Hydrogel Fibers Research Articles

Insulin Crystals Grown in Short-Peptide Supramolecular Hydrogels Show Enhanced Thermal Stability and Slower Release Profile.

Protein therapeutics have a major role in medicine in that they are used to treat diverse pathologies. Their three-dimensional structures not only offer higher specificity and lower toxicity than small organic compounds but also make them less stable, limiting their in vivo half-life. Protein analogues obtained by recombinant DNA technology or by chemical modification and/or the use of drug delivery vehicles has been adopted to improve or modulate the in vivo pharmacological activity of proteins. Nevertheless, strategies to improve the shelf-life of protein pharmaceuticals have been less explored, which has challenged the preservation of their activity. Herein, we present a methodology that simultaneously increases the stability of proteins and modulates the release profile, and implement it with human insulin as a proof of concept. Two novel thermally stable insulin composite crystal formulations intended for the therapeutic treatment of diabetes are reported. These composite crystals have been obtained by crystallizing insulin in agarose and fluorenylmethoxycarbonyl-dialanine (Fmoc-AA) hydrogels. This process affords composite crystals, in which hydrogel fibers are occluded. The insulin in both crystalline formulations remains unaltered at 50 °C for 7 days. Differential scanning calorimetry, high-performance liquid chromatography, mass spectrometry, and in vivo studies have shown that insulin does not degrade after the heat treatment. The nature of the hydrogel modifies the physicochemical properties of the crystals. Crystals grown in Fmoc-AA hydrogel are more stable and have a slower dissolution rate than crystals grown in agarose. This methodology paves the way for the development of more stable protein pharmaceuticals overcoming some of the existing limitations.

Recent Advances in Fiber-Hydrogel Composites for Wound Healing and Drug Delivery Systems.

In the last decades, much research has been done to fasten wound healing and target-direct drug delivery. Hydrogel-based scaffolds have been a recurrent solution in both cases, with some reaching already the market, even though their mechanical stability remains a challenge. To overcome this limitation, reinforcement of hydrogels with fibers has been explored. The structural resemblance of fiber–hydrogel composites to natural tissues has been a driving force for the optimization and exploration of these systems in biomedicine. Indeed, the combination of hydrogel-forming techniques and fiber spinning approaches has been crucial in the development of scaffolding systems with improved mechanical strength and medicinal properties. In this review, a comprehensive overview of the recently developed fiber–hydrogel composite strategies for wound healing and drug delivery is provided. The methodologies employed in fiber and hydrogel formation are also highlighted, together with the most compatible polymer combinations, as well as drug incorporation approaches creating stimuli-sensitive and triggered drug release towards an enhanced host response.

Abstract P784: A Novel Rat Model of Embolic Cerebral Ischemia Using a Cell-Implantable Radiopaque Hydrogel Micro Fiber

Introduction: The failure of neuroprotective treatment-related clinical trials may be partially caused by unestablished animal models. We aimed to develop a novel focal stroke model using a cell-implantable radiopaque hydrogel micro fiber. The micro fiber is made of barium alginate hydrogel containing zirconia, and fabricated in a dual coaxial laminar flow microfluidic device. Methods: Using male Sprague Dawley rats (n=10), a catheter (ID 0.42mm, OD 0.55mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel micro fiber (0.4 mm in diameter, 1 mm in length) was advanced in the catheter by slow injection of heparinized physiological saline to establish local occlusion. 9.4-T MRI and 2% 2,3,5-triphenyl tetrazolium chloride staining were performed 24 hours after the creation of the stroke model. Results: The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized at all rats. The median operating time was 8.5 min (interquartile range; 6.25-12 min). The median infarct volume (mm 3 ) was 262 (interquartile range; 260-274) 24 hours after occlusion. Conclusions: We present a novel rat model for focal infarct only in the middle cerebral artery territory using a radiopaque hydrogel micro fiber. Furthermore, this model can be used for regeneration research of cerebral infarction because the hydrogel micro fiber can encapsulate stem cell.Figure Legends A: Puncture of the caudal ventral artery in a rat. B: Cerebral angiography of a rat. C: Occlusion of the anterior cerebral artery-middle cerebral artery bifurcation by a radiopaque hydrogel fiber (arrowhead). D: MR angiography detected selective occlusion of left middle cerebral artery. E: T2-weighted image showed infarct only in the middle cerebral artery after 24 hours occlusion. A radiopaque fiber did not affect the 9.4-T MRI. F: Radiopaque hydrogel fiber encapsulated HeLa cells.

Fibrous Hydrogels under Multi‐Axial Deformation: Persistence Length as the Main Determinant of Compression Softening

AbstractWhen hydrogels are designed for biological applications, the mechanical properties are carefully chosen to match their precise application. However, traditional methodologies of mechanical characterization (simple shear or compression/extension) commonly ignore the multiaxiality of in vivo deformations. A recent study highlights that biopolymers and tissue indeed show a complex response to combined uniaxial and shear strains. In this study a synthetic yet biomimetic fibrous hydrogel is used, which is based on polyisocyanides and forms a self‐assembled network of branched semiflexible chains, similar in architecture networks of structural biopolymers like actin, collagen, and fibrin. Its synthetic nature allows to decouple key parameters of these networks and individually understand their impact on the mechanical response under multiaxial deformation. Experimentally, it is found that the persistence length is a key parameter of biological networks, which tunes softening of gels under compression: The stiffer the polymer, the more the network softens in compression. This study provides insights into tissue behavior that likely is only obtainable from synthetic model systems and is able to direct further the design of new synthetic biomimetic soft materials that are in high demand as tunable bio‐free extracellular matrix materials.

Controlled-release of free bacteriophage nanoparticles from 3D-plotted hydrogel fibrous structure as potential antibacterial wound dressing

To combat the emergence of drug-resistant bacteria, a locally isolated bacteriophage (HZJ) targeting H5α Escherichia coli was used as an antibacterial agent to make wound dressing samples in this study. The phages were physically embedded within an alginate hydrogel sample so that they could later be released with their tails being free during the infection process, which preserves their lytic activity. The HZJ phage isolated in the study have a 20 min latent period and are stable between pH 6 and pH 9 and at temperatures below 45 °C. The addition of phage to an E. coli culture suppressed over 99% of bacterial growth in 2-h (p < 0.001). Phage-embedded hydrogel fibers were used to create porous wound dressing material using three-dimensional (3D) printing. The majority of phage lytic activity (85%–90%) was preserved after encapsulation. After they were embedded in samples, HZJ lysed 57% to 67% of bacteria (p < 0.001) within 2 h and the antibacterial effects lasted at least 24 h. The small amount of phage released in 2 h was able to quickly replicate and effectively lysed the majority of the bacterial hosts. Phage-embedded alginate samples released 10% of its incorporated phage particles in 24 h. The SEM micrographs show that, compared to phage-free samples, fewer E.coli cells were observed on phage-embedded samples 2 h after bacteria were exposed to the samples. The phage-embedded sample was not cytotoxic to L929 cells. The presence of HZJ in alginate hydrogel promoted cell growth (p < 0.01) and adhesion to the samples. Further, the existence of phage did not alter the tensile strength and modulus of samples (p > 0.05). An antibacterial dressing capable of slowly releasing lytic phages and effectively suppressing bacterial growth for up to 24 h was produced in this study. This model represents an attractive means to reduce use of antibiotics and other additives in conventional dressings.

One-Step Generation of Aqueous-Droplet-Filled Hydrogel Fibers as Organoid Carriers Using an All-in-Water Microfluidic System.

Hydrogel fibers are promising carriers for biological applications due to their flexible mechanical properties, well-defined spatial distribution, and excellent biocompatibility. In particular, the droplet-filled hydrogel fibers with the controllable dimension and location of droplets display great advantages to enhance the loading capacity of multiple components and biofunctions. In this work, we proposed a new all-in-water microfluidic system that allows for one-step fabrication of aqueous-droplet-filled hydrogel fibers (ADHFs) with unique morphology and tunable configurations. In the system, the aqueous droplets with equidistance are successfully arranged within the alginate calcium fibers, relying on the design of the pump valve cycle and the select of two immiscible liquids with a stable aqueous interface. The architecture of the ADHF can be flexibly controlled by adjusting the three phase flow rates and the valve switch cycle. The produced ADHFs exhibit high controllability, uniformity, biocompatibility, and stability. The established system enabled the formation of functional human islet organoids in situ through encapsulating pancreatic endocrine progenitor cells within microfibers. The generated islet organoids within droplets exhibit high cell viability and islet-specific function of insulin secretion. The proposed approach provides a new way to fabricate multifunctional hydrogel fibers for materials sciences, tissue engineering, and regenerative medicine.

Bio-Inspired Lotus-Fiber-like Spiral Hydrogel Bacterial Cellulose Fibers.

Hydrogel materials with high water content and good biocompatibility are drawing more and more attention now, especially for biomedical use. However, it still remains a challenge to construct hydrogel fibers with enough strength and toughness for practical applications. Herein, we report a bio-inspired lotus-fiber-mimetic spiral structure hydrogel bacterial cellulose fiber with high strength, high toughness, high stretchability, and energy dissipation, named biomimetic hydrogel fiber (BHF). The spiral-like structure endows BHF with excellent stretchability through plastic deformation and local failure, assisted by the breaking-reforming nature of the hydrogen bonding network among cellulose nanofibers. With the high strength, high stretchability, high energy dissipation, high hydrophilicity, porous structure, and excellent biocompatibility, BHF is a promising hydrogel fiber for biomedicine. The outstanding stretchability and energy dissipation of BHF allow it to absorb energy from the tissue deformation around a wound and effectively protect the wound from rupture, which makes BHF an ideal surgical suture.

Electrodynamic assisted self-assembled fibrous hydrogel microcapsules: a novel 3D in vitro platform for assessment of nanoparticle toxicity.

Nanoparticle (NP) toxicity assessment is a critical step in assessing the health impacts of NP exposure to both consumers and occupational workers. In vitro assessment models comprising cells cultured in a two-dimensional tissue culture plate (2D-TCP) are an efficient and cost-effective choice for estimating the safety risks of NPs. However, in vitro culture of cells in 2D-TCPs distorts cell–integrin and cell–cell interactions and is not able to replicate an in vivo phenotype. Three-dimensional (3D) in vitro platforms provide a unique alternative to bridge the gap between traditional 2D in vitro and in vivo models. In this study, novel microcapsules of alginate hydrogel incorporated with natural polymeric nanofibers (chitin nanofibrils) and synthetic polymeric nanofibers poly(lactide-co-glycolide) are designed as a 3D in vitro platform. This study demonstrates for the first time that electrodynamic assisted self-assembled fibrous 3D hydrogel (3D-SAF hydrogel) microcapsules with a size in the range of 300–500 μm in diameter with a Young's modulus of 12.7–42 kPa can be obtained by varying the amount of nanofibers in the hydrogel precursor solutions. The 3D-SAF microcapsules were found to mimic the in vivo cellular microenvironment for cells to grow, as evaluated using A549 cells. Higher cellular spreading and prolonged proliferation of A549 cells were observed in 3D-SAF microcapsules compared to control microcapsules without the nanofibers. The 3D-SAF microcapsule integrated well plate was used to assess the toxicity of model NPs, e.g., Al2O3 and ZnO. The toxicity levels of the model NPs were found to be dependent on the chemistry of the NPs and their physical agglomeration in the test media. Our results demonstrate that 3D-SAF microcapsules with an in vivo mimicking microenvironment can be developed as a physiologically relevant platform for high-throughput toxicity screening of NPs or pharmaceutical drugs.

Water-resistant and stretchable conductive ionic hydrogel fibers reinforced by carboxymethyl cellulose

Conductive ionic hydrogels (CIH) have been widely studied for the development of stretchable electronic devices, such as sensors, electrodes, and actuators. Most of these CIH are made into 3D or 2D shape, while 1D CIH (hydrogel fibers) is often difficult to make because of the low mechanical robustness of common CIH. Herein, we use gel spinning method to prepare a robust CIH fiber with high strength, large stretchability, and good conductivity. The robust CIH fiber is drawn from the composite gel of sodium polyacrylate (PAAS) and sodium carboxymethyl cellulose (CMC). In the composite CIH fiber, the soft PAAS presents good conductivity and stretchability, while the rigid CMC significantly enhances the strength and toughness of the PAAS/CMC fiber. To protect the conductive PAAS/CMC fiber from damage by water, a thin layer of hydrophobic polymethyl acrylate (PMA) or polybutyl acrylate (PBA) is coated on the PAAS/CMC fiber as a water-resistant and insulating cover. The obtained PAAS/CMC-PMA and PAAS/CMC-PBA CIH fibers present high tensile strength (up to 28 MPa), high tensile toughness (up to 43 MJ/m3), and good electrical conductivity (up to 0.35 S/m), which are useful for textile-based stretchable electronic devices.

Spinning continuous high-strength bacterial cellulose hydrogel fibers for multifunctional bioelectronic interfaces

The realization of the reconciliation of contradictory multi-properties required for hydrogel fibers as bioelectronic interfaces.

Gelation Methods to Assemble Fibrous Proteins.

Gelation is an efficient way to fabricate fibrous protein materials. Briefly, it is an aggregation process where protein molecules assembly from a random structure into an organized structure such as nanofibrillar networks. According to their mechanisms, the fibrous proteins gelation can be classified into physical gelation and chemical gelation. The physical gelation is formed by the conformational transformation of fibroin proteins, which can be triggered by temperature, concentration, pH, or shear force. On the other hand, the chemical gelation is to cross-link fibrous proteins through chemical and/or enzymatic reactions. In this chapter, we summarize the protocols for preparing fibrous protein hydrogels, including both physical and chemical methods. The mechanisms of these gelation methods are also highlighted.

Patterned Photocrosslinking to Establish Stiffness Gradients and Local Anisotropies in Fibrous 3D Hydrogels

Cells are known to constantly interact with their local extracellular matrix (ECM) and respond to a variety of biochemical and mechanical cues received from the ECM. Nonetheless, comprehensive understanding of cell-ECM interactions has been elusive. Many studies rely on analysis of cell behavior on 2D substrates, which do not reflect a natural cell environment. Further, lack of dynamic control over local stiffness gradients and fiber alignment hinders progress in studies in naturally derived fibrous 3D cultures. Here, we present a cell-safe method of patterned photocrosslinking, which can aid in studying biological hypotheses related to mechanotransduction in 3D hydrogels. As previously described by our group, ruthenium-catalyzed photocrosslinking (RCP) of selected ECM regions promotes localized increase in stiffness mediated by focused blue laser light in a confocal microscope. In this study, we further demonstrate that RCP can induce localized strain stiffening and fiber alignment outside of the selected crosslinked region and induce stiffness anisotropy biased towards the direction of fiber alignment. MDA-MB-231 cells are shown to respond to RCP-induced changes in local ECM architecture and display more elongated morphology and higher directionality and speed of cell migration, as compared to control cells. Further, the effect of patterned crosslinking on a stiffness landscape is measured using multi-axes optical tweezers active microrheology (AMR) with backscattered laser beam illumination. AMR validates RCP as a suitable tool for creating distinct stiffness landscapes and differentiating the effect of contact guidance and durotaxis phenomena on cell migration, further underscoring the usefulness of RCP in cell-ECM studies.

Self-assembly of stimuli-responsive coiled-coil fibrous hydrogels.

Owing to their tunable properties, hydrogels comprised of stimuli-sensitive polymers are one of the most appealing scaffolds with applications in tissue engineering, drug delivery and other biomedical fields. We previously reported a thermoresponsive hydrogel formed using a coiled-coil protein, Q. Here, we expand our studies to identify the gelation of Q protein at distinct pH conditions, creating a protein hydrogel system that is sensitive to temperature and pH. Through secondary structure analysis, transmission electron microscopy, and rheology, we observed that Q self-assembles and forms fiber-based hydrogels exhibiting upper critical solution temperature behavior with increased elastic properties at pH 7.4 and pH 10. At pH 6, however, Q forms polydisperse nanoparticles, which do not further self-assemble and undergo gelation. The high net positive charge of Q at pH 6 creates significant electrostatic repulsion, preventing its gelation. This study will potentially guide the development of novel scaffolds and functional biomaterials that are sensitive towards biologically relevant stimuli.

Highly improved water tolerance of hydrogel fibers with a carbon nanotube sheath for rotational, contractile and elongational actuation

Coating a carbon nanotube sheath improved the water tolerance of hydrogel fibers, and inserting a twist produces large-stroke torsional, contractile, and elongational fiber actuators.

Fibrous aramid hydrogel supported antibacterial agents for accelerating bacterial-infected wound healing

Bacterial infections severely retard the wound healing process. Antibacterial drugs were loaded onto aramid nanofibers (ANFs) hydrogels through a convenient strategy to fabricate dressings for bacterial infected wound healing. ANFs hydrogels owned good mechanical properties, high water content (>98%), high water adsorption property (>10,000%) and good water retention ability (a water retention of >5000% after incubating at RH 30% for 8 h), capable to absorb and retain the wound exudate to form a moist environment. The incorporation of antibacterial drugs promised the ANFs hydrogels with durable antibacterial properties. Furthermore, the drug loaded ANFs hydrogels had no cytotoxicity nor hemolytic potential. In vivo skin wound healing results confirmed that the composite hydrogels accelerated the healing rate of infection wounds on mice and were suitable as a potential anti-infective wound dressing.

Impact of Citrate and Lipid-Functionalized Magnetic Nanoparticles in Dehydropeptide Supramolecular Magnetogels: Properties, Design and Drug Release.

Currently, the nanoparticle functionalization effect on supramolecular peptide-based hydrogels remains undescribed, but is expected to affect the hydrogels’ self-assembly and final magnetic gel properties. Herein, two different functionalized nanoparticles: citrate-stabilized (14.4 ± 2.6 nm) and lipid-coated (8.9 ± 2.1 nm) magnetic nanoparticles, were used for the formation of dehydropeptide-based supramolecular magnetogels consisting of the ultra-short hydrogelator Cbz-L-Met-Z-ΔPhe-OH, with an assessment of their effect over gel properties. The lipid-coated nanoparticles were distributed along the hydrogel fibers, while citrate-stabilized nanoparticles were aggregated upon gelation, which resulted into a heating efficiency improvement and decrease, respectively. Further, the lipid-coated nanoparticles did not affect drug encapsulation and displayed improved drug release reproducibility compared to citrate-stabilized nanoparticles, despite the latter attaining a stronger AMF-trigger. This report points out that adsorption of nanoparticles to hydrogel fibers, which display domains that improve or do not affect drug encapsulation, can be explored as a means to optimize the development of supramolecular magnetogels to advance theranostic applications.

Electrospun polyvinylpyrrolidone (PVP) hydrogels containing hydroxycinnamic acid derivatives as potential wound dressings

Polyvinylpyrrolidone (commonly known as povidone or PVP) rapidly dissolves in water. This significantly hinders its use in sustained release formulations developed for the biomedical field. Electrospun fibers of PVP dissolve even faster due to larger surface to volume ratio. In this work, we propose a way to circumvent this problem by developing and using functional fibrous materials in hydrogel form. In particular, we demonstrate that ethanolic solutions of PVP containing two hydroxycinnamic acid derivatives, namely p-coumaric and ferulic acids could be electrospun into functional hydrogel fiber mats. After electrospinning, the formed composite mats were first thermally treated at 130 °C for 20 h and subsequently were immersed in aqueous media, where they turned into hydrogels. Thermal annealing did not degrade hydroxycinnamic acid derivatives, preserving their functionality. We propose these hydrogel fiber mats as potential wound dressings and to that end, in vitro tests showed up to 8 days of antioxidants’ release, and consequent protection of A549 epithelial cells against oxidative stresses. Biocompatibility tests using human red blood cells, A549 and HaCaT cell lines indicated no adverse effects. Model studies of mice skin burns induced by UV-B radiation showed that the hydrogel fiber dressings significantly reduced the levels of matrix metallopeptidase, (MMP-9), and glutathione peroxidase 1 (GPX-1), which are usually upregulated by reactive oxidative species on burnt skin. Finally, ex-vivo human skin investigations demonstrated skin regeneration and control of the inflammatory phase as indicated by low levels of pro-inflammatory cytokines (IL-6 and IL-8). Therefore, our outcomes indicate that the developed PVP-based fiber hydrogels, produced using a simple protocol, are promising candidates for active wound dressings.

Hydrogel based Fabry-Pérot cavity for a pH sensor.

A simple, reliable, and quick reactive Fabry-Pérot (FP) structure-based fiber optic pH sensor is presented. The pH-sensitive hydrogel and single-mode fiber (SMF) are placed inside a fused silica capillary to form the FP cavity. The gel thickness is characterized by the spin coating method with respect to different spin speeds. The proposed sensor shows a pH sensitivity of 0.30 nm/pH along with a fast response time of 15 s to 20 s for different pH solvents in the acidic range. Also, the temperature sensitivity of the FPI sensor is found to be -0.56 nm/°C.

Image analysis method for heterogeneity and porosity characterization of biomimetic hydrogels.

This work presents an image processing procedure for characterization of porosity and heterogeneity of fully hydrated hydrogels based on the analysis of cryogenic scanning electron microscopy (cryo-SEM) images. An algorithm consisting of different filtering, morphological transformation, and thresholding steps to denoise the image whilst emphasizing the hydrogel fibres edges for extracting the pores features is explained. Finally, the information of hydrogel porosity and heterogeneity is presented in form of pore size distribution, spatial contours maps and kernel density dot plots. The obtained results reveal that a non-parametric kernel density plot effectively determines the spatial heterogeneity and porosity of the hydrogel.

Wet-spun bi-component alginate based hydrogel fibers: Development and in-vitro evaluation as a potential moist wound care dressing

In this study, bi-component alginate-hyaluronic acid (AHA) fibers were developed by using two different routes. In the first method, sodium alginate dope solution was extruded into a coagulation bath containing CaCl2 and subsequently dip-coated with hyaluronic acid (HA) whereas, in the second method, hyaluronic acid-containing sodium alginate dope solution was directly extruded into CaCl2 bath. The resulting AHA fibers were then dehydrated in 25–100% v/v acetone solutions and dried in air. The fibers were characterized by surface morphology, physicochemical analysis, mechanical performance, swelling percentage, and total liquid absorption (g/g), cell viability, and release behavior. The results showed that AHA fibers produced by the second method have better mechanical performance, high liquid absorption, and swelling percentage with a more controlled release of hyaluronic acid. The AHA fibers showed high biocompatibility toward nHDF cell line in in-vitro testing, and the MVTR values (650–800 g/m2/day) are in a suitable range for maintaining a moist wound surface proving to be appropriate for promoting wound healing.