Design and Synthesis of π-Extended Resveratrol Analogues and In Vitro Antioxidant and Anti-Inflammatory Activity Evaluation.

The research on resveratrol (1) has been conducted intensively over a long time due to its proven antioxidant activity and disease-fighting capabilities. Many efforts have also been made to increase these biological effects. In the present study, six new extended aromatic resveratrol analogues containing naphthalene (2) and its bioisosteres quinoline (3 and 4), isoquinoline (5) quinoxaline (6) and quinazoline (7) scaffolds were designed and synthesized using an annulation strategy. The antioxidant and anti-inflammatory activities of these compounds were investigated. All compounds showed better antioxidant activity than resveratrol in ABTS assay. As for the anti-inflammatory test, 5 and 7 exhibited better activity than resveratrol. It is worth noting that nitrogen substitution on the extended aromatic resveratrol analogues has a significant impact on cell viability. Taking the antioxidant activities and NO inhibition activities into consideration, we conclude that isoquinoline analogue 5 may qualify for the further investigation of antioxidant and anti-inflammatory therapy. Furthermore, our study results suggest that in order to improve the biological activity of polyphenolic compounds, extended aromaticity and nitrogen substitution strategy could be a viable method for the design of future drug candidates.

Postoperative Long-Term Monitoring of Mechanical Characteristics in Reconstructed Soft Tissues Using Biocompatible, Immune-Tolerant, and Wireless Electronic Sutures.

Accurate postoperative assessment of varying mechanical properties is crucial for customizing patient-specific treatments and optimizing rehabilitation strategies following Achilles tendon (AT) rupture and reconstruction surgery. This study introduces a wireless, chip-less, and immune-tolerant in vivo strain-sensing suture designed to continuously monitor mechanical stiffness variations in the reconstructed AT throughout the healing process. This innovative sensing suture integrates a standard medical suturing thread with a wireless fiber strain-sensing system, which incorporates a fiber strain sensor and a double-layered inductive coil for wireless readout. The winding design of Au nanoparticle-based fiber electrodes and a hollow core contribute to the fiber strain sensor's high sensitivity (factor of 6.2 and 15.1 pF for revised sensitivity), negligible hysteresis, and durability over 10,000 stretching cycles. To ensure biocompatibility and immune tolerance during extended in vivo periods, an antibiofouling lubricant layer was applied to the sensing suture. Using this sensing system, we successfully monitored the strain responses of the reconstructed AT in an in vivo porcine model. This facilitated the postoperative assessment of mechanical stiffness variations through a well-established analytical model during the healing period.

Lubricant skin on diverse biomaterials with complex shapes via polydopamine-mediated surface functionalization for biomedical applications.

Implantable biomedical devices require an anti-biofouling, mechanically robust, low friction surface for a prolonged lifespan and improved performance. However, there exist no methods that could provide uniform and effective coatings for medical devices with complex shapes and materials to prevent immune-related side effects and thrombosis when they encounter biological tissues. Here, we report a lubricant skin (L-skin), a coating method based on the application of thin layers of bio-adhesive and lubricant-swellable perfluoropolymer that impart anti-biofouling, frictionless, robust, and heat-mediated self-healing properties. We demonstrate biocompatible, mechanically robust, and sterilization-safe L-skin in applications of bioprinting, microfluidics, catheter, and long and narrow medical tubing. We envision that diverse applications of L-skin improve device longevity, as well as anti-biofouling attributes in biomedical devices with complex shapes and material compositions.

Resealable Antithrombotic Artificial Vascular Graft Integrated with a Self-Healing Blood Flow Sensor.

Coronary artery bypass grafting is commonly used to treat cardiovascular diseases by replacing blocked blood vessels with autologous or artificial blood vessels. Nevertheless, the availability of autologous vessels in infants and the elderly and low long-term patency rate of grafts hinder extensive application of autologous vessels in clinical practice. The biological and mechanical properties of the resealable antithrombotic artificial vascular graft (RAAVG) fabricated herein, comprising a bioelectronic conduit based on a tough self-healing polymer (T-SHP) and a lubricious inner coating, match with the functions of autologous blood vessels. The self-healing and elastic properties of the T-SHP confer resistance against mechanical stimuli and promote conformal sealing of suturing regions, thereby preventing leakage (stable fixation under a strain of 50%). The inner layer of the RAAVG presents antibiofouling properties against blood cells and proteins, and antithrombotic properties, owing to its lubricious coating. Moreover, the blood-flow sensor fabricated using the T-SHP and carbon nanotubes is seamlessly integrated into the RAAVG via self-healing and allows highly sensitive monitoring of blood flow at low and high flow rates (10- and 100 mL min-1, respectively). Biocompatibility and feasibility of RAAVG as an artificial graft were demonstrated via ex vivo, and in vivo experiment using a rodent model. The use of RAAVGs to replace blocked blood vessels can improve the long-term patency rate of coronary artery bypass grafts.

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.

Intrinsically Nonswellable Multifunctional Hydrogel with Dynamic Nanoconfinement Networks for Robust Tissue-Adaptable Bioelectronics.

Developing bioelectronics that retains their long-term functionalities in the human body during daily activities is a current critical issue. To accomplish this, robust tissue adaptability and biointerfacing of bioelectronics should be achieved. Hydrogels have emerged as promising materials for bioelectronics that can softly adapt to and interface with tissues. However, hydrogels lack toughness, requisite electrical properties, and fabrication methodologies. Additionally, the water-swellable property of hydrogels weakens their mechanical properties. In this work, an intrinsically nonswellable multifunctional hydrogel exhibiting tissue-like moduli ranging from 10 to 100 kPa, toughness (400-873 J m-3 ), stretchability (≈1000% strain), and rapid self-healing ability (within 5 min), is developed. The incorporation of carboxyl- and hydroxyl-functionalized carbon nanotubes (fCNTs) ensures high conductivity of the hydrogel (≈40 S m-1 ), which can be maintained and recovered even after stretching or rupture. After a simple chemical modification, the hydrogel shows tissue-adhesive properties (≈50 kPa) against the target tissues. Moreover, the hydrogel can be 3D printed with a high resolution (≈100 µm) through heat treatment owing to its shear-thinning capacity, endowing it with fabrication versatility. The hydrogel is successfully applied to underwater electromyography (EMG) detection and ex vivo bladder expansion monitoring, demonstrating its potential for practical bioelectronics.

A Lubricated Nonimmunogenic Neural Probe for Acute Insertion Trauma Minimization and Long-Term Signal Recording.

Brain-machine interfaces (BMIs) that link the brain to a machine are promising for the treatment of neurological disorders through the bi-directional translation of neural information over extended periods. However, the longevity of such implanted devices remains limited by the deterioration of their signal sensitivity over time due to acute inflammation from insertion trauma and chronic inflammation caused by the foreign body reaction. To address this challenge, a lubricated surface is fabricated to minimize friction during insertion and avoid immunogenicity during neural signal recording. Reduced friction force leads to 86% less impulse on the brain tissue, and thus immediately increases the number of measured signal electrodes by 102% upon insertion. Furthermore, the signal measurable period increases from 8 to 16 weeks due to the prevention of gliosis. By significantly reducing insertion damage and the foreign body reaction, the lubricated immune-stealthy probe surface (LIPS) can maximize the longevity of implantable BMIs.

A multifunctional electronic suture for continuous strain monitoring and on-demand drug release.

Surgical sutures are widely used for closing wounds in skin. However, the monitoring of wound integrity and promoting tissue regeneration at the same time still remains a challenge. To address this, we developed a drug-releasing electronic suture system (DRESS) to monitor the suture integrity in real-time and enhance tissue regeneration by triggered drug release. DRESS was fabricated by using a single fiber with a core-shell structure consisting of a stretchable conductive fiber core and a thermoresponsive polymer shell containing drugs. The highly conductive fiber core acts as a strain sensor that enables continuous monitoring of suture strain with high sensitivity (a gauge factor of ∼686) and mechanical durability (being able to endure more than 3000 stretching cycles). The thermoresponsive shell layer composed of flexible poly(vinyl alcohol) (PVA) grafted onto poly(N-isopropylacrylamide) (PNIPAm) facilitates on-demand drug release via Joule heating. The results of an in vitro scratch assay showed a 66% decrease in wound area upon heat-activation after 48 hours demonstrating the stimuli-responsive therapeutic efficacy of DRESS by promoting cell migration. Moreover, ex vivo testing on porcine skin demonstrated the applicability of DRESS as a electronic suture. The approach used for DRESS provides insight into multifunctional sutures and offers additional therapeutic and diagnostic options for clinical applications.

Development of an enzymatic encapsulation process for a cycloamylose inclusion complex with resveratrol.

Cyclodextrin glucanotransferase (CGTase; EC 2.4.1.19) produces cycloamyloses (CAs), which are large cyclic glucans, and subsequently transforms them to α-, ß-, and γ-cyclodextrins. We developed a novel encapsulation process based on the cyclization activity of CGTase and applied it to the formation of CA inclusion complexes with resveratrol (RVT), which has limited bioavailability due to its low water solubility. The encapsulated RVT (CA-RVT) was purified using preparative high-performance liquid chromatography. The water solubility of CA-RVT was 6,000-fold higher than that of RVT. CA-RVT in water demonstrated 98% stability for 1 week at 4 °C. According to radical scavenging activity and anti-inflammatory assays, CA-RVT in aqueous solution exhibited similar activities as an equal amount of RVT in dimethyl sulfoxide, suggesting the limited solubility of RVT can be overcome through CA encapsulation by CGTase, thus enhancing its nutraceutical value as a functional ingredient in the food industry.

Lubricant-infused directly engraved nano-microstructures for mechanically durable endoscope lens with anti-biofouling and anti-fogging properties.

While a clear operating field during endoscopy is essential for accurate diagnosis and effective surgery, fogging or biofouling of the lens can cause loss of visibility during these procedures. Conventional cleaning methods such as the use of an irrigation unit, anti-fogging surfactant, or particle-based porous coatings infused with lubricants have been used but proven insufficient to prevent loss of visibility. Herein, a mechanically robust anti-fogging and anti-biofouling endoscope lens was developed by forming a lubricant-infused directly engraved nano-/micro-structured surface (LIDENS) on the lens. This structure was directly engraved onto the lens via line-by-line ablation with a femtosecond laser. This directly engraved nano/microstructure provides LIDENS lenses with superior mechanical robustness compared to lenses with conventional particle-based coatings, enabling the maintenance of clear visibility throughout typical procedures. The LIDENS lens was chemically modified with a fluorinated self-assembled monolayer (F-SAM) followed by infusion of medical-grade perfluorocarbon lubricants. This provides the lens with high transparency (> 70%) along with superior and long-lasting repellency towards various liquids. This excellent liquid repellency was also shown to be maintained during blood dipping, spraying, and droplet condensation experiments. We believe that endoscopic lenses with the LIDENS offer excellent benefits to endoscopic surgery by securing clear visibility for stable operation.

Antibacterial infection and immune-evasive coating for orthopedic implants.

Bacterial infection and infection-induced immune response have been a life-threatening risk for patients having orthopedic implant surgeries. Conventional biomaterials are vulnerable to biocontamination, which causes bacterial invasion in wounded areas, leading to postoperative infection. Therefore, development of anti-infection and immune-evasive coating for orthopedic implants is urgently needed. Here, we developed an advanced surface modification technique for orthopedic implants termed lubricated orthopedic implant surface (LOIS), which was inspired by slippery surface of Nepenthes pitcher plant. LOIS presents a long-lasting, extreme liquid repellency against diverse liquids and biosubstances including cells, proteins, calcium, and bacteria. In addition, we confirmed mechanical durability against scratches and fixation force by simulating inevitable damages during surgical procedure ex vivo. The antibiofouling and anti-infection capability of LOIS were thoroughly investigated using an osteomyelitis femoral fracture model of rabbits. We envision that the LOIS with antibiofouling properties and mechanical durability is a step forward in infection-free orthopedic surgeries.

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression.

nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886's tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886's impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886- cells) have activated AKT and altered expression of cell cycle genes. nc886- cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886- cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.

Recent Advances in High-throughput Platforms with Engineered Biomaterial Microarrays for Screening of Cell and Tissue Behavior.

In the last decades, bioengineers have developed myriad biomaterials for regenerative medicine. Development of screening techniques is essential for understanding complex behavior of cells in the biological microenvironments. Conventional approaches to the screening of cellular behavior in vitro have limitations in terms of accuracy, reusability, labor-intensive screening, and versatility. Thus, drug screening and toxicology test through in vitro screening platforms have been underwhelming. Recent advances in the high-throughput screening platforms somewhat overcome the limitations of in vitro screening platforms via repopulating human tissues' biophysical and biomchemical microenvironments with the ability to continuous monitoring of miniaturized human tissue behavior. Herein, we review current trends in the screening platform in which a high-throughput system composed of engineered microarray devices is developed to investigate cell-biomaterial interaction. Furthermore, diverse methods to achieve continuous monitoring of cell behavior via developments of biosensor integrated high-throughput platforms, and future perspectives on high-throughput screening will be provided.