth factors, this extract was used as pre-treatment for the hydrogel coating to additionally stimulate cell interactions. The performed advanced characterization proved that GelMA and MuMA coatings can modulate fibroblasts response on PP meshes, either as such or supplemented with PRP extract as a blood-derived bioactivator. GelMA supported the best cellular response. These findings may extend the applicative potential of functionalized gelatin opening a new path on the research and engineering of a new generation of bioactive meshes.

Bio-inspired Hydrogels as Multi-task Anti-icing Hydrogel Coatings

In a recent report in Matter, Zhu, Wang, He and co-workers report a straightforward and effective strategy for the design of icephobic hydrogel coatings on the basis of polydimethylsiloxane (PDMS)-grafted polyelectrolyte hydrogels. These passive anti-icing and de-icing coatings were demonstrated to synergistically suppress ice nucleation, ice propagation, and ice adhesion.

Fabrication of Bioinspired Hydrogels: Challenges and Opportunities

Since the birth of synthetic hydrogel 60 years ago, hydrogels possessing various useful properties and functions have been developed. The research directions of hydrogels have expanded to diverse a...

Bioinspired Thermosensitive Hydrogel as a Vitreous Substitute: Synthesis, Properties, and Progress of Animal Studies.

In many vitreal diseases, the surgeon removes the natural vitreous and replaces it with silicone oils, gases, or balanced salt solutions to fill the eyeball and hold the retina in position. However, these materials are often associated with complications and have properties that differ from natural vitreous. Herein, we report an extension of our previous work on the synthesis of a biomimetic hydrogel that is composed of thiolated gellan as an analogue of type II collagen and poly(methacrylamide-co-methacrylate-co-bis(methacryloyl)cystamine), a polyelectrolyte, as an analogue of hyaluronic acid. This thermosensitive hydrogel can be injected into the eye as a viscous solution at 45 °C. It then forms a physical gel in situ when it reaches body temperature, and later forms disulfide covalent crosslinks. In this article, we evaluated two different formulations of the biomimetic hydrogels for their physical, mechanical, and optical properties, and we determined their biocompatibility with several cell lines. Finally, we report on the progress of the four-month preclinical evaluation of our bio-inspired vitreous substitute in comparison to silicone oil or a balanced salt solution. We assessed the eyes with a slit-lamp examination, intraocular pressure measurements, electroretinography, and optical coherence tomography. Preliminary results are very encouraging for the continuing evaluation of our bio-inspired hydrogel in clinical trials.

Bio-inspired hydrogel composed of hyaluronic acid and alginate as a potential bioink for 3D bioprinting of articular cartilage engineering constructs

Bioprinting is a promising tool to fabricate well-organized cell-laden constructs for repair and regeneration of articular cartilage. The selection of a suitable bioink, in terms of composition and mechanical properties, is crucial for the development of viable cartilage substitutes. In this study, we focused on the use of one of the main cartilage components, hyaluronic acid (HA), to design and formulate a new bioink for cartilage tissue 3D bioprinting. Major characteristics required for this application such as printability, biocompatibility, and biodegradability were analyzed. To produce cartilage constructs with optimal mechanical properties, HA-based bioink was co-printed with polylactic acid (PLA). HA-based bioink was found to improve cell functionality by an increase in the expression of chondrogenic gene markers and specific matrix deposition and, therefore, tissue formation. These results indicate that it is a promising bioink candidate for cartilage tissue engineering based in 3D bioprinting. Statement of SignificanceThe recent appearance of 3D printing technology has enabled great advances in the treatment of osteochondral disorders by fabrication of cartilage tissue constructs that restore and/or regenerate damaged tissue. In this attempt, the selection of a suitable biomaterial, in terms of composition and mechanical properties, is crucial. In this study, we describe for first time the development of a bioink based on the main component of cartilage, HA, with suitable biological and mechanical properties, without involving toxic procedure, and its application in cartilage tissue bioprinting. Hybrid constructs prepared by co-printing this bioink and thermoplastic polymer PLA provided an optimal niche for chondrocyte growth and maintenance as well as mechanical properties necessary to support load forces exerted in native tissue. We highlight the translation potential of this HA-based bioink in the clinical arena.

Cytosine-functionalized bioinspired hydrogels for ocular delivery of antioxidant transferulic acid.

Contact lenses (CLs) are being pointed out as feasible platforms for controlled delivery of ophthalmic drugs. Bioinspired strategies may endow CLs with affinity for a given drug by mimicking its physiological receptor using adequate functional monomers and tuning their conformation in the space through the molecular imprinting technology. However, there are some active substances, such as efficient antioxidant agents, that cannot be used as templates because they degrade during polymerization or even hinder the polymerization itself. Therefore, the development of CLs able to sustain the release of antioxidants for the prevention and/or treatment of several age-related and light-induced eye diseases has not been explored yet. Searching for an alternative bioinspired strategy, the present work relies on the fact that some drugs owe their therapeutic action to their ability to interact with nucleotides that build up DNA and RNA. Thus, the aim of this work was to design hydrogels functionalized with the nitrogenous base cytosine for the controlled uptake and release of transferulic acid (TA) having a complementary chemical structure in terms of hydrogen bonding and π-π stacking ability. Hydrogels were prepared from mixtures of 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA) and ethyleneglycolphenylether methacrylate (EGPEM). GMA was used as a bridge to immobilize cytosine after hydrogel synthesis, while EGPEM was added to reinforce hydrophobic interactions with TA. The hydrogels were characterized in terms of suitability to be used as CLs (swelling, light transmission, mechanical properties, biocompatibility) and capability to host TA and sustain its release in lachrymal fluid while maintaining the antioxidant activity. Relevantly, the bioinspired CLs favored TA accumulation in cornea and sclera tissues.

Single-injecting, bioinspired nanocomposite hydrogel that can recruit host immune cells in situ to elicit potent and long-lasting humoral immune responses

Vaccination is an effective medical intervention for preventing disease. However, without an adjuvant, most subunit vaccines are poorly immunogenic. This work develops a bioinspired nanocomposite hyaluronic acid hydrogel system that incorporates N-trimethyl chitosan nanoparticles (TMC/NPs) that carry a model subunit vaccine ovalbumin (OVA) that can elicit a potent and prolonged antigen-specific humoral response. Experimental results indicate that the nanocomposite hydrogel system (NPs-Gel) can retain a large proportion of its TMC/NPs that are bonded by covalent/electrostatic interactions and extend the release of the encapsulated OVA, enabling their localization at the site of hydrogel injection. The positively charged TMC/NPs can be effectively internalized by dendritic cells, significantly augmenting their maturation, suggesting that TMC can function as an adjuvant-based OVA delivery system. Upon subcutaneous implantation in mice, the NPs-Gel acts as an in situ depot that recruits and concentrates immune cells. The TMC/NPs that do not have any specific interactions with the hydrogel network are released rapidly and internalized by the neighboring immune cells, providing a priming dose, while those retained inside the NPs-Gel are ingested by the recruited and concentrated immune cells over time, acting as a booster dose, eliciting high titers of OVA-specific antibody responses. These experimental results suggest particulate vaccines that are integrated in such a bioinspired hydrogel system may be used as single-injection prime-boost vaccines, enabling effective and persistent humoral immune responses.

Supramolecular Modification of a Sequence-Controlled Collagen-Mimicking Polymer.

Structurally and functionally well-defined recombinant proteins are an interesting class of sequence-controlled macromolecules to which different crosslinking chemistries can be applied to tune their biological properties. Herein, we take advantage of a 571-residue recombinant peptide based on human collagen type I (RCPhC1), which we functionalized with supramolecular 4-fold hydrogen bonding ureido-pyrimidinone (UPy) moieties. By grafting supramolecular UPy moieties onto the backbone of RCPhC1 (UPy-RCPhC1), increased control over the polymer structure, assembly, gelation, and mechanical properties was achieved. In addition, by increasing the degree of UPy functionalization on RCPhC1, cardiomyocyte progenitor cells were cultured on “soft” (∼26 kPa) versus “stiff” (∼68–190 kPa) UPy-RCPhC1 hydrogels. Interestingly, increased stress fiber formation, focal adhesions, and proliferation were observed on stiffer compared to softer substrates, owing to the formation of stronger cell–material interactions. In conclusion, a bioinspired hydrogel material was designed by a combination of two well-known natural components, i.e., a protein as sequence-controlled polymer and UPy units inspired on nucleobases.

Insect Cuticle-Mimetic Hydrogels with High Mechanical Properties Achieved via the Combination of Chitin Nanofiber and Gelatin.

By mimicking the natural sclerotization process of insect cuticles, a novel nanofiber-reinforced gelatin hydrogel was developed with improved mechanical properties, which was further strengthened through quinone cross-linking. Because quinone cross-linking reacts between amino groups by increasing the amino group content on the chitin crystalline surface through alkali treatment, surface-deacetylated chitin nanofibers (SD-ChNFs) were prepared to facilitate the cross-linking reaction between SD-ChNF and gelatin. This technique resulted in a tough hydrogel with a dark color. In comparison to a non-cross-linked version, the quinone-cross-linked SD-ChNF/gelatin hydrogel exhibited significantly improved tensile performance. Notably, by controlling the cross-linking reaction time from 6 to 48 h, the tensile strength of the quinone-cross-linked hydrogels can be modified and can reach as high as 2.96 MPa while displaying a variable brown color. Given the eco-friendly, biocompatible, and sustainable properties of chitin and gelatin, these bioinspired hydrogels provide potential applications in the agricultural and biomedical fields.

Composite Nanostructures and Adhesion Analysis of Natural Plant Hydrogels Investigated by Atomic Force Microscopy.

Hydrogels designed by biomimetism and bioinspiration have been considered as a promising biomaterial for biomedical applications due to their biocompatible characteristics. Though biomimetic or bioinspired hydrogels have been widely studied by biochemical analysis, so far the detailed organizations and properties of native natural hydrogels are still not fully understood. The advent of atomic force microscopy (AFM) provides a potent tool for probing the biological samples in their living states with nanometer spatial resolution, which offers new possibilities for addressing the biological and material issues at the nanoscale. In this paper, AFM was utilized to characterize the structures and adhesive properties of the natural hydrogels produced by the carnivorous plant sundew. AFM morphological images of the mucilage secreted by three types of sundew show the composite nanostructures of the mucilage (e.g., nanoparticles, nanofibers, and porous polymeric networks), which are correlated with the mucilage's adhesive features revealed by AFM force measurements and peak force tapping mechanical imaging. The research demonstrates the prominent capabilities of AFM in characterizing the nanoscopic structures and properties of natural hydrogels with unprecedented spatial resolution, which is useful for understanding the underlying mechanisms guiding the behaviors of natural hydrogels and will potentially benefit the studies of biomimetic and bioinspired biomaterials.

Bioinspired Hydrogels for 3D Organoid Culture.

Organoids have stepped into the limelight as unique in vitro systems for modeling organ development, function and disease. This review provides a perspective on how chemically defined, bio-inspired hydrogels could be used for replacing ill-defined matrices derived from the native extracellular matrix (ECM) that are used for generating organoids in 3D stem cell culture. In particular, we propose the use of self-healing and light-responsive matrices that should afford control over the inherently stochastic self-organization process that currently underlies organoid morphogenesis. Such designer ECMs could accelerate the translation of organoid technology from the laboratory into various real-life applications.

Process- and bio-inspired hydrogels for 3D bioprinting of soft free-standing neural and glial tissues

A bio-inspired hydrogel for 3D bioprinting of soft free-standing neural tissues is presented. The novel filler-free bioinks were designed by combining natural polymers for extracellular matrix biomimicry with synthetic polymers to endow desirable rheological properties for 3D bioprinting. Crosslinking of thiolated Pluronic F-127 with dopamine-conjugated (DC) gelatin and DC hyaluronic acid through a thiol–catechol reaction resulted in thermally gelling bioinks with Herschel–Bulkley fluid rheological behavior. Microextrusion 3D bioprinting was used to fabricate free-standing cell-laden tissue constructs. The bioinks exhibited flattened parabolic velocity profiles with tunable low shear regions. Two pathways were investigated for curing the bioink: chelation and photocuring. The storage modulus of the cured bioinks ranged from 6.7 to 11.7 kPa. The iron (III) chelation chemistry produced crosslinked neural tissues of relatively lower storage modulus than the photocuring approach. In vitro cell viability studies using the 3D bioprinted neural tissues showed that the cured bioink was biocompatible based on minimal cytotoxic response observed over seven days in culture relative to control studies using alginate hydrogels. Rodent Schwann cell-, rodent neuronal cell-, and human glioma cell-laden tissue constructs were printed and cultured over seven days and exhibited comparable viability relative to alginate bioink controls. The ability to fabricate soft, free-standing 3D neural tissues with low modulus has implications in the biofabrication of microphysiological neural systems for disease modeling as well as neural tissues and innervated tissues for regenerative medicine.

Interpenetrating Polymer Network Hydrogels of Gelatin and Poly(ethylene glycol) as an Engineered 3D Tumor Microenvironment

An emerging trend in cancer research is to develop engineered tumor models using bio-inspired biomaterials that can mimic the native tumor microenvironment. Although various bio-inspired hydrogels have been utilized, it is still challenging to develop advanced polymeric hydrogel materials that can more accurately reconstruct critical aspects of the native tumor microenvironment. Herein, we present interpenetrating polymer network (IPN) hydrogels composed of thiolated gelatin and tyramine-conjugated poly(ethylene glycol), which form IPN hydrogels via horseradish peroxidase-mediated dual cross-linking reactions. We demonstrate that the IPN hydrogels exhibit independently controllable physicochemical properties. Also, the IPN hydrogels show resistance to the proteolytic enzymes and cytocompatibility for long-term culture of human fibrosarcoma (HT1080) cells. Moreover, we utilize the engineered tumor construct as a platform to evaluate the effect of matrix stiffness on cancer cell proliferation and drug resistance against the anticancer drug 5-fluorouracil as a model drug. In conclusion, we suggest that our IPN hydrogel is a promising material to study cancer biology and to screen innovative therapeutic agents for better clinical outcomes.

Bio-mimetic synthetic cell hydrogel magnetometer

We present a bio-inspired hydrogel magnetometer where the cell potential (Voc) between two hydrogels is used to measure an external magnetic field. Ferromagnetic particles located in the hydrogels move in response to the external field and change the Voc (sensitivity ~ 3.7 V T−1). As the field becomes larger than a critical field Bc (~38 mT), these particles puncture the hydrogel boundary shorting out the concentration gradient region and abruptly reducing the Voc (sensitivity ~ 23.5 V T−1). In this regime, the Voc behaves similar to the neuron firing. In subsequent measurement cycles, the particles remain in punctured holes and the sensor behaviour is neuron-like with lower sensitivity (~20 V T−1). Voc also changes as a function of pressure (8 mV kPa−1) and temperature (2 mV K−1). After 4 h, the ionic concentration gradient diminishes in the device, and similar to biological cell fatigue, Voc decreases and can be recharged with many different techniques.

In search of bioinspired hydrogels from amphiphilic peptides: a template for nanoparticle stabilization for the sustained release of anticancer drugs

This report presents the efficiency of palmitic acid-based proteolytically stable, biocompatible hydrogelators for the sustained release of anticancer drugs.

Tissue Regeneration: Bioinspired Hydrogel Electrospun Fibers for Spinal Cord Regeneration (Adv. Funct. Mater. 4/2019)

In article number 1806899, Bruno Sarmento, Wenguo Cui, Liang Chen, and co-workers construct a new aligned hydrogel microfiber scaffold, which is inspired by the intricate physiological anatomy and unique physical properties of the spinal cord, using hydrogel and electrospinning for treating spinal cord injuries.