Engineering Hydrogels for the Development of Three-Dimensional In Vitro Models.

The superiority of in vitro 3D cultures over conventional 2D cell cultures is well recognized by the scientific community for its relevance in mimicking the native tissue architecture and functionality. The recent paradigm shift in the field of tissue engineering toward the development of 3D in vitro models can be realized with its myriad of applications, including drug screening, developing alternative diagnostics, and regenerative medicine. Hydrogels are considered the most suitable biomaterial for developing an in vitro model owing to their similarity in features to the extracellular microenvironment of native tissue. In this review article, recent progress in the use of hydrogel-based biomaterial for the development of 3D in vitro biomimetic tissue models is highlighted. Discussions of hydrogel sources and the latest hybrid system with different combinations of biopolymers are also presented. The hydrogel crosslinking mechanism and design consideration are summarized, followed by different types of available hydrogel module systems along with recent microfabrication technologies. We also present the latest developments in engineering hydrogel-based 3D in vitro models targeting specific tissues. Finally, we discuss the challenges surrounding current in vitro platforms and 3D models in the light of future perspectives for an improved biomimetic in vitro organ system.

3D Bio-Printability of Hybrid Pre-Crosslinked Hydrogels.

Maintaining shape fidelity of 3D bio-printed scaffolds with soft biomaterials is an ongoing challenge. Here, a rheological investigation focusing on identifying useful physical and mechanical properties directly related to the geometric fidelity of 3D bio-printed scaffolds is presented. To ensure during- and post-printing shape fidelity of the scaffolds, various percentages of Carboxymethyl Cellulose (CMC) (viscosity enhancer) and different calcium salts (CaCl2 and CaSO4, physical cross-linkers) were mixed into alginate before extrusion to realize shape fidelity. The overall solid content of Alginate-Carboxymethyl Cellulose (CMC) was limited to 6%. A set of rheological tests, e.g., flow curves, amplitude tests, and three interval thixotropic tests, were performed to identify and compare the shear-thinning capacity, gelation points, and recovery rate of various compositions. The geometrical fidelity of the fabricated scaffolds was defined by printability and collapse tests. The effect of using multiple cross-linkers simultaneously was assessed. Various large-scale scaffolds were fabricated (up to 5.0 cm) using a pre-crosslinked hybrid. Scaffolds were assessed for the ability to support the growth of Escherichia coli using the Most Probable Number technique to quantify bacteria immediately after inoculation and 24 h later. This pre-crosslinking-based rheological property controlling technique can open a new avenue for 3D bio-fabrication of scaffolds, ensuring proper geometry.

Incorporation of dumbbell-shaped and Y-shaped cross-linkers in adjustable pullulan/polydopamine hydrogels for selective adsorption of cationic dyes.

Hydrogel adsorbents have attracted considerable attention due to their sludge minimization, good water permeability and renewable performance. Here, a promising strategy for the one-step preparation of pullulan/polydopamine hybird hydrogels (PPGels) was presented. Dumbbell-shaped cross-linker neopentyl glycol diglycidyl ether (NGDE, 2 arms) and Y-shaped cross-linker trimethylolpropane triglycidyl ether (TTE, 3 arms) were selected to study the relationship between cross-linker structure and hydrogel performances. The NGDE possessing less molecular repulsive force and higher reactivity demonstrated more effective cross-linking with the pullulan, which leaded to a decrease in pore size of the hydrogel. Meanwhile, the introduction of polydopamine significantly enhanced the adsorption ability and gave the resulting hybrid gel the specific selectivity toward cationic dyes (96 mg/g for crystal violet, 25.8 mg/g for methylene blue and barely not adsorption for azophloxine). Our data suggested that the electrostatic interaction played a vital role in the dye adsorption process, and the adsorption data could be explained by pseudo-second-order model and Langmuir isotherm model. Furthermore, the obtained PPGel could be easily separated after adsorption. This study describes the relationship between cross-linker structure and properties of pullulan/polydopamine hybrid gels, which provides a new strategy to create polysaccharide-based adsorbents for wastewater remediation.

Construction of Super-Hydrophobic Lignocellulosic Nanofibrils Aerogels as Speedy Oil Absorbents.

Lignocellulosic nanofibrils (LCNF) aerogels have a three-dimensional structure, with large specific surface area, low density, which is promising to be developed into a new type of adsorbent with high absorption capacity. However, LCNF aerogels have the problem of simultaneous oil and water adsorption. This high hydrophilicity directly leads to low adsorption efficiency in oil-water systems. This paper suggests a facile and economical method for the synthesis of biocompatible CE-LCNF aerogels using LCNF and Castor oil triglycidyl ether (CE) was successfully established. The use of LCNF enabled aerogels to possess remarkably uniform pore size and structural integrity, while the introduction of hydrophobic silica produced stable superhydrophobicity for more than 50 days at room temperature. These aerogels presented desirable hydrophobicity (131.6°), excellent oil adsorption capacity (62.5 g/g) and excellent selective sorption property, making them ideal absorbents for oil spill cleaning. The effects of ratios of LCNF to CE composition, temperatures and oil viscosity on the oil adsorption performance of aerogels were estimated. The results displayed that the aerogels had the maximum adsorption capacity at 25 °C. The pseudo-secondary model had higher validity in oil adsorption kinetic theories compared to the pseudo-first-order model. The CE-LCNF aerogels were excellent super-absorbents for oil removal. Moreover, the LCNF was renewable and nontoxic, which has the potential to promote environmental applications.

Adhesive polydopamine-based photothermal hybrid hydrogel for on-demand lidocaine delivery, effective anti-bacteria, and prolonged local long-lasting analgesia.

Considering the astonishing prevalence of localized pain affecting billions of patients worldwide, the development of advanced analgesic formulations or delivery systems to achieve clinical applicability is of great significance. In this study, an integrated PDA-based LiH@PDA@Ag@PAA@Gelatin system was designed for sustained delivery of lidocaine hydrochloride (LiH). By optimizing the preparation process and formulation of the hydrogel, the hydrogel exhibited superior mechanical properties, reversibility, adhesion strength, and self-healing attributes. Moreover, PDA@Ag nanoparticles were evenly dispersed within the hydrogel, and the optimized PDA@Ag@PAA@Gelatin showed a higher photothermal conversion efficiency than that of pure PDA. Importantly, LiH@PDA@Ag@PAA@Gelatin could effectively capture and eradicate bacteria through the synergistic interaction between near-infrared (NIR), PDA, Ag and LiH. In vitro and in vivo tests demonstrated that LiH@PDA@Ag@PAA@Gelatin exhibited higher drug delivery efficiency compared to commercial lidocaine patches. By evaluating the mechanical pain withdrawal threshold of the spared nerve injury (SNI) model in rats, it was proven that LiH@PDA@Ag@PAA@Gelatin enhanced and prolonged the analgesic effect of LiH. Furthermore, LiH@PDA@Ag@PAA@Gelatin induced by NIR possessed excellent on-demand photothermal analgesic ability. Therefore, this study develops a convenient method for preparing localized analgesic hydrogel patches, providing an important step towards advancing PDA-based on-demand pain relief applications.

A Cellulose/Chitosan Dual Cross-Linked Multifunctional and Resilient Hydrogel for Emergent Open Wound Management.

Adhesive hydrogel holds huge potential in biomedical applications, such as hemostasis and emergent wound management during outpatient treatment or surgery. However, most adhesive hydrogels underperform to offer robust adhesions on the wet tissue, increasing the risk of hemorrhage and reducing the fault tolerance of surgery. To address this issue, this work develops a polysaccharide-based bioadhesive hydrogel tape (ACAN) consisting of dual cross-linking of allyl cellulose (AC) and carboxymethyl chitosan (CMCS). The hygroscopicity of AC and CMCS networks enables ACAN to remove interfacial water from the tissue surface and initializes a physical cross-link instantly. Subsequently, covalent cross-links are developed with amine moieties to sustain long-term and robust adhesion. The dual cross-linked ACAN also has good cytocompatibility with controllable mechanical properties matching to the tissue, where the addition of CMCS provides remarkable antibacterial properties and hemostatic capability. Moreover, compared with commercially available 3 M film, ACAN provides an ultrafast wound healing on tissue. The ACAN hybrid hydrogels have advantages such as biocompatibility and antibacterial, hemostatic, and wound healing properties, shedding new light on first-aid tape design and advancing the cellulose-based materials technology for high-performance biomedical applications.

Alginate-CaCO3 hybrid colloidal hydrogel with tunable physicochemical properties for cell growth.

Biomaterials composed of food polysaccharides are of great interest for future biomedical applications due to their great biocompatibility, tunable mechanical properties, and complex architectural designs that play a crucial role in the modulation of cell adhesion and proliferation. In this work, a facile approach was designed to obtain novel 3D alginate-CaCO3 hybrid hydrogel particles in situ. Controlling the gel concentration from 3 to 20 mg·mL-1 allows us to control the alginate-CaCO3 hydrogel particles' size and density (size variation from 1.86 to 2.34 mm and density from 1.22 to 1.29 mg/mm3). This variable also has a considerable influence on the mineralization process resulting in CaCO3 particles with varied sizes and amounts within the hydrogel beads. The measurements of Young's modulus showed that the inclusion of CaCO3 particles into the alginate hydrogel improved its mechanical properties, and Young's modulus of these hybrid hydrogel particles had a linear relationship with alginate content and hydrogel particle size. Cell experiments indicated that alginate-CaCO3 hybrid hydrogel particles can support osteoblastic cell proliferation and growth. In particular, the amount of hydroxyapatite deposition on the cell membrane significantly increased after the treatment of cells with hybrid hydrogel particles, up to 20-fold. This work offers a strategy for constructing inorganic particle-doped polysaccharide hybrid hydrogel scaffolds that provide the potential to support cell growth.

Metal-amplified sonodynamic therapy of Ti-based chitosan-polyvinyl alcohol hybrid hydrogel dressing against subcutaneous Staphylococcus aureus infection.

Ultrasound (US)-mediated sonodynamic therapy (SDT) has received extensive attention in pathogen elimination for non-invasiveness and high spatial and temporal accuracy. Considering that hydrogel can provide a healing-friendly environment for wounds, in this work, hybrid hydrogels are constructed by embedding Ag doped TiO2 nanoparticles in chitosan-polyvinyl alcohol hydrogels for enhanced sonodynamic antibacterial therapy. With metal silver doped, TiO2 nanoparticles sonosensitivity is improved to generate more reactive oxygen species (ROS), which endows hybrid hydrogels with high-efficient antibacterial properties. In vivo results show that hybrid hydrogel dressing can prevent infection and promote wound closure within 2 days. The healing ratio excess 95 % with no pus produced at the end of treatment. The therapeutic mechanism was identified that heterojunction formed in Ag doped TiO2 facilitates the separation of charge carriers under US irradiation, leading to elevating ROS generation. The generated ROS promote hybrid hydrogels sonodynamic antibacterial therapeutic efficacy to thoroughly eliminate pathogen via disrupting bacterial cell membrane integrity, decreasing membrane fluidity and increasing membrane permeability. Besides, biofilm formation could be effectively inhibited. This work developed a hybrid hydrogel with amplified SDT effect for wound healing, which is expected to provide inspiration of hybrid hydrogels design and Ti-based nanomaterials sonosensitivity enhancement.

GO/Cu Nanosheet-Integrated Hydrogel Platform as a Bioactive and Biocompatible Scaffold for Enhanced Calvarial Bone Regeneration.

Purpose: The treatment of craniofacial bone defects caused by trauma, tumors, and infectious and degenerative diseases is a significant issue in current clinical practice. Following the rapid development of bone tissue engineering (BTE) in the last decade, bioactive scaffolds coupled with multifunctional properties are in high demand with regard to effective therapy for bone defects. Herein, an innovative bone scaffold consisting of GO/Cu nanoderivatives and GelMA-based organic-inorganic hybrids was reported for repairing full-thickness calvarial bone defect. Methods: In this study, motivated by the versatile biological functions of nanomaterials and synthetic hydrogels, copper nanoparticle (CuNP)-decorated graphene oxide (GO) nanosheets (GO/Cu) were combined with methacrylated gelatin (GelMA)-based organic-inorganic hybrids to construct porous bone scaffolds that mimic the extracellular matrix (ECM) of bone tissues by photocrosslinking. The material characterizations, in vitro cytocompatibility, macrophage polarization and osteogenesis of the biohybrid hydrogel scaffolds were investigated, and two different animal models (BALB/c mice and SD rats) were established to further confirm the in vivo neovascularization, macrophage recruitment, biocompatibility, biosafety and bone regenerative potential. Results: We found that GO/Cu-functionalized GelMA/ß-TCP hydrogel scaffolds exhibited evidently promoted osteogenic activities, M2 type macrophage polarization, increased secretion of anti-inflammatory factors and excellent cytocompatibility, with favorable surface characteristics and sustainable release of Cu2+. Additionally, improved neovascularization, macrophage recruitment and tissue integration were found in mice implanted with the bioactive hydrogels. More importantly, the observations of microCT reconstruction and histological analysis in a calvarial bone defect model in rats treated with GO/Cu-incorporated hydrogel scaffolds demonstrated significantly increased bone morphometric values and newly formed bone tissues, indicating accelerated bone healing. Conclusion: Taken together, this BTE-based bone repair strategy provides a promising and feasible method for constructing multifunctional GO/Cu nanocomposite-incorporated biohybrid hydrogel scaffolds with facilitated osteogenesis, angiogenesis and immunoregulation in one system, with the optimization of material properties and biosafety, it thereby demonstrates great application potential for correcting craniofacial bone defects in future clinical scenarios.

Self-adhesive, conductive, and multifunctional hybrid hydrogel for flexible/wearable electronics based on triboelectric and piezoresistive sensor.

Flexible electronics are highly developed nowadays in human-machine interfaces (HMI). However, challenges such as lack of flexibility, conductivity, and versatility always greatly hindered flexible electronics applications. In this work, a multifunctional hybrid hydrogel (H-hydrogel) was prepared by combining two kinds of 1D polymer chains (polyacrylamide and polydopamine) and two kinds of 2D nanosheets (Ti3C2Tx MXene and graphene oxide nanosheets) as quadruple crosslinkers. The introduced Ti3C2Tx MXene and graphene oxide nanosheets are bonded with the PAM and PDA polymer chains by hydrogen bonds. This unique crosslinking and stable structure endow the H-hydrogel with advantages such as good flexibility, electrical conductivity, self-adhesion, and mechanical robustness. The two kinds of nanosheets not only improved the mechanical strength and conductivity of the H-hydrogel, but also helped to form the double electric layers (DELs) between the nanosheets and the bulk-free water phase inside the H-hydrogel. When utilized as the electrode of a triboelectric nanogenerator (TENG), high electrical output performances were realized due to the dynamic balance of the DELs between the nanosheets and the H-hydrogel's inside water molecules. Moreover, flexible sensors, including triboelectric, and strain/pressure sensors, were achieved for human motion detection at low frequencies. This hydrogel is promising for HMI and e-skin.

Chemical Modification of Human Decellularized Extracellular Matrix for Incorporation into Phototunable Hybrid-Hydrogel Models of Tissue Fibrosis.

Tissue fibrosis remains a serious health condition with high morbidity and mortality rates. There is a critical need to engineer model systems that better recapitulate the spatial and temporal changes in the fibrotic extracellular microenvironment and enable study of the cellular and molecular alterations that occur during pathogenesis. Here, we present a process for chemically modifying human decellularized extracellular matrix (dECM) and incorporating it into a dynamically tunable hybrid-hydrogel system containing a poly(ethylene glycol)-α methacrylate (PEGαMA) backbone. Following modification and characterization, an off-stoichiometry thiol-ene Michael addition reaction resulted in hybrid-hydrogels with mechanical properties that could be tuned to recapitulate many healthy tissue types. Next, photoinitiated, free-radical homopolymerization of excess α-methacrylates increased crosslinking density and hybrid-hydrogel elastic modulus to mimic a fibrotic microenvironment. The incorporation of dECM into the PEGαMA hydrogel decreased the elastic modulus and, relative to fully synthetic hydrogels, increased the swelling ratio, the average molecular weight between crosslinks, and the mesh size of hybrid-hydrogel networks. These changes were proportional to the amount of dECM incorporated into the network. Dynamic stiffening increased the elastic modulus and decreased the swelling ratio, average molecular weight between crosslinks, and the mesh size of hybrid-hydrogels, as expected. Stiffening also activated human fibroblasts, as measured by increases in average cellular aspect ratio (1.59 ± 0.02 to 2.98 ± 0.20) and expression of α-smooth muscle actin (αSMA). Fibroblasts expressing αSMA increased from 25.8 to 49.1% upon dynamic stiffening, demonstrating that hybrid-hydrogels containing human dECM support investigation of dynamic mechanosensing. These results improve our understanding of the biomolecular networks formed within hybrid-hydrogels: this fully human phototunable hybrid-hydrogel system will enable researchers to control and decouple the biochemical changes that occur during fibrotic pathogenesis from the resulting increases in stiffness to study the dynamic cell-matrix interactions that perpetuate fibrotic diseases.

Long-Lasting Thixotropic Natural Polymeric Hydrogel Based on Silk Nanofibrils.

Hydrogels are considered to be ideal biomedical materials as their physical properties are similar to the physiological tissue environment. In particular, thixotropic hydrogels have received increasing attention from researchers because of their injectability. Herein, a simple and rapid method was developed for the preparation of a regenerated silk fibroin (RSF) hydrogel with long-lasting and excellent thixotropy. The thixotropic RSF hydrogel was readily formed by ultrasonic treatment of the pretreated RSF solution for 2 min followed by incubation at 40 °C for 10 min. The storage modulus of the RSF hydrogels recovered to more than 90% of the original value within 20 s after withstanding 1000% shear strain. By avoiding complicated chemical or physical treatments and by addition of crosslinking agents and/or other chemical components, the obtained RSF hydrogels maintained excellent biocompatibility. Hence, the cells implanted inside the hydrogel can grow and proliferate normally. By virtue of ultrasonic treatment during the preparation, functional nanoparticles can be uniformly dispersed in the RSF solution to prepare RSF-based hybrid hydrogels with various functions. As an application example, hydroxyapatite (HAP) with osteoinductivity was mixed with RSF solution to prepare the RSF/HAP hybrid hydrogel. The RSF/HAP hybrid hydrogel maintained biocompatibility and thixotropy of the original RSF hydrogel and promoted osteoblastic differentiation of cells owing to the addition of HAP. Therefore, the RSF hydrogel prepared in this work has a strong application prospect in the biomedical field including, but not limited to, bone repair.

Gelatin modified with alkoxysilanes (GelmSi) forms hybrid hydrogels for bioengineering applications.

Biopolymers are ideal candidates for the development of hydrogels for tissue engineering applications. However, chemical modifications are required to further improve their mechanical properties, in particular to cross-link them for long-lasting applications or biofabrication. Herein, we developed a novel gelatin-based hydrogel precursor, "GelmSi" which consist on modified gelatin with triethoxysilyl groups. Gelatin was chosen as starting material because of its biocompatibility and bioactivity, favouring cell adhesion and migration. Alkoxysilane moieties were introduced in a controlled manner on the lysine side chains of gelatin to obtain a hybrid precursor which reacts in physiological conditions, forming covalent siloxane bonds and allowing the formation of a three-dimensional chemical network. On the contrary to unmodified gelatin, siloxane covalent network dramatically increases the stiffness and the thermal stability of the resulting gelatin-based hydrogel, making it suitable for cell encapsulation and cell culture. The biorthogonality and versatility of the GelmSi hybrid hydrogel unlock a broad range of gelatin-based bioengineering applications.

Anatomy, molecular structures, and hyaluronic acid - Gelatin injectable hydrogels as a therapeutic alternative for hyaline cartilage recovery: A review.

Cartilage damage caused by trauma or osteoarthritis is a common joint disease that can increase the social and economic burden in society. Due to its avascular characteristics, the poor migration ability of chondrocytes, and a low number of progenitor cells, the self-healing ability of cartilage defects has been significantly limited. Hydrogels have been developed into one of the most suitable biomaterials for the regeneration of cartilage because of its characteristics such as high-water absorption, biodegradation, porosity, and biocompatibility similar to natural extracellular matrix. Therefore, the present review article presents a conceptual framework that summarizes the anatomical, molecular structure and biochemical properties of hyaline cartilage located in long bones: articular cartilage and growth plate. Moreover, the importance of preparation and application of hyaluronic acid - gelatin hydrogels for cartilage tissue engineering are included. Hydrogels possess benefits of stimulating the production of Agc1, Col2α1-IIa, and SOX9, molecules important for the synthesis and composition of the extracellular matrix of cartilage. Accordingly, they are believed to be promising biomaterials of therapeutic alternatives to treat cartilage damage.

Enzymatically-mineralized double-network hydrogels with ultrahigh mechanical strength, toughness, and stiffness.

Background: Synthetic hydrogels are commonly mechanically weak which limits the scope of their applications. Methods: In this study, we synthesized an organic-inorganic hybrid hydrogel with ultrahigh strength, stiffness, and toughness via enzyme-induced mineralization of calcium phosphate in a double network of bacterial cellulose nanofibers and alginate-Ca2+. Results: Cellulose nanofibers formed the first rigid network via hydrogen binding and templated the deposition of calcium phosphate, while alginate-Ca2+ formed the second energy-dissipating network via ionic interaction. The two networks created a brick-mortar-like structure, in which the "tortuous fracture path" mechanism by breaking the interlaced calcium phosphate-coated bacterial cellulose nanofibers and the hysteresis by unzipping the ionic alginate-Ca2+ network made a great contribution to the mechanical properties of the hydrogels. Conclusion: The optimized hydrogel exhibited ultrahigh fracture stress of 48 MPa, Young's modulus of 1329 MPa, and fracture energy of 3013 J/m2, which are barely possessed by the reported synthetic hydrogels. Finally, the hydrogel represented potential use in subchondral bone defect repair in an ex vivo model.

Effective degradation of tetracycline via recyclable cellulose nanofibrils/polyvinyl alcohol/Fe3O4 hybrid hydrogel as a photo-Fenton catalyst.

In this work, the method of in-situ co-precipitation was used to prepare PVA/CNF/Fe3O4 hybrid hydrogel, and the relationship between its structure and performance was explored. The Fe3O4NPs prepared by this method were dispersed on the carrier PVA/CNF hydrogel and were easy to recover. The catalytic degradation of tetracycline was investigated using PVA/CNF/Fe3O4 hybrid hydrogel as photo-Fenton catalysts. The results showed that light and hydrogel carriers were pivotal factors in promoting Fe2+ and Fe3+ cycling and that the PVA/CNF/Fe3O4 hybrid hydrogel as catalysts were able to activate H2O2 to generate a large amount of oxygen radical •OH, resulting in efficient removal of tetracycline. The tetracycline degradation followed a proposed first-order kinetic model and achieved a removal rate of about 98% in 120 min at an optimum pH of 3, H2O2 100 mM, catalyst 0.3 g/L, and a temperature of 25 °C.

Removal of inhibitory furan aldehydes in lignocellulosic hydrolysates via chitosan-chitin nanofiber hybrid hydrogel beads.

To obtain fermentable sugars from lignocellulose, various inhibitors, especially furan aldehydes, are usually generated during the pretreatment process. These inhibitors are harmful to subsequent microbial growth and fermentation. In this study, a novel detoxification strategy was proposed to remove 5-hydroxymethylfurfural (HMF) and furfural while retaining glucose and xylose using self-prepared chitosan-chitin nanofiber hybrid hydrogel beads (C-CNBs). After C-CNBs treatment, the removal rates of HMF and furfural from sugarcane bagasse hydrolysates reached 63.1% and 68.4%, while the loss rates of glucose and xylose were only 6.3% and 8.2%, respectively. Two typical industrial strains grew well in monosaccharide-rich detoxified hydrolysates, with a specific growth rate at least 4.1 times that of undetoxified hydrolysates. Furthermore, adsorption mechanism analysis revealed that the Schiff base reaction and mesopore filling were involved in furan aldehyde adsorption. In total, C-CNBs provide an efficient and practical approach for the removal of furan aldehydes from lignocellulosic hydrolysates.

Scarless Healing of Injured Vocal Folds Using an Injectable Hyaluronic Acid-Waterborne Polyurethane Hybrid Hydrogel to Tune Inflammation and Collagen Deposition.

Vocal fold (VF) scarring results from injury to the unique layered structure and is one of the main reasons for long-lasting dysphonia. A minimally invasive procedure with injectable hydrogels is a promising method for therapy. However, current surgical techniques or standard injectable fillers do not yield satisfactory outcomes. In this work, an injectable hybrid hydrogel consisting of oxide hyaluronic acid and hydrazide-modified waterborne polyurethane emulsion was injected precisely into the injury site and cross-linked in situ by a dynamic hydrazone bond. The prepared hydrogel displays excellent injectability and self-healing ability, showing favorable biocompatibility and biodegradability to facilitate endogenous newborn cell migration and growth for tissue regeneration. With the aim of evaluating the antifibrosis and regeneration capacity of the hybrid hydrogel in the VF scarring model, the morphology and vibration characteristics of VFs, inflammatory response, and healing status were collected. The hybrid hydrogel can decrease the inflammation and increase the ratio of collagen III/collagen I to heal damaged scar-free tissue. Fascinatingly, the mucosal wave oscillations of healing VF by injecting the hybrid hydrogel were vibrated like the normal VF, achieving functional restoration. This work highlights the utility of hybrid hydrogels consisting of synthetic biodegradable waterborne polyurethane emulsions and natural hyaluronic acid as promising biomaterials for scarless healing of damaged VFs.

Molecular Engineering of Rigid Hydrogels Co-assembled from Collagenous Helical Peptides Based on a Single Triplet Motif.

The potential of ultra-short peptides to self-assemble into well-ordered functional nanostructures makes them promising minimal components for mimicking the basic ingredient of nature and diverse biomaterials. However, selection and modular design of perfect de novo sequences are extremely tricky due to their vast possible combinatorial space. Moreover, a single amino acid substitution can drastically alter the supramolecular packing structure of short peptide assemblies. Here, we report the design of rigid hybrid hydrogels produced by sequence engineering of a new series of ultra-short collagen-mimicking tripeptides. Connecting glycine with different combinations of proline and its post-translational product 4-hydroxyproline, the single triplet motif, displays the natural collagen-helix-like structure. Improved mechanical rigidity is obtained via co-assembly with the non-collagenous hydrogelator, fluorenylmethoxycarbonyl (Fmoc) diphenylalanine. Characterizations of the supramolecular interactions that promote the self-supporting and self-healing properties of the co-assemblies are performed by physicochemical experiments and atomistic models. Our results clearly demonstrate the significance of sequence engineering to design functional peptide motifs with desired physicochemical and electromechanical properties and reveal co-assembly as a promising strategy for the utilization of small, readily accessible biomimetic building blocks to generate hybrid biomolecular assemblies with structural heterogeneity and functionality of natural materials.

Surface Modification of Decellularized Heart Valve by the POSS-PEG Hybrid Hydrogel to Prepare a Composite Scaffold Material with Anticalcification Potential.

Tissue-engineered heart valves (TEHVs) are the most promising replacement for heart valve transplantation. Decellularized heart valve (DHV) is one of the most common scaffold materials for TEHVs. In actual clinical applications, the most widely used method for treating DHV is cross-linking it with glutaraldehyde, but this method could cause serious problems such as calcification. In this study, we introduced polyhedral oligomeric silsesquioxane (POSS) nanoparticles into a poly(ethylene glycol) (PEG) hydrogel to prepare a POSS-PEG hybrid hydrogel, and then coated them on the surface of DHV to prepare the composite scaffold. The chemical structures, microscopic morphologies, cell compatibilities, blood compatibilities, and anticalcification properties were further investigated. Experimental results showed that the composite scaffold had good blood compatibility and excellent cell compatibility and could promote cell adhesion and proliferation. In vivo and in vitro anticalcification experiments showed that the introduction of POSS nanoparticles could reduce the degree of calcification significantly and the composite scaffold had obvious anticalcification ability. The DHV surface-coated with the POSS-PEG hybrid hydrogel is an alternative scaffold material with anticalcification potential for an artificial heart valve, which provides an idea for the preparation of TEHVs.