Magneto-acoustic protein nanostructures for non-invasive imaging of tissue mechanics in vivo.

Measuring cellular and tissue mechanics inside intact living organisms is essential for interrogating the roles of force in physiological and disease processes. Current agents for studying the mechanobiology of intact, living organisms are limited by poor light penetration and material stability. Magnetomotive ultrasound is an emerging modality for real-time in vivo imaging of tissue mechanics. Nonetheless, it has poor sensitivity and spatiotemporal resolution. Here we describe magneto-gas vesicles (MGVs), protein nanostructures based on gas vesicles and magnetic nanoparticles that produce differential ultrasound signals in response to varying mechanical properties of surrounding tissues. These hybrid nanomaterials significantly improve signal strength and detection sensitivity. Furthermore, MGVs enable non-invasive, long-term and quantitative measurements of mechanical properties within three-dimensional tissues and in vivo fibrosis models. Using MGVs as novel contrast agents, we demonstrate their potential for non-invasive imaging of tissue elasticity, offering insights into mechanobiology and its application to disease diagnosis and treatment.

A Mechanically Resilient and Tissue-Conformable Hydrogel with Hemostatic and Antibacterial Capabilities for Wound Care.

Hydrogels are used in wound dressings because of their tissue-like softness and biocompatibility. However, the clinical translation of hydrogels remains challenging because of their long-term stability, water swellability, and poor tissue adhesiveness. Here, tannic acid (TA) is introduced into a double network (DN) hydrogel consisting of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) to realize a tough, self-healable, nonswellable, conformally tissue-adhesive, hemostatic, and antibacterial hydrogel. The TA within the DN hydrogel forms a dynamic network, enabling rapid self-healing (within 5 min) and offering effective energy dissipation for toughness and viscoelasticity. Furthermore, the hydrophobic moieties of TA provide a water-shielding effect, rendering the hydrogel nonswellable. A simple chemical modification to the hydrogel further strengthens its interfacial adhesion with tissues (shear strength of ≈31 kPa). Interestingly, the TA also can serve as an effective hemostatic (blood-clotting index of 58.40 ± 1.5) and antibacterial component, which are required for a successful wound dressing. The antibacterial effects of the hydrogel are tested against Escherichia coli and Staphylococcus aureus. Finally, the hydrogel is prepared in patch form and applied to a mouse model to test in vivo biocompatibility and hemostatic performances.

3D printing of mechanically tough and self-healing hydrogels with carbon nanotube fillers.

Hydrogels have the potential to play a crucial role in bioelectronics, as they share many properties with human tissues. However, to effectively bridge the gap between electronics and biological systems, hydrogels must possess multiple functionalities, including toughness, stretchability, self-healing ability, three-dimensional (3D) printability, and electrical conductivity. Fabricating such tough and self-healing materials has been reported, but it still remains a challenge to fulfill all of those features, and in particular, 3D printing of hydrogel is in the early stage of the research. In this paper, we present a 3D printable, tough, and self-healing multi-functional hydrogel in one platform made from a blend of poly(vinyl alcohol) (PVA), tannic acid (TA), and poly(acrylic acid) (PAA) hydrogel ink (PVA/TA/PAA hydrogel ink). Based on a reversible hydrogen-bond (H-bond)-based double network, the developed 3D printable hydrogel ink showed excellent printability via shear-thinning behavior, allowing high printing resolution (~100 µm) and successful fabrication of 3D-printed structure by layer-by-layer printing. Moreover, the PVA/TA/PAA hydrogel ink exhibited high toughness (tensile loading of up to ~45.6 kPa), stretchability (elongation of approximately 650%), tissue-like Young's modulus (~15 kPa), and self-healing ability within 5 min. Furthermore, carbon nanotube (CNT) fillers were successfully added to enhance the electrical conductivity of the hydrogel. We confirmed the practicality of the hydrogel inks for bioelectronics by demonstrating biocompatibility, tissue adhesiveness, and strain sensing ability through PVA/TA/PAA/CNT hydrogel ink.

Ferritin Nanoshuttle for Long-Lasting Self-Healing of Phenolic Hydrogels.

Herein, we highlight a novel finding that ferritin can play a crucial role in the "self-healing lifetime" of soft phenolic materials. Ferritin interacts with a catechol-functionalized polymer to form a self-healable and adhesive hydrogel bidirectionally by providing and retrieving Fe3+. As a result of its unique role as a nanoshuttle to store and release iron, ferritin significantly increases the self-healing lifetime of the hydrogel compared with that afforded by catechol-Fe3+ coordination through direct Fe3+ addition without ferritin. Ferritin also induces stable oxidative coupling between catechol moieties following metal coordination, which contributes to double cross-linking networks of catechol-catechol adducts and catechol-Fe3+ coordination. Thus, ferritin-mediated cross-linking can provide phenolic hydrogels with the advantages of hydrogels prepared by both metal coordination and oxidative coupling, thereby overcoming the limitations of the current cross-linking methods of phenolic hydrogels and broadening their versatility in biomedical applications.

Endoscopically injectable and self-crosslinkable hydrogel-mediated stem cell transplantation for alleviating esophageal stricture after endoscopic submucosal dissection.

Esophageal stricture after extensive endoscopic submucosal dissection impairs the quality of life of patients with superficial esophageal carcinoma. Beyond the limitations of conventional treatments including endoscopic balloon dilatation and the application of oral/topical corticosteroids, several cell therapies have been recently attempted. However, such methods are still limited in clinical situations and existing setups, and the efficacies are less in some cases since the transplanted cells hardly remain at the resection site for a long time due to swallowing and peristalsis of the esophagus. Thus, a cell transplantation platform directly applicable with clinically established equipment and enabling stable retention of transplanted cells can be a promising therapeutic option for better clinical outcomes. Inspired by ascidians that rapidly self-regenerate, this study demonstrates endoscopically injectable and self-crosslinkable hyaluronate that allows both endoscopic injection in a liquid state and self-crosslinking as an in situ-forming scaffold for stem cell therapy. The pre-gel solution may compatibly be applied with endoscopic tubes and needles of small diameters, based on the improved injectability compared to the previously reported endoscopically injectable hydrogel system. The hydrogel can be formed via self-crosslinking under in vivo oxidative environment, while also exhibiting superior biocompatibility. Finally, the mixture containing adipose-derived stem cells and the hydrogel can significantly alleviate esophageal stricture after endoscopic submucosal dissection (75% of circumference, 5 cm in length) in a porcine model through paracrine effects of the stem cell in the hydrogel, which modulate regenerative processes. The stricture rates on Day 21 were 79.5% ± 2.0%, 62.8% ± 1.7%, and 37.9% ± 2.9% in the control, stem cell only, and stem cell-hydrogel groups, respectively (p < 0.05). Therefore, this endoscopically injectable hydrogel-based therapeutic cell delivery system can serve as a promising platform for cell therapies in various clinically relevant situations.

Adhesive Hydrogel Patch-Mediated Combination Drug Therapy Induces Regenerative Wound Healing through Reconstruction of Regenerative Microenvironment.

Regenerative wound healing involves the scarless wound healing as observed in fetal skin. Multiple features of regenerative wound healing have been well studied; however, the practical application of pro-regenerative materials to recapitulate the regenerative wound healing in adult skins has not yet been achieved. In this study, the authors identified that their novel pro-regenerative material, pyrogallol-functionalized hyaluronic acid (HA-PG) patches in combination with protein transduction domain-fused Dishevelled (Dvl)-binding motif (PTD-DBM), a peptide inhibiting the CXXC-type zinc finger protein 5 (CXXC5)-Dvl interaction, promoted regenerative wound healing in mice. The HA-PG patches loaded with this competitor peptide and valproic acid (VPA), a glycogen synthase kinase 3ß (GSK3ß) inhibitor, significantly inhibited scar formation during wound healing. The HA-PG patches with PTD-DBM and/or VPA inhibit the expression of differentiated cell markers such as α-smooth muscle actin (α-SMA) while inducing the expression of stem cell markers such as CD105 and Nestin. Moreover, Collagen III, an important factor for regenerative healing, is critically induced by the HA-PG patches with PTD-DBM and/or VPA, as also seen in VPA-treated Cxxc5-/- mouse fibroblasts. Overall, these findings suggest that the novel regeneration-promoting material can be utilized as a potential therapeutic agent to promote both wound healing and scar attenuation.

In situ diagnosis and simultaneous treatment of cardiac diseases using a single-device platform.

The in situ diagnosis of cardiac activities with simultaneous therapeutic electrical stimulation of the heart is key to preventing cardiac arrhythmia. Here, we present an unconventional single-device platform that enables in situ monitoring even in a wet condition and control of beating heart motions without interferences to the recording signal. This platform consists of the active-matrix array of pressure-sensitive transistors for detecting cardiac beatings, biocompatible, low-impedance electrodes for cardiac stimulations, and an alginate-based hydrogel adhesive for attaching this platform conformally to the epicardium. In contrast to conventional electrophysiological sensing using electrodes, the pressure-sensitive transistors measured mechanophysiological characteristics by monitoring the spatiotemporal distributions of cardiac pressures during heart beating motions. In vivo tests show mechanophysiological readings having good correlation with electrocardiography and negligible interference with the electrical artifacts caused during cardiac stimulations. This platform can therapeutically synchronize the rhythm of abnormal heartbeats through efficient pacing of cardiac arrhythmia.

pH-Universal Catechol-Amine Chemistry for Versatile Hyaluronic Acid Bioadhesives.

Catechol, a major mussel-inspired underwater adhesive moiety, has been used to develop functional adhesive hydrogels for biomedical applications. However, oxidative catechol chemistry for interpolymer crosslinking and adhesion is exclusively effective under alkaline conditions, with limited applications in non-alkaline conditions. To overcome this limitation, pH-universal catechol-amine chemistry to recapitulate naturally occurring biochemical events induced by pH variation in the mussel foot is suggested. Aldehyde moieties are introduced to hyaluronic acid (HA) by partial oxidation, which enables dual-mode catechol tethering to the HA via both stable amide and reactive secondary amine bonds. Because of the presence of additional reactive amine groups, the resultant aldehyde-modified HA conjugated with catechol (AH-CA) is effectively crosslinked in acidic and neutral pH conditions. The AH-CA hydrogel exhibits not only fast gelation via active crosslinking regardless of pH conditions, but also strong adhesion and excellent biocompatibility. The hydrogel enables rapid and robust wound sealing and hemostasis in neutral and alkaline conditions. The hydrogel also mediates effective therapeutic stem cell and drug delivery even in dynamic and harsh environments, such as a motile heart and acidic stomach. Therefore, the AH-CA hydrogel can serve as a versatile biomaterial in a wide range of pH conditions in vivo.

Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids.

Matrigel, a mouse tumor extracellular matrix protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and regenerative medicine due to its tumor-derived origin, batch-to-batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal tissue-derived extracellular matrix hydrogels are suitable substitutes for Matrigel in gastrointestinal organoid culture. We found that the development and function of gastric or intestinal organoids grown in tissue extracellular matrix hydrogels are comparable or often superior to those in Matrigel. In addition, gastrointestinal extracellular matrix hydrogels enabled long-term subculture and transplantation of organoids by providing gastrointestinal tissue-mimetic microenvironments. Tissue-specific and age-related extracellular matrix profiles that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that extracellular matrix hydrogels derived from decellularized gastrointestinal tissues are effective alternatives to the current gold standard, Matrigel, and produce organoids suitable for gastrointestinal disease modeling, drug development, and tissue regeneration.

Molecular epidemiology of rabies virus isolates from South Korea.

A molecular epidemiological study was performed on 13 Korean virus isolates, which were collected from wild and domestic animals diagnosed as rabid between 1998 and 2004. Seven samples were from domestic animals such as dogs and cattle infected by rabid raccoon dogs (Nyctereutes procyonoides koreensis), and the rest of the six samples were from raccoon dogs in the wild. The study was carried out based on the comparison of nucleotide and amino acid sequences of nucleoprotein (N) and glycoprotein (G) coding regions and nucleotide sequence of the G-L intergenic (Psi) non-coding region of the isolates. The similarities of nucleotide and amino acid sequence were at least 97.8 and 98.5%, respectively, between all Korean isolates. Phylogenetic analyses of the isolate showed that they formed a monophyletic group closely related to the Arctic strains but distant from other Asian strains, including Chinese strains. The fact that the raccoon dog is the main epidemic carrier of rabies in Korea and the results of these studies supported the conclusion of previous studies (Kuzmin et al.) that the raccoon dogs take part in the circulation of rabies virus within their natural territories in the Far East. The Korean isolates can be divided into two subgroups. All the topology of the most likelihood tree of Korean isolates using nucleotide and amino acid sequences of N, G and G-L region reflected not the species but the year of isolation and geographical location of the virus isolates. This study presents the detailed description of the molecular epidemiology of rabies virus in Korea.

Molecular epidemiological investigation of foot-and-mouth disease virus in Korea in 2000.

The genetic relatedness of 7 Korean type O field strains of foot-and-mouth disease virus (FMDV) in clinical specimens collected from 5 different geographic locations in 2000 was investigated. The sequence of 162 nucleotides (nt 478-639) at the 3' end of the 1D (VP1) genes was determined from amplified cDNA fragments, and subjected to the analysis for the sequence identity/divergence and phylogenetic relationship. The overall nucleotide sequence divergence among the 7 field strains was 0 to 3.8%, suggesting that they are closely related to each other. Phylogenetic analysis with the known Middle East-South Asia (ME-SA) topotype strains showed that the 7 Korean field strains formed two distinct clusters within the same lineage of the ME-SA topotype strains. Cluster 1 consisted of the strains of the primary foci of infection (Paju and Hongseong), and closely related to the strains prevailed in the Far East. Cluster 2 comprised those of subsequently affected regions (Boryeong, Yongin, and Chungju), and was further diverged from the Cluster 1. The result of phylogenetic analysis indicated that the Korean strains may have evolved from a common ancestor of the Pan Asia strains, and that at least 2 phylogenetically clustered variants within the same lineage were prevalent during the epidemic. The potential origin and sources of the virus introduction to Korea were discussed.

Foot-and-mouth disease eradication efforts in the Republic of Korea.

On March 20, 2000, a suspected vesicular disease in cattle was reported to the National Veterinary Research and Quarantine Service (NVRQS) of the Republic of Korea. This represented the index case of a foot-and-mouth disease (FMD) outbreak, which spread through several provinces. The Republic of Korea had been free of FMD for 66 years prior to the reintroduction of the virus and had recently suspended imports of pork and pork products from neighboring Japan owing to a reported FMD out-break in that country. The Korean outbreak was ultimately controlled through the combination of preemptive slaughter, animal movement restrictions, and a strategy of ring vaccination. The purpose of this paper is to review the current FMD situation in Korea in the aftermath of its 2000 epizootic and how it may affect future efforts to eradicate or reduce risk of reintroduction of the disease into Korea.