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    Bio-inspired self-healing structural color hydrogel. Fu Fanfan,Chen Zhuoyue,Zhao Ze,Wang Huan,Shang Luoran,Gu Zhongze,Zhao Yuanjin Proceedings of the National Academy of Sciences of the United States of America Biologically inspired self-healing structural color hydrogels were developed by adding a glucose oxidase (GOX)- and catalase (CAT)-filled glutaraldehyde cross-linked BSA hydrogel into methacrylated gelatin (GelMA) inverse opal scaffolds. The composite hydrogel materials with the polymerized GelMA scaffold could maintain the stability of an inverse opal structure and its resultant structural colors, whereas the protein hydrogel filler could impart self-healing capability through the reversible covalent attachment of glutaraldehyde to lysine residues of BSA and enzyme additives. A series of unprecedented structural color materials could be created by assembling and healing the elements of the composite hydrogel. In addition, as both the GelMA and the protein hydrogels were derived from organisms, the composite materials presented high biocompatibility and plasticity. These features of self-healing structural color hydrogels make them excellent functional materials for different applications. 10.1073/pnas.1703616114
    Cell-laden interpenetrating network hydrogels formed from methacrylated gelatin and silk fibroin via a combination of sonication and photocrosslinking approaches. Xiao Wenqian,Li Jiale,Qu Xiaohang,Wang Linling,Tan Yunfei,Li Kejiang,Li Hang,Yue Xiangzhi,Li Bo,Liao Xiaoling Materials science & engineering. C, Materials for biological applications The regeneration of load-bearing soft tissues has long driven the research and development of bioactive hydrogels. A major challenge facing the application of hydrogels to load-bearing tissues is the development of hydrogels with appropriate biological functionality and biomechanical stability that closely mimic the host tissue. In this paper, we describe a newly synthesized cell-laden interpenetrating polymer network (IPN) hydrogel based on gelatin methacrylate (GelMA) and silk fibroin (SF) that was formed via sequential sonication and photocrosslinking. The experimental results revealed that SF-GelMA IPN hydrogels exhibited high swelling ratios, excellent mechanical properties, resistance to enzymatic degradation by collagenase, and porous internal microstructures. Moreover, these properties could be tailored by changing the prepolymer components. MC3T3-E1 pre-osteoblasts attached to and subsequently proliferated on the IPN hydrogels, as demonstrated by fluorescein diacetate/propidium iodide (FDA/PI) staining and Cell Counting Kit-8 (CCK-8) analysis. In addition, the encapsulation of MC3T3-E1 pre-osteoblasts and a subsequent cell viability assay demonstrated that the entire IPN formation process was compatible with cells and that the growth of encapsulated cells could be tuned by adjusting the GelMA concentration, underlining their versatility for various load-bearing soft tissue engineering. Overall, this study introduces a class of mechanically robust and tunable cell-laden IPN hydrogels which have great potential as load-bearing soft tissue engineering scaffold. 10.1016/j.msec.2019.01.079
    Synthesis and characterization of photocrosslinkable gelatin and silk fibroin interpenetrating polymer network hydrogels. Xiao Wenqian,He Jiankang,Nichol Jason W,Wang Lianyong,Hutson Ché B,Wang Ben,Du Yanan,Fan Hongsong,Khademhosseini Ali Acta biomaterialia To effectively repair or replace damaged tissues, it is necessary to design scaffolds with tunable structural and biomechanical properties that closely mimic the host tissue. In this paper, we describe a newly synthesized photocrosslinkable interpenetrating polymer network (IPN) hydrogel based on gelatin methacrylate (GelMA) and silk fibroin (SF) formed by sequential polymerization, which possesses tunable structural and biological properties. Experimental results revealed that IPNs, where both the GelMA and SF were independently crosslinked in interpenetrating networks, demonstrated a lower swelling ratio, higher compressive modulus and lower degradation rate as compared to the GelMA and semi-IPN hydrogels, where only GelMA was crosslinked. These differences were likely caused by a higher degree of overall crosslinking due to the presence of crystallized SF in the IPN hydrogels. NIH-3T3 fibroblasts readily attached to, spread and proliferated on the surface of IPN hydrogels, as demonstrated by F-actin staining and analysis of mitochondrial activity (MTT). In addition, photolithography combined with lyophilization techniques was used to fabricate three-dimensional micropatterned and porous microscaffolds from GelMA-SF IPN hydrogels, furthering their versatility for use in various microscale tissue engineering applications. Overall, this study introduces a class of photocrosslinkable, mechanically robust and tunable IPN hydrogels that could be useful for various tissue engineering and regenerative medicine applications. 10.1016/j.actbio.2011.01.016
    FLASH: Fluorescently LAbelled Sensitive Hydrogel to monitor bioscaffolds degradation during neocartilage generation. Onofrillo Carmine,Duchi Serena,Francis Sam,O'Connell Cathal D,Caballero Aguilar Lilith M,Doyle Stephanie,Yue Zhilian,Wallace Gordon G,Choong Peter F,Di Bella Claudia Biomaterials Regenerative therapies based on photocrosslinkable hydrogels and stem cells are of growing interest in the field of cartilage repair. Cell-mediated degradation is critical for the successful clinical translation of implanted hydrogels. However, characterising cell-mediated degradation, while simultaneously monitoring the deposition of a distinct new matrix, remains a major challenge. In this study we generated a Fluorescently LAbelled Sensitive Hydrogel (FLASH) to correlate the degradation of a hydrogel bioscaffold with neocartilage formation. Gelatine Methacryloyl (GelMA) was covalently bound to the FITC fluorophore to generate FLASH and bioscaffolds were produced by casting different concentrations of FLASH GelMA, with and without human adipose-derived stem cells (hADSCs) undergoing chondrogenesis. The loss of fluorescence from FLASH bioscaffolds was correlated with changes in mechanical properties, expression of chondrogenic markers and accumulation of a cartilaginous extracellular matrix. The ability of the system to be used as a sensor to monitor bioscaffold degradability during chondrogenesis was evaluated in vitro, in a human ex vivo model of cartilage repair and in a full chondral defect in vivo rabbit model. This study represents a step towards the generation of a high throughput monitoring system to evaluate de novo cartilage formation in tissue engineering therapies. 10.1016/j.biomaterials.2020.120383
    Impact of Endotoxins in Gelatine Hydrogels on Chondrogenic Differentiation and Inflammatory Cytokine Secretion In Vitro. Groen Wilhelmina M G A C,Utomo Lizette,Castilho Miguel,Gawlitta Debby,Malda Jos,Weeren P René van,Levato Riccardo,Korthagen Nicoline M International journal of molecular sciences Gelatine methacryloyl (GelMA) hydrogels are widely used in studies aimed at cartilage regeneration. However, the endotoxin content of commercially available GelMAs and gelatines used in these studies is often overlooked, even though endotoxins may influence several cellular functions. Moreover, regulations for clinical use of biomaterials dictate a stringent endotoxin limit. We determined the endotoxin level of five different GelMAs and evaluated the effect on the chondrogenic differentiation of equine mesenchymal stromal cells (MSCs). Cartilage-like matrix production was evaluated by biochemical assays and immunohistochemistry. Furthermore, equine peripheral blood mononuclear cells (PBMCs) were cultured on the hydrogels for 24 h, followed by the assessment of tumour necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL)2 as inflammatory markers. The GelMAs were found to have widely varying endotoxin content (two with >1000 EU/mL and three with <10 EU/mL), however, this was not a critical factor determining in vitro cartilage-like matrix production of embedded MSCs. PBMCs did produce significantly higher TNF-α and CCL2 in response to the GelMA with the highest endotoxin level compared to the other GelMAs. Although limited effects on chondrogenic differentiation were found in this study, caution with the use of commercial hydrogels is warranted in the translation from in vitro to in vivo studies because of regulatory constraints and potential inflammatory effects of the content of these hydrogels. 10.3390/ijms21228571
    Interpenetrating polymer network hydrogels composed of chitosan and photocrosslinkable gelatin with enhanced mechanical properties for tissue engineering. Suo Hairui,Zhang Deming,Yin Jun,Qian Jin,Wu Zi Liang,Fu Jianzhong Materials science & engineering. C, Materials for biological applications Gelatin and chitosan (CS) are widely used natural biomaterials for tissue engineering scaffolds, but the poor mechanical properties of pure gelatin or CS hydrogels become a big obstacle that limits their use as scaffolds, especially in load-bearing tissues. This study provided a novel mechanism of forming interpenetrating network (IPN) of gelatin methacryloyl (GelMA) and CS hydrogels by covalent bonds and hydrophobic interactions through photocrosslinking and basification, respectively. By characterization of the compressive and tensile moduli, ultimate tensile stress and strain, it was found that semi-IPN and IPN structure can greatly enhance the mechanical properties of GelMA-CS hydrogels compared to the single network CS or GelMA. Moreover, the increase of either GelMA or CS concentration can strengthen the hydrogel network. Then, the swelling, enzymatic degradation, and morphology of GelMA-CS hydrogels were also systematically investigated. The excellent biocompatibility of GelMA-CS hydrogels was demonstrated by large spreading area of bone mesenchymal stem cells on hydrogel surfaces when CS concentration was <2% (w/v). According to this study, the multiple requirements of properties can be fulfilled by carefully selecting the GelMA and CS compositions for IPN hydrogels. 10.1016/j.msec.2018.07.016
    Comparative study of gelatin methacrylate hydrogels from different sources for biofabrication applications. Wang Zongjie,Tian Zhenlin,Menard Fredric,Kim Keekyoung Biofabrication Gelatin methacrylate (GelMA) hydrogel is a promising bioink for biofabrication applications due to its cost-effectiveness, ease of synthesis and biocompatibility to allow cell adhesion. However, the GelMA synthesized from a widely used porcine skin gelatin has a thermal gelation problem at room temperature. Here, we present thermally stable GelMA hydrogels at room temperature while maintaining the mechanical and biological properties comparable to porcine GelMA. The novel GelMA hydrogels were synthesized from fish skin and cold soluble gelatin. We systematically characterized the properties of the GelMA hydrogels from different sources. The properties include the degree of methacrylation, compressive Young's modulus, mass swelling ratio, viscosity, and cell adhesion and proliferation in 2D and 3D microenvironments. It has been found that the cold soluble GelMA was comparable to the porcine skin GelMA but could offer low viscosity and thermal stability at room temperature. We performed a droplet generation experiment to demonstrate the benefit of using the cold soluble GelMA for biofabrication. The cold soluble GelMA showed a more reliable and stable droplet fabrication process. Taken together, the cold soluble GelMA is a promising bioink solution and may greatly benefit the research in biofabrication. 10.1088/1758-5090/aa83cf
    On-Chip Fabrication of Cell-Attached Microstructures using Photo-Cross-Linkable Biodegradable Hydrogel. Takeuchi Masaru,Kozuka Taro,Kim Eunhye,Ichikawa Akihiko,Hasegawa Yasuhisa,Huang Qiang,Fukuda Toshio Journal of functional biomaterials We developed a procedure for fabricating movable biological cell structures using biodegradable materials on a microfluidic chip. A photo-cross-linkable biodegradable hydrogel gelatin methacrylate (GelMA) was used to fabricate arbitrary microstructure shapes under a microscope using patterned ultraviolet light. The GelMA microstructures were movable inside the microfluidic channel after applying a hydrophobic coating material. The fabricated microstructures were self-assembled inside the microfluidic chip using our method of fluid forcing. The synthesis procedure of GelMA was optimized by changing the dialysis temperature, which kept the GelMA at a suitable pH for cell culture. RLC-18 rat liver cells (Riken BioResource Research Center, Tsukuba, Japan) were cultured inside the GelMA and on the GelMA microstructures to check cell growth. The cells were then stretched for 1 day in the cell culture and grew well on the GelMA microstructures. However, they did not grow well inside the GelMA microstructures. The GelMA microstructures were partially dissolved after 4 days of cell culture because of their biodegradability after the cells were placed on the microstructures. The results indicated that the proposed procedure used to fabricate cell structures using GelMA can be used as a building block to assemble three-dimensional tissue-like cell structures in vitro inside microfluidic devices. 10.3390/jfb11010018
    Microfluidic-enabled bottom-up hydrogels from annealable naturally-derived protein microbeads. Sheikhi Amir,de Rutte Joseph,Haghniaz Reihaneh,Akouissi Outman,Sohrabi Alireza,Di Carlo Dino,Khademhosseini Ali Biomaterials Naturally-derived proteins, such as collagen, elastin, fibroin, and gelatin (denatured collagen) hold a remarkable promise for tissue engineering and regenerative medicine. Gelatin methacryloyl (GelMA), synthesized from the methacryloyl modification of gelatin, mimicking the structure of extracellular matrix, has widely been used as a universal multi-responsive scaffold for a broad spectrum of applications, spanning from cell therapy to bioprinting and organoid development. Despite the widespread applications of GelMA, coupled stiffness and porosity has inhibited its applications in 3D cellular engineering wherein a stiff scaffold with large pores is demanded (e.g., at concentrations >10 wt%). Taking advantage of the orthogonal thermo-chemical responsivity of GelMA, we have developed microfluidic-assisted annealable GelMA beads, that are first stabilized by temperature-mediated physical crosslinking, flowed to form a scaffold structure, and then chemically annealed using light to fabricate novel bead-based 3D GelMA scaffolds with high mechanical resilience. We show how beaded GelMA (B-GelMA) provides a self-standing microporous environment with an orthogonal void fraction and stiffness, promoting cell adhesion, proliferation, and rapid 3D seeding at a high polymer concentration (∼20 wt%) that would otherwise be impossible for bulk GelMA. B-GelMA, decorated with methacryloyl and arginylglycylaspartic acid (RGD) peptide motifs, does not require additional functionalization for annealing and cell adhesion, providing a versatile biorthogonal platform with orthogonal stiffness and porosity for a myriad of biomedical applications. This technology provides a universal method to convert polymeric materials with orthogonal physico-chemical responsivity to modular platforms, opening a new horizon for converting bulk hydrogels to beaded hydrogels (B-hydrogels) with decoupled porosity and stiffness. 10.1016/j.biomaterials.2018.10.040
    Cell-laden photocrosslinked GelMA-DexMA copolymer hydrogels with tunable mechanical properties for tissue engineering. Wang Hang,Zhou Lei,Liao Jingwen,Tan Ying,Ouyang Kongyou,Ning Chenyun,Ni Guoxin,Tan Guoxin Journal of materials science. Materials in medicine To effectively repair or replace damaged tissues, it is necessary to design three dimensional (3D) extracellular matrix (ECM) mimicking scaffolds with tunable biomechanical properties close to the desired tissue application. In the present work, gelatin methacrylate (GelMA) and dextran glycidyl methacrylate (DexMA) with tunable mechanical and biological properties were utilized to prepared novel bicomponent polymeric hydrogels by cross-linking polymerization using photoinitiation. We controlled the degree of substitution (DS) of glycidyl methacrylate in DexMA so that they could obtain relevant mechanical properties. The results indicated that copolymer hydrogels demonstrated a lower swelling ratio and higher compressive modulus as compared to the GelMA. Moreover, all of the hydrogels exhibited a honeycomb-like architecture, the pore sizes decreased as DS increased, and NIH-3T3 fibroblasts encapsulated in these hydrogels all exhibited excellent viability. These characteristics suggest a class of photocrosslinkable, tunable mechanically copolymer hydrogels that may find potential application in tissue engineering and regenerative medicine applications. 10.1007/s10856-014-5261-x
    Surface acoustic waves induced micropatterning of cells in gelatin methacryloyl (GelMA) hydrogels. Naseer Shahid M,Manbachi Amir,Samandari Mohamadmahdi,Walch Philipp,Gao Yuan,Zhang Yu Shrike,Davoudi Farideh,Wang Wesley,Abrinia Karen,Cooper Jonathan M,Khademhosseini Ali,Shin Su Ryon Biofabrication Acoustic force patterning is an emerging technology that provides a platform to control the spatial location of cells in a rapid, accurate, yet contactless manner. However, very few studies have been reported on the usage of acoustic force patterning for the rapid arrangement of biological objects, such as cells, in a three-dimensional (3D) environment. In this study, we report on a bio-acoustic force patterning technique, which uses surface acoustic waves (SAWs) for the rapid arrangement of cells within an extracellular matrix-based hydrogel such as gelatin methacryloyl (GelMA). A proof-of-principle was achieved through both simulations and experiments based on the in-house fabricated piezoelectric SAW transducers, which enabled us to explore the effects of various parameters on the performance of the built construct. The SAWs were applied in a fashion that generated standing SAWs (SSAWs) on the substrate, the energy of which subsequently was transferred into the gel, creating a rapid, and contactless alignment of the cells (<10 s, based on the experimental conditions). Following ultraviolet radiation induced photo-crosslinking of the cell encapsulated GelMA pre-polymer solution, the patterned cardiac cells readily spread after alignment in the GelMA hydrogel and demonstrated beating activity in 5-7 days. The described acoustic force assembly method can be utilized not only to control the spatial distribution of the cells inside a 3D construct, but can also preserve the viability and functionality of the patterned cells (e.g. beating rates of cardiac cells). This platform can be potentially employed in a diverse range of applications, whether it is for tissue engineering, in vitro cell studies, or creating 3D biomimetic tissue structures. 10.1088/1758-5090/aa585e
    Understanding the impact of crosslinked PCL/PEG/GelMA electrospun nanofibers on bactericidal activity. De Paula Mirian Michelle Machado,Bassous Nicole Joy,Afewerki Samson,Harb Samarah Vargas,Ghannadian Paria,Marciano Fernanda Roberta,Viana Bartolomeu Cruz,Tim Carla Roberta,Webster Thomas Jay,Lobo Anderson Oliveira PloS one Herein, we report the design of electrospun ultrathin fibers based on the combination of three different polymers polycaprolactone (PCL), polyethylene glycol (PEG), and gelatin methacryloyl (GelMA), and their potential bactericidal activity against three different bacteria Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the morphology, chemical structure and wettability before and after UV photocrosslinking of the produced scaffolds. Results showed that the developed scaffolds presented hydrophilic properties after PEG and GelMA incorporation. Moreover, they were able to significantly reduce gram-positive, negative, and MRSA bacteria mainly after UV photocrosslinking (PCL:PEG:GelMa-UV). Furthermore, we performed a series of study for gaining a better mechanistic understanding of the scaffolds bactericidal activity through protein adsorption study and analysis of the reactive oxygen species (ROS) levels. Furthermore, the in vivo subcutaneous implantation performed in rats confirmed the biocompatibility of our designed scaffolds. 10.1371/journal.pone.0209386