3D-Printed proangiogenic patches of photo-crosslinked gelatin and polyurethane hydrogels laden with vascular cells for treating vascular ischemic diseases.

Engineering vascularized tissues remains a promising approach for treating ischemic cardiovascular diseases. The availability of 3D-bioprinted vascular grafts that induce therapeutic angiogenesis can help avoid necrosis and excision of ischemic tissues. Here, using a combination of living cells and biodegradable hydrogels, we fabricated 3D-printed biocompatible proangiogenic patches from endothelial cell-laden photo-crosslinked gelatin (EC-PCG) bioink and smooth muscle cell-encapsulated polyurethane (SMC-PU) bioink. Implantation of 3D-bioprinted proangiogenic patches in a mouse model showed that EC-PCG served as an angiogenic capillary bed, whereas patterned SMC-PU increased the density of microvessels. Moreover, the assembled patterns between EC-PCG and SMC-PU induced the geometrically guided generation of microvessels with blood perfusion. In a rodent model of hindlimb ischemia, the vascular patches rescued blood flow to distal tissues, prevented toe/foot necrosis, promoted muscle remodeling, and increased the capillary density, thereby improving the heat-escape behavior of ischemic animals. Thus, our 3D-printed vascular cell-laden bioinks constitute efficient and scalable biomaterials that facilitate the engineering of vascular patches capable of directing therapeutic angiogenesis for treating ischemic vascular diseases.

Self-Healing Hydrogel Containing Decellularized Liver Matrix and Endothelial Cell-Covered Hepatocyte Spheroids for Rescue of Injured Hepatocytes.

Liver fibrosis occurs in many chronic liver diseases, while severe fibrosis can lead to liver failure. A chitosan-phenol based self-healing hydrogel (CP) integrated with decellularized liver matrix (DLM) is proposed in this study as a 3D gel matrix to carry hepatocytes for possible therapy of liver fibrosis. To mimic the physiological liver microenvironment, DLM is extracted from pigs and mixed with CP hydrogel to generate DLM-CP self-healing hydrogel. Hepatocyte spheroids coated with endothelial cells (ECs) are fabricated using a customized method and embedded in the hydrogel. Hepatocytes injured by exposure to CCl4 -containing medium are used as the in vitro toxin-mediated liver fibrosis model, where the EC-covered hepatocyte spheroids embedded in the hydrogel are co-cultured with the injured hepatocytes. The urea synthesis of the injured hepatocytes reaches 91% of the normal level after 7 days of co-culture, indicating that the hepatic function of injured hepatocytes is rescued by the hybrid spheroid-laden DLM-CP hydrogel. Moreover, the relative lactate dehydrogenase activity of the injured hepatocytes is decreased 49% by the hybrid spheroid-laden DLM-CP hydrogel after 7 days of co-culture, suggesting reduced damage in the injured hepatocytes. The combination of hepatocyte/EC hybrid spheroids and DLM-CP hydrogel presents a promising therapeutic strategy for hepatic fibrosis.

Interaction of vascular endothelial cells with hydrophilic fullerene nanoarchitectured structures in 2D and 3D environments.

The interaction between diverse nanoarchitectured fullerenes and cells is crucial for biomedical applications. Here, we detailed the preparation of hydrophilic self-assembled fullerenes by the liquid-liquid interfacial precipitation (LLIP) method and hydrophilic coating of the materials as a possible vascularization strategy. The interactions of vascular endothelial cells (ECs) with hydrophilic fullerene nanotubes (FNT-P) and hydrophilic fullerene nanowhiskers (FNW-P) were investigated. The average length and diameter of FNT-P were 16 ± 2 µm and 3.4 ± 0.4 µm (i.e. aspect ratios of 4.6), respectively. The average length and diameter of FNW-P were 65 ± 8 µm and 1.2 ± 0.2 µm (i.e. aspect ratios of 53.9), respectively. For two-dimensional (2D) culture after 7 days, the ECs remained viable and proliferated up to ~ 420% and ~ 400% with FNT-P and FNW-P of 50 µg/mL, respectively. Furthermore, an optimized chitosan-based self-healing hydrogel with a modulus of ~400 Pa was developed and used to incorporate self-assembled fullerenes as in vitro three-dimensional (3D) platforms to investigate the impact of FNT-P and FNW-P on ECs within a 3D environment. The addition of FNW-P or FNT-P (50 µg/mL) in the hydrogel system led to proliferation rates of ECs up to ~323% and ~280%, respectively, after 7 days of culture. The ECs in FNW-P hydrogel displayed an elongated shape with aligned morphology, while those in FNT-P hydrogel exhibited a rounded and clustered distribution. Vascular-related gene expressions of ECs were significantly upregulated through interactions with these fullerenes. Thus, the combined use of different nanoarchitectured self-assembled fullerenes and self-healing hydrogels may offer environmental cues influencing EC development in a 3D biomimetic microenvironment, holding promise for advancing vascularization strategy in tissue engineering.

Self-assembled fullerenes with large aspect ratios modulate the morphology and gene expression of endothelial cells within a soft biomimetic 3D microenvironment, representing a promising new vascularization strategy in tissue engineering.

Effects of the Degree of Phenol Substitution on Molecular Structures and Properties of Chitosan-Phenol-Based Self-Healing Hydrogels.

Click chemistry is commonly used to prepare hydrogels, and chitosan-phenol prepared by using a Schiff base has been widely employed in the field of biomaterials. Chitosan-phenol is a derivative of chitosan; the phenol groups can disrupt both the inter- and intramolecular hydrogen bonds in chitosan, thereby reducing its crystallinity and improving its water solubility. In addition, chitosan-phenol exhibits various beneficial physiological functions. However, it is still unclear whether the degree of phenol substitution in the chitosan main chain affects the molecular interactions and structural properties of the self-healing hydrogels. To explore this issue, we investigated the molecular structure and network of self-healing hydrogels composed of chitosan-phenol with varying degrees of phenol substitution and dibenzaldehyde poly(ethylene oxide) (DB-PEO) using molecular dynamics simulations. We observed that when the degree of phenol substitution in the self-healing hydrogel was less than 15%, an increase in the degree of phenol substitution led to an increase in the interactions between chitosan-phenol and DB-PEO, and it enhanced the dynamic covalent bond cross-linking generated through the Schiff base reaction. However, when the degree of phenol substitution exceeded 15%, excessive phenol groups caused excessive intramolecular interactions within chitosan-phenol molecules, which reduced the binding between chitosan-phenol and DB-PEO. Our results revealed the influence of the degree of phenol substitution on the molecular structure of the self-healing hydrogels and showed an optimal degree of phenol substitution. These findings provide important insights for the future design of self-healing hydrogels based on chitosan and should help in enhancing the applicability of hydrogels in the field of biomedicine.

3D-bioprintable endothelial cell-laden sacrificial ink for fabrication of microvessel networks.

Although various research efforts have been made to produce a vascular-like network structure as scaffolds for tissue engineering, there are still several limitations. Meanwhile, no articles have been published on the direct embedding of cells within a glucose sensitive sacrificial hydrogel followed by three-dimensional (3D) bioprinting to fabricate vascular structures. In this study, the hydrogel composed of reversibly crosslinked poly(ethylene glycol) diacrylate and dithiothreitol with borax and branched polyethylenimine was used as the sacrificial hydrogel to fabricate vascular-like network structure. The component proportion ratio of the sacrificial hydrogel was optimized to achieve proper self-healing, injectable, glucose-sensitive, and 3D printing properties through the balance of boronate ester bond, hydrogen bond, and steric hinderance effect. The endothelial cells (ECs) can be directly embedded into sacrificial hydrogel and then bioprinted through a 110µm nozzle into the neural stem cell (NSC)-laden non-sacrificial hydrogel, forming the customized EC-laden vascularized microchannel (one-step). The EC-laden sacrificial hydrogel was dissolved immediately in the medium while cells kept growing. The ECs proliferated well within the vascularized microchannel structure and were able to migrate to the non-sacrificial hydrogel in one day. ECs and NSCs interacted around the vascularized microchannel to form capillary-like structure and vascular-like structure expressing CD31 in 14 d. The sacrificial hydrogel conveniently prepared from commercially available chemicals through simple mixing can be used in 3D bioprinting to create customized and complex but easily removable vascularized structure for tissue engineering applications.

Potential targeting of the tumor microenvironment to improve cancer virotherapy.

In 2015, oncolytic virotherapy was approved for clinical use, and in 2017, recombinant adeno-associated virus (AAV) delivery was also approved. However, systemic administration remains challenging due to the limited number of viruses that successfully reach the target site. Although the US Food and Drug Administration (FDA) permits the use of higher doses of AAV to achieve greater rates of transduction, most AAV still accumulates in the liver, potentially leading to toxicity there and elsewhere. Targeting the tumor microenvironment is a promising strategy for cancer treatment due to the critical role of the tumor microenvironment in controlling tumor progression and influencing the response to therapies. Newly discovered evidence indicates that administration routes focusing on the tumor microenvironment can promote delivery specificity and transduction efficacy within the tumor. Here, we review approaches that involve modifying viral surface features, modulating the immune system, and targeting the physicochemical characteristics in tumor microenvironment to regulate therapeutic delivery. Targeting tumor acidosis presents advantages that can be leveraged to enhance virotherapy outcomes and to develop new therapeutic approaches that can be integrated with standard treatments.

Self-healing hydrogel as an injectable implant: translation in brain diseases.

Tissue engineering biomaterials are aimed to mimic natural tissue and promote new tissue formation for the treatment of impaired or diseased tissues. Highly porous biomaterial scaffolds are often used to carry cells or drugs to regenerate tissue-like structures. Meanwhile, self-healing hydrogel as a category of smart soft hydrogel with the ability to automatically repair its own structure after damage has been developed for various applications through designs of dynamic crosslinking networks. Due to flexibility, biocompatibility, and ease of functionalization, self-healing hydrogel has great potential in regenerative medicine, especially in restoring the structure and function of impaired neural tissue. Recent researchers have developed self-healing hydrogel as drug/cell carriers or tissue support matrices for targeted injection via minimally invasive surgery, which has become a promising strategy in treating brain diseases. In this review, the development history of self-healing hydrogel for biomedical applications and the design strategies according to different crosslinking (gel formation) mechanisms are summarized. The current therapeutic progress of self-healing hydrogels for brain diseases is described as well, with an emphasis on the potential therapeutic applications validated by in vivo experiments. The most recent aspect as well as the design rationale of self-healing hydrogel for different brain diseases is also addressed.

Fabrication of Eco-Friendly Wearable Strain Sensor Arrays via Facile Contact Printing for Healthcare Applications.

Wearable flexible strain sensors with spatial resolution enable the acquisition and analysis of complex actions for noninvasive personalized healthcare applications. To provide secure contact with skin and to avoid environmental pollution after usage, sensors with biocompatibility and biodegradability are highly desirable. Herein, wearable flexible strain sensors composed of crosslinked gold nanoparticle (GNP) thin films as the active conductive layer and transparent biodegradable polyurethane (PU) films as the flexible substrate are developed. The patterned GNP films (micrometer- to millimeter-scale square and rectangle geometry, alphabetic characters, and wave and array patterns) are transferred onto the biodegradable PU film via a facile, clean, rapid and high-precision contact printing method, without the need of a sacrificial polymer carrier or organic solvents. The GNP-PU strain sensor with low Young's modulus (≈17.8 MPa) and high stretchability showed good stability and durability (10 000 cycles) as well as degradability (42% weight loss after 17 days at 74 °C in water). The GNP-PU strain sensor arrays with spatiotemporal strain resolution are applied as wearable eco-friendly electronics for monitoring subtle physiological signals (e.g., mapping of arterial lines and sensing pulse waveforms) and large-strain actions (e.g., finger bending).

Molecular interactions of tannic acid and matrix metalloproteinases 2 and 9.

Tannic acid (TA) has antibacterial, antioxidant, and anti-inflammatory properties and acts as an adhesive, hemostatic, and crosslinking agent in hydrogels. Matrix metalloproteinases (MMPs), a family of endopeptidase enzymes, play important roles in tissue remodeling and wound healing. TA has been reported to inhibit MMP-2/- 9 activities, thereby improving both tissue remodeling and wound healing. However, the mechanism of interaction of TA with MMP-2 and MMP-9 has not been fully elucidated. In this study, the full atomistic modeling approach was applied to explore the mechanisms and structures of TA binding with MMP-2 and MMP-9. Macromolecular models of the TA-MMP-2/- 9 complex were built by docking based on experimentally resolved MMP structures, and further equilibrium processes were examined by molecular dynamics (MD) simulations to investigate the binding mechanism and structural dynamics of the TA-MMP-2/- 9 complexes. The molecular interactions between TA and MMPs, including H-bond formation and hydrophobic and electrostatic interactions, were analyzed and decoupled to elucidate the dominant factors in TA-MMP binding. TA binds to MMPs mainly at two binding regions, residues 163-164 and 220-223 in MMP-2 and residues 179-190 and 228-248 in MMP-9. Two arms of TA participate in binding MMP-2 with 3.61 hydrogen bonds. On the other hand, TA binds MMP-9 with a distinct configuration involving four arms with 4.75 hydrogen bonds, resulting in a tighter binding conformation. Understanding the binding mechanism and structural dynamics of TA with these two MMPs provides crucial and fundamental knowledge regarding the inhibitory and stabilizing effects of TA on MMPs.

Self-Healing of Recombinant Spider Silk Gel and Coating.

Self-healing properties, originating from the natural healing process, are highly desirable for the fitness-enhancing functionality of biomimetic materials. Herein, we fabricated the biomimetic recombinant spider silk by genetic engineering, in which Escherichia coli (E. coli) was employed as a heterologous expression host. The self-assembled recombinant spider silk hydrogel was obtained through the dialysis process (purity > 85%). The recombinant spider silk hydrogel with a storage modulus of ~250 Pa demonstrated autonomous self-healing and high strain-sensitive properties (critical strain ~50%) at 25 °C. The in situ small-angle X-ray scattering (in situ SAXS) analyses revealed that the self-healing mechanism was associated with the stick-slip behavior of the ß-sheet nanocrystals (each of ~2-4 nm) based on the slope variation (i.e., ~-0.4 at 100%/200% strains, and ~-0.9 at 1% strain) of SAXS curves in the high q-range. The self-healing phenomenon may occur through the rupture and reformation of the reversible hydrogen bonding within the ß-sheet nanocrystals. Furthermore, the recombinant spider silk as a dry coating material demonstrated self-healing under humidity as well as cell affinity. The electrical conductivity of the dry silk coating was ~0.4 mS/m. Neural stem cells (NSCs) proliferated on the coated surface and showed a 2.3-fold number expansion after 3 days of culture. The biomimetic self-healing recombinant spider silk gel and thinly coated surface may have good potential in biomedical applications.

A self-healing hydrogel and injectable cryogel of gelatin methacryloyl-polyurethane double network for 3D printing.

Three-dimensional (3D) printing of soft biomaterials facilitates the progress of personalized medicine. The development for different forms of 3D-printable biomaterials can promotes the potential manufacturing for artificial organs and provides biomaterials with the required properties. In this study, gelatin methacryloyl (GelMA) and dialdehyde-functionalized polyurethane (DFPU) were combined to create a double crosslinking system and develop 3D-printable GelMA-PU biodegradable hydrogel and cryogel. The GelMA-PU system demonstrates a combination of self-healing ability and 3D printability and provides two distinct forms of 3D-printable biomaterials with smart functions, high printing resolution, and biocompatibility. The hydrogel was printed into individual modules through an 80 µm or larger nozzle and further assembled into complex structures through adhesive and self-healing abilities, which could be stabilized by secondary photocrosslinking. The 3D-printed hydrogel was adhesive, light transmittable, and could embed a light emitting diode (LED). Furthermore, the hydrogel laden with human mesenchymal stem cells (hMSCs) was successfully printed and showed cell proliferation. Meanwhile, 3D-printed cryogel was achieved by printing on a subzero temperature platform through a 210 µm nozzle. After secondary photocrosslinking and drying, the cryogel was deliverable through a 16-gage (1194 µm) syringe needle and can promote the proliferation of hMSCs. The GelMA-PU system extends the ink pool for 3D printing of biomaterials and has potential applications in tissue engineering scaffolds, minimally invasive surgery devices, and electronic wound dressings. STATEMENT OF SIGNIFICANCE: The 3D-printable biomaterials developed in this work are GelMA-based ink with smart funcitons and have potentials for various customized medical applications. The synthesized GelMA-polyurethane double network hydrogel can be 3D-printed into individual modules (e.g., 11 × 11 × 5 mm3) through an 80 µm or larger size nozzle, which are then assembled into a taller structure over five times of the initial height by self-healing and secondary photocrosslinking. The hydrogel is adhesive, light transmittable, and biocompatible that can either carry human mesenchymal stem cells (hMSCs) as bioink or embed a red light LED (620 nm) with potential applications in electronic skin dressing. Meanwhile, the 3D-printed highly compressible cryogel (e.g., 6 × 6 × 1 mm3) is deliverable by a 16-gage (1194 µm) syringe needle and supports the proliferation of hMSCs also.

Antiviral and Antibacterial Sulfated Polysaccharide-Chitosan Nanocomposite Particles as a Drug Carrier.

Drug delivery system (DDS) refers to the method of delivering drugs to the targeted sites with minimal risk. One popular strategy of DDS is using nanoparticles as a drug carrier, which are made from biocompatible and degradable polymers. Here, nanoparticles composed of Arthrospira-derived sulfated polysaccharide (AP) and chitosan were developed and expected to possess the capabilities of antiviral, antibacterial, and pH-sensitive properties. The composite nanoparticles, abbreviated as APC, were optimized for stability of morphology and size (~160 nm) in the physiological environment (pH = 7.4). Potent antibacterial (over 2 µg/mL) and antiviral (over 6.596 µg/mL) properties were verified in vitro. The pH-sensitive release behavior and release kinetics of drug-loaded APC nanoparticles were examined for various categories of drugs, including hydrophilic, hydrophobic, and protein drugs, under different pH values of the surroundings. Effects of APC nanoparticles were also evaluated in lung cancer cells and neural stem cells. The use of APC nanoparticles as a drug delivery system maintained the bioactivity of the drug to inhibit the proliferation of lung cancer cells (with ~40% reduction) and to relieve the growth inhibitory effect on neural stem cells. These findings indicate that the pH-sensitive and biocompatible composite nanoparticles of sulfated polysaccharide and chitosan well keep the antiviral and antibacterial properties and may serve as a promising multifunctional drug carrier for further biomedical applications.

Development of double network polyurethane-chitosan composite bioinks for soft neural tissue engineering.

Three-dimensional (3D) bioprinting is an emerging manufacturing technology to print materials with cells for tissue engineering applications. In this study, we prepared novel ternary soft segment-based biodegradable polyurethane (tPU) using waterborne processes. The ternary soft segment included poly(ε-caprolactone) (PCL), polylactide, and poly(3-hydroxybutyrate) (PHB). tPU2 with a soft segment of PCL, poly(D,L-lactide), and PHB in a molar ratio of 0.7 : 0.2 : 0.1 demonstrated lower stiffness (∼2.3 kPa) and a greater tan δ value (∼0.64) and maintained good vitality (91.3%) of neural stem cells (NSCs) among various tPUs. The bioprinted tPU2 constructs facilitated cell proliferation (∼200% in 7 days) and neural differentiation of NSCs. Meanwhile, tPU2 formed double network composite hydrogels with gelatin or agarose, and the composite hydrogels showed good biocompatibility and achieved high-resolution (∼80 µm nozzle) bioprinting. In addition, a new series of double network polyurethane-chitosan composite (PUC) hydrogels were developed by combining tPU2 with a self-healing chitosan hydrogel. The PUC hydrogel demonstrated self-healing properties and bioprintability without the need for a post-crosslinking process. The bioprinted PUC composite hydrogel promoted cell proliferation (∼300% in 7 days) and neural differentiation of NSCs better than the tPU2 bioink. This study revealed new formulae of a polyurethane bioink and a polyurethane-chitosan composite bioink for 3D bioprinting and tissue engineering applications.

Bioactive self-healing hydrogel based on tannic acid modified gold nano-crosslinker as an injectable brain implant for treating Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is one of the most common long-term neurodegenerative diseases. Current treatments for PD are mostly based on surgery and medication because of the limitation and challenges in selecting proper biomaterials. In this study, an injectable bioactive hydrogel based on novel tannic acid crosslinker was developed to treat PD. METHODS: The oxidized tannic acid modified gold nano-crosslinker was synthesized and used to effectively crosslink chitosan for preparation of the bioactive self-healing hydrogel. The crosslinking density, conductivity, self-healing ability, and injectability of the hydrogel were characterized. Abilities of the hydrogel to promote the proliferation and differentiation of neural stem cells (NSCs) were assessed in vitro. Anti-inflammatory property was analyzed on J774A.1 macrophages. The hydrogel was injected in the PD rat model for evaluation of the motor function recovery, electrophysiological performance improvement, and histological repair. RESULTS: The hydrogel exhibited self-healing property and 34G (~ 80 µm) needle injectability. NSCs grown in the hydrogel displayed long-term proliferation and differentiation toward neurons in vitro. Besides, the hydrogel owned strong anti-inflammatory and antioxidative capabilities to rescue inflamed NSCs (~ 90%). Brain injection of the bioactive hydrogel recovered the motor function of PD rats. Electrophysiological measurements showed evident alleviation of irregular discharge of nerve cells in the subthalamic nucleus of PD rats administered with the hydrogel. Histological examination confirmed that the hydrogel alone significantly increased the density of tyrosine hydroxylase positive neurons and fibers as well as reduced inflammation, with a high efficacy similar to drug-loaded hydrogel. CONCLUSION: The new bioactive hydrogel serves as an effective brain injectable implant to treat PD and a promising biomaterial for developing novel strategies to treat brain diseases.

A Biomimetic Bilayer Hydrogel Actuator Based on Thermoresponsive Gelatin Methacryloyl-Poly(N-isopropylacrylamide) Hydrogel with Three-Dimensional Printability.

Development of hydrogel-based actuators with programmable deformation is an important topic that arouses much attention in fundamental and applied research. Most of these actuators are nonbiodegradable or work under nonphysiological conditions. Herein, a temperature-responsive and biodegradable gelatin methacryloyl (GelMA)-poly(N-isopropylacrylamide) hydrogel (i.e., GN hydrogel) network was explored as the active layer of a bilayer actuator. Small-angle X-ray scattering (SAXS) revealed that the GN hydrogel formed a mesoglobular structure (∼230 Å) upon a thermally induced phase transition. Rheological data supported that the GN hydrogel possessed 3D printability and tunable mechanical properties. A bilayer hydrogel actuator composed of active GN and passive GelMA layers was optimized by varying the layer thickness and compositions to achieve large, reproducible, and anisotropic bending with a curvature of ∼5.5 cm-1. Different patterns of the active layer were designed for actuation in programmable control. The 3D printed GN hydrogel constructs showed significant volume reduction (∼25-60% depending on construct design) at 37 °C with the resolution enhanced by the thermo-triggered actuation, while they were able to fully reswell at room temperature. A more intricate 3D printed butterfly actuator demonstrated the ability to mimic the wing movement through thermoresponsiveness. Furthermore, myoblasts laden in the GN hydrogel exhibited significant proliferation of ∼376% in 14 days. This study provides a new fabrication approach for developing biomimetic devices, artificial muscles, and soft robotics for biomedical applications.

Stretchable and biodegradable chitosan-polyurethane-cellulose nanofiber composites as anisotropic materials.

Chitosan is a naturally derived biodegradable polymer with abundancy, sustainability, and ease of chemical modification. Polyurethanes are a family of elastic biocompatible polymers, and composites of polyurethanes have versatile properties and applications. Chitosan-polyurethane composites were recently developed but had insufficient strength and limited stretchability. In the current study, cellulose nanofibers (CNFs) were integrated in chitosan-polyurethane composites to prepare stretchable and anisotropic materials. A biodegradable polyurethane was first synthesized, end-capped with aldehyde to become dialdehyde polyurethane (DP) nanoparticles, and added with CNFs to prepare the DP-CNF composite crosslinker (DPF). The waterborne DPF crosslinker was then blended with chitosan solution to make polyurethane-CNF-chitosan (DPFC) composites. After blending, DPFC may form hydrogel in ~33 min at room temperature, which confirmed crosslinking. Composite films cast and dried from the blends showed good elongation (~420.2 %) at 60 °C. Anisotropic films were then generated by tension annealing with pre-strain. The annealed films with 200 % pre-strain exhibited large elastic anisotropy with ~4.9 anisotropic ratio. In situ SAXS/WAXS analyses unveiled that rearrangement and alignment of the microstructure during tension annealing accounted for the anisotropy. The anisotropic composite films had the ability to orient the growth of neural stem cells and showed the potential for biomimetic and tissue engineering applications.

Enhancement of Cell Behavior by the Polysaccharide Extract of Arthrospira and Potential Biomedical Applications.

Arthrospira is one of the most studied cyanobacteria and has been reported with practical applications. Among the substances derived from Arthrospira, polysaccharides have received relatively less attention than phycocyanins, though they have more abundant structural variations and specific properties. Herein, a new Arthrospira-derived sulfated polysaccharide was explored for its potential bioactive functions. The ability of this sulfated polysaccharide to promote the behavior of neural stem cells (NSCs) in three-dimensional hydrogel was examined for the first time. NSCs encapsulated in the sulfated polysaccharide-containing hydrogel showed better proliferation than the control hydrogel as well as a unique cell clustering behavior, i.e., formation of multicellular spherical clusters (40-60 µm). The sulfated polysaccharide, in an appropriate range of concentration (5 mg/mL), also maintained the stemness of NSCs in hydrogel and facilitated their differentiation. In addition, the potentials of the new sulfated polysaccharide as a coating material and as a component for drug carrier were verified. The sulfated polysaccharide-modified substrate exhibited superhydrophilicity (contact angle ~9°) and promoted cell adhesion to the substrate. Composite nanoparticles composed of the sulfated polysaccharide and other differently charged polysaccharides were produced with an average diameter of ~240 nm and estimated drug loading of ~18%. The new Arthrospira-derived sulfated polysaccharide is a promising candidate for cell culture, surface-modification, and drug-delivery applications in the biomedical field.

Correction: Hung et al. Anti-Inflammatory Fibronectin-AgNP for Regulation of Biological Performance and Endothelial Differentiation Ability of Mesenchymal Stem Cells. Int. J. Mol. Sci. 2021, 22, 9262.

The authors wish to make the following correction to this paper [...].

Gelation and the Self-Healing Behavior of the Chitosan-Catechol Hydrogel.

Mussel-inspired adhesive hydrogels have been developed in biomedical fields due to their strong adhesive property, cohesive capability, biocompatibility, and hemostatic ability. Catechol-functionalized chitosan is a potential polymer used to prepare adhesive hydrogels. However, the unique gelation mechanism and self-healing properties of catechol-grafted chitosan alone have not yet been explored. Herein, catechol-grafted chitosan (CC) was synthesized and further concentrated to obtain the self-healing CC hydrogels. The gelation mechanism of CC hydrogels may be attributed to the formation of hydrogen bonding, cation-π interactions, Michael addition, or Schiff base reactions during concentration phases. Rheological studies showed that the CC hydrogel owned self-healing properties in repeated damage-healing cycles. Coherent small-angle X-ray scattering (SAXS) analyses revealed the formation of a mesoscale structure (~9 nm) as the solid content of the hydrogel increased. In situ SAXS combined with rheometry verified the strain-dependent behavior of the CC hydrogel. The CC hydrogel displayed the osmotic-responsive behavior and enhanced adhesive strength (0.38 N/cm2) after immersion in the physiological saline. The CC scaffold prepared by lyophilizing the CC hydrogel revealed a macroporous structure (~200 µm), a high swelling ratio (9656%), good compressibility, and durability. This work provides an insight into the design of using chitosan-catechol alone to produce hydrogels or scaffolds with tunable mechanical properties for further applications in biomedical fields.

Tough, Self-Healing, and Conductive Elastomer ─Ionic PEGgel.

Ionically conductive elastomers are necessary for realizing human-machine interfaces, bioelectronic applications, or durable wearable sensors. Current design strategies, however, often suffer from solvent leakage and evaporation, or from poor mechanical properties. Here, we report a strategy to fabricate ionic elastomers (IHPs) demonstrating high conductivity (0.04 S m-1), excellent electrochemical stability (>60,000 cycles), ultra-stretchability (up to 1400%), high toughness (7.16 MJ m-3), and fast self-healing properties, enabling the restoration of ionic conductivity within seconds, as well as no solvent leakage. The ionic elastomer is composed of in situ formed physically cross-linked poly(2-hydroxyethyl methacrylate) networks and poly(ethylene glycol) (PEG). The long molecular chains of PEG serve as a solvent for dissolving electrolytes, improve its long-term stability, reduce solvent leakage, and ensure the outstanding mechanical properties of the IHP. Surprisingly, the incorporation of ions into PEG simultaneously enhances the strength and toughness of the elastomer. The strengthening and toughening mechanisms were further revealed by molecular simulation. We demonstrate an application of the IHPs as (a) flexible sensors for strain or temperature sensing, (b) skin electrodes for recording electrocardiograms, and (c) a tough and sensing material for pneumatic artificial muscles. The proposed strategy is simple and easily scalable and can further inspire the design of novel ionic elastomers for ionotronics applications.