Remendable Cross-Linked Alginate/Gelatin Hydrogels Incorporating Nanofibers for Wound Repair and Regeneration.

Wound dressings made from natural-derived polymers are highly valued for their biocompatibility, biodegradability, and biofunctionality. However, natural polymer-based hydrogels can come with their own set of limitations, such as low mechanical strength, limited cell affinity, and the potential cytotoxicity of cross-linkers, which delineate the boundaries of their usage and hamper their practical application. To overcome the limitation of natural-derived polymers, this study utilized a mixture of oxidized alginate and gelatin with 5 mg/mL polycaprolactone (PCL):gelatin nanofiber fragments at a ratio of 7:3 (OGN-7) to develop a hydrogel composite wound dressing that can be injected and has the ability to be remended. The in situ formation of the remendable hydrogel is facilitated by dual cross-linking of oxidized alginate chains with gelatin and PCL/gelatin nanofibers through Schiff-base mechanisms, supported by the physical integration of nanofibers, thereby obviating the need for additional cross-linking agents. Furthermore, OGN-7 exhibits increased stiffness (γ = 79.4-316.3%), reduced gelation time (543 ± 5 to 475 ± 5 s), improved remendability of the hydrogel, and excellent biocompatibility. Notably, OGN-7 achieves full fusion within 1 h of incubation and maintains structural integrity under external stress, effectively overcoming the inherent mechanical weaknesses of natural polymer-based dressings and enhancing biofunctionality. The therapeutic efficacy of OGN-7 was validated through a full-thickness in vivo wound healing analysis, which demonstrated that OGN-7 significantly accelerates wound closure compared to alginate-based dressings and control groups. Histological analysis further revealed that re-epithelialization and collagen deposition were markedly enhanced in the regenerating skin of the OGN-7 group, confirming the superior therapeutic performance of OGN-7. In summary, OGN-7 optimized the synergistic effects of natural polymers, which enhances their collective functionality as a wound dressing and expands their utility across diverse biomedical applications.

3D in vitro synovial hyperplasia model on polycaprolactone-micropatterned nanofibrous microwells for screening disease-modifying anti-rheumatic drugs.

Rheumatoid arthritis (RA) is known to be caused by autoimmune disorders and can be partially alleviated through Disease-Modifying Antirheumatic Drugs (DMARDs) therapy. However, due to significant variations in the physical environment and condition of each RA patient, the types and doses of DMARDs prescribed can differ greatly. Consequently, there is a need for a platform based on patient-derived cells to determine the effectiveness of specific DMARDs for individual patient. In this study, we established an RA three-dimensional (3D) spheroid that mimics the human body's 3D environment, enabling high-throughput assays by culturing patient-derived synovial cells on a macroscale-patterned polycaprolactone (PCL) scaffold. Fibroblast-like synoviocytes (FLSs) from patient and human umbilical vein endothelial cells (HUVECs) were co-cultured to simulate vascular delivery. Additionally, RA characteristics were identified at both the genetic and cytokine levels using real-time polymerase chain reaction (RT-qPCR) and dot blot assay. The similarities in junctions and adhesion were demonstrated in both actual RA patient tissues and 3D spheroids. The 3D RA spheroid was treated with representative DMARDs, observing changes in reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH) levels, and inflammatory cytokine responses to confirm the varying cell reactions depending on the DMARDs used. This study underscores the significance of the 3D drug screening platform, which can be applied to diverse inflammatory disease treatments as a personalized drug screening system. We anticipate that this platform will become an indispensable tool for advancing and developing personalized DMARD treatment strategies.

A micro-fragmented collagen gel as a cell-assembling platform for critical limb ischemia repair.

Critical limb ischemia (CLI) is a devastating disease characterized by the progressive blockage of blood vessels. Although the paracrine effect of growth factors in stem cell therapy made it a promising angiogenic therapy for CLI, poor cell survival in the harsh ischemic microenvironment limited its efficacy. Thus, an imperative need exists for a stem-cell delivery method that enhances cell survival. Here, a collagen microgel (CMG) cell-delivery scaffold (40 × 20 µm) was fabricated via micro-fragmentation from collagen-hyaluronic acid polyionic complex to improve transplantation efficiency. Culturing human adipose-derived stem cells (hASCs) with CMG enabled integrin receptors to interact with CMG to form injectable 3-dimensional constructs (CMG-hASCs) with a microporous microarchitecture and enhanced mass transfer. CMG-hASCs exhibited higher cell survival (p < 0.0001) and angiogenic potential in tube formation and aortic ring angiogenesis assays than cell aggregates. Injection of CMG-hASCs intramuscularly into CLI mice increased blood perfusion and limb salvage ratios by 40 % and 60 %, respectively, compared to cell aggregate-treated mice. Further immunofluorescent analysis revealed that transplanted CMG-hASCs have greater muscle regenerative and angiogenic potential, with enhanced cell survival than cell aggregates (p < 0.05). Collectively, we propose CMG as a cell-assembling platform and CMG-hASCs as promising therapeutics to treat CLI.

Hydrogel/Nanofiber Composite Wound Dressing Optimized for Skin Layer Regeneration through the Mechanotransduction-Based Microcellular Environment.

Wound dressings have been designed to provide the optimal environment to fibroblasts, keratinocytes, and macrophages to promote wound healing while inhibiting potential microbial infection. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel with a gelatin backbone that contains natural cell binding motifs such as arginine-glycine-aspartic acid (RGD) and MMP-sensitive degradation sites, making it an ideal material for wound dressing. However, GelMA alone is unable to stably protect the wound and regulate cellular activities due to its weak mechanical properties and nonmicropatterned surface, limiting its application as a wound dressing. Herein, we report the development of a hydrogel-nanofiber composite wound dressing utilizing GelMA and poly(caprolactone) (PCL)/gelatin nanofiber, which can systematically manage the skin regeneration process with an enhanced mechanical property and micropatterned surface. GelMA sandwiched between electrospun aligned and interlaced nanofibers that mimic epidermis and dermis layers, respectively, increased the stiffness of the resulting hydrogel composite with a comparable swelling rate as GelMA. Fabricated hydrogel composite was determined to be biocompatible and nontoxic. In addition to the beneficial effect of GelMA in accelerating wound healing, subsequent histological analysis revealed upregulated re-epithelialization of granulation tissue and deposition of mature collagen. Hydrogel composite interacted with fibroblasts to regulate their morphology, proliferation, and collagen synthesis, as well as the expression of α-SMA, TGF-ß, and collagen I and III during the wound healing process both in vitro and in vivo. Taken together, we propose hydrogel/nanofiber composite as a wound dressing of the next generation that can induce skin tissue layer regeneration beyond the basic wound closure promotion of present dressings.

Multibranched Au-Ag-Pt Nanoparticle as a Nanozyme for the Colorimetric Assay of Hydrogen Peroxide and Glucose.

Many studies have recently produced artificial enzymes with metal nanoparticles (NPs) to overcome the limitations of natural enzymes, such as low stability, high cost, and storage problems. In particular, gold NPs exhibit peroxidase-like activity and are strongly influenced by external parameters, such as pH, temperature, size, shape, and functional layer, which change the enzyme activity. Here, chitosan-capped multibranched Au-Ag-Pt NPs (CCNPs) that mimic peroxidase were synthesized using various peroxidase-mimicking strategies. The results demonstrated that enzyme activity sequentially increased because of the multibranched Au-Ag NPs coated with Pt and chitosan. The enzyme activity of the particle was evaluated through the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), which causes a color change into blue. This change was observable with the naked eye and could be used practically. The color change depended on the concentration of hydrogen peroxide (H2O2), and it was shown that the CCNPs could be applied to measure H2O2 with a limit of detection (LOD) of 0.054 mM. Furthermore, with glucose oxidase, the CCNPs can be used for glucose detection with an LOD of 0.289 mM. Also, the potential of the CCNP application in human serum was shown through the serum test. Thus, this study suggested the utilization of the multibranched Au-Ag-Pt NPs that mimic the peroxidase activity of natural enzymes and the possibility of application in various biological analyses.

Structures and strategies for enhanced sensitivity of polydiacetylene(PDA) based biosensor platforms.

Polydiacetylene (PDA) is a versatile polymer that has been studied in numerous fields because of its unique optical properties derived from alternating multiple bonds in the polymer backbone. The conjugated structure in the polymer backbone enables PDA to possess the ability of blue-red colorimetric transition when π-π interactions in the PDA backbone chain are disturbed by the external environment. The chromatic property of PDA disturbed by external stimuli can also emit fluorescence in the red region. Owing to the unique characteristics of PDA, it has been widely studied in facile and label-free sensing applications based on colorimetric or fluorescence signals for several decades. Among the various PDA structures, membrane structures assembled by amphiphilic molecules are widely used as a versatile platform because facile modification of the synthetic membrane provides extensive applications, such as receptor-ligand interactions, resulting in potent biosensors. To use PDA as a sensory material, several methods have been studied to endow the specificity to PDA molecules and to amplify the signal from PDA supramolecules. This is because selective and sensitive detection of target materials is required at an appropriate level corresponding to each material for applicable sensor applications. This review focuses on factors that affect the sensitivity of PDA composites and several strategies to enhance the sensitivity of the PDA sensor to various structures. Owing to these strategies, the PDA sensor system has achieved a higher level of sensitivity and selectivity, enabling it to detect multiple target materials for a full field of application.

Kaleidoscopic fluorescent arrays for machine-learning-based point-of-care chemical sensing.

Multiplexed analysis allows simultaneous measurements of multiple targets, improving the detection sensitivity and accuracy. However, highly multiplexed analysis has been challenging for point-of-care (POC) sensing, which requires a simple, portable, robust, and affordable detection system. In this work, we developed paper-based POC sensing arrays consisting of kaleidoscopic fluorescent compounds. Using an indolizine structure as a fluorescent core skeleton, named Kaleidolizine (KIz), a library of 75 different fluorescent KIz derivatives were designed and synthesized. These KIz derivatives are simultaneously excited by a single ultraviolet (UV) light source and emit diverse fluorescence colors and intensities. For multiplexed POC sensing system, fluorescent compounds array on cellulose paper was prepared and the pattern of fluorescence changes of KIz on array were specific to target chemicals adsorbed on that paper. Furthermore, we developed a machine-learning algorithm for automated, rapid analysis of color and intensity changes of individual sensing arrays. We showed that the paper sensor arrays could differentiate 35 different volatile organic compounds using a smartphone-based handheld detection system. Powered by the custom-developed machine-learning algorithm, we achieved the detection accuracy of 97% in the VOC detection. The highly multiplexed paper sensor could have favorable applications for monitoring a broad-range of environmental toxins, heavy metals, explosives, pathogens.

Correlation between Drop Impact Energy and Residual Compressive Strength According to the Lamination of CFRP with EVA Sheets.

Carbon-fiber-reinforced plastic is an important building material; however, its application is limited because of its brittleness, leading to vulnerability under shock. Thus, the strength performance of carbon-fiber-reinforced plastics needs to be improved. Here, the drop impact test was conducted to analyze the impact energy and fracture characteristics of carbon-fiber-reinforced plastics and ethylene vinyl acetate sheets. The compression after impact test was performed to assess the residual compressive strength. The thermal energy generated was measured as change in temperature at the time of fracture to investigate the relationship between thermal and mechanical properties. The impact absorption efficiency of 100% was achieved when the carbon-fiber-reinforced plastics specimen was laminated with four or more sheets of ethylene vinyl acetate. The thermal energy generated during impact, the impact load, and the compression after impact test strength was reduced with the increasing number of laminated ethylene vinyl acetate layers. Our results showed that, by carefully selecting the optimal conditions of fabricating the carbon-fiber-reinforced plastic/ethylene vinyl acetate composites, carbon composite materials can be used for impact mitigation.

The effect of cognitive training in patients with mild cognitive impairment and early Alzheimer's disease: a preliminary study.

BACKGROUND AND PURPOSE: The objective of this study was to determine the benefits of cognitive training in patients with amnestic mild cognitive impairment (aMCI) and those with early Alzheimer's disease (AD). METHODS: Eleven patients with aMCI and nine with early AD (stage 4 on the Global Deterioration Scale) participated in this study. Six participants with aMCI and six with AD were allocated to the cognitive training group, while five participants with aMCI and three with AD were allocated to a wait-list control group. Multicomponent cognitive training was administered in 18 weekly, individual sessions. Outcome measures were undertaken at baseline, and at 2 weeks and 3 months of follow-up. RESULTS: In the trained MCI group, there were significant improvements in the delayed-recall scores on the Seoul Verbal Learning Test at both the 2-week and 3-month follow-ups compared with baseline (baseline, 1.6±1.5; 2 weeks, 4.4±1.5, p=0.04; 3 months, 4.6±2.3, p=0.04). The phonemic fluency scores (1.0±0.8 vs. 5.0±1.8, p=0.07) and Korean Mini-Mental State Examination scores (18.8±0.5 vs. 23.8±2.2, p=0.07) also showed a tendency toward improvement at the 2-week follow-up compared to baseline in the trained AD group. CONCLUSIONS: This study provides evidence of the effectiveness of cognitive training in aMCI and early AD. The efficacy of cognitive training programs remains to be verified in studies with larger samples and a randomized design.

Use of mean spot urine sodium concentrations to estimate daily sodium intake in patients with chronic kidney disease.

OBJECTIVE: Sodium intake is an important issue for patients with chronic kidney disease (CKD). The two most widely used methods to measure sodium are 24-h urinary sodium excretion (24HUNa), which can be difficult to perform routinely, and sodium intake by dietary recall, which can be inaccurate. This study evaluated use of the mean value of three spot urinary sodium (UNa) concentrations to estimate daily sodium intake in patients with CKD. METHODS: This cross-sectional study enrolled 305 patients with CKD, none of whom were on dialysis, who visited the nephrology clinic at the Asan Medical Center (Seoul, Korea). We performed three spot UNa tests, three calculations of the UNa/creatinine (UCr) ratio, one measurement of 24HUNa, and one measurement of sodium intake by dietary recall. RESULTS: The 24HUNa and mean spot UNa values were significantly lower in patients with more advanced CKD (P = 0.006 and P < 0.001, respectively). One-time spot UNa was significantly higher in the evening than in the morning for patients with stage III, IV, or V CKD. Total sodium intake, but not sodium nutrient density (milligrams of sodium per 1000 kcal), was significantly different for patients with different stages of CKD (P = 0.001). The correlation coefficient between 24HUNa and mean spot UNa was 0.477 (95% confidence interval [CI] 0.384-0.562, P < 0.001), slightly higher than that between 24HUNa excretion and mean spot UNa/UCr (r = 0.313, 95% CI 0.207-0.465, P < 0.001). There was a linear relation between spot UNa and 24HUNa: mean spot UNa = 0.27 × 24HUNa + 60. Therefore, a 24HUNa excretion of 87 mEq (sodium intake 2 g/d) corresponded to a mean spot UNa level of 83 mEq/L. The correlation coefficient between sodium intake and mean spot UNa was 0.435 (95% CI 0.336-0.524, P < 0.001), significantly higher than that between sodium intake and mean spot UNa/UCr (r = 0.197, 95% CI 0.091-0.301, P = 0.001). Mean spot UNa tended to be better correlated with 24HUNa than with sodium intake. CONCLUSION: Mean spot UNa is a simple and effective method that can be used to monitor sodium intake in patients with CKD. A daily intake of 2 g of sodium corresponds to a mean spot UNa level of approximately 83 mEq/L in patients with CKD.

Syndrome of inappropriate antidiuretic hormone secretion associated with pramipexole in a patient with Parkinson's disease.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by a variety of drugs. Dopaminergic drugs might enhance the secretion of the antidiuretic hormone arginine vasopressin by reducing γ-amino butyric acid release through the dopaminergic receptor in supraoptic nucleus. A 75-year-old woman with Parkinson's disease developed asthenia, delirium, aggravated parkinsonian symptoms, and hypotonic hyponatremia along with the diagnostic criteria for SIADH during dose escalation of pramipexole. After pramipexole withdrawal, these symptoms disappeared, and sodium levels returned to normal values. The serum sodium levels of patients receiving pramipexole should be monitored, especially during dose escalation.

Syndrome of inappropriate antidiuretic hormone secretion associated with pramipexole in a patient with Parkinson's disease.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by a variety of drugs. Dopaminergic drugs might enhance the secretion of the antidiuretic hormone arginine vasopressin by reducing γ-amino butyric acid release through the dopaminergic receptor in supraoptic nucleus. A 75-year-old woman with Parkinson's disease developed asthenia, delirium, aggravated parkinsonian symptoms, and hypotonic hyponatremia along with the diagnostic criteria for SIADH during dose escalation of pramipexole. After pramipexole withdrawal, these symptoms disappeared, and sodium levels returned to normal values. The serum sodium levels of patients receiving pramipexole should be monitored, especially during dose escalation.

Persistent elevation of C-reactive protein and ischemic heart disease in patients with continuous ambulatory peritoneal dialysis.

We evaluated the association between a persistent elevation of C-reactive protein (CRP) level and the presence or severity of ischemic heart disease (IHD) in patients with continuous ambulatory peritoneal dialysis (CAPD). Seventy-three patients, who were over 40 years old, underwent dipyridamole thallium single photon emission computed tomography (SPECT), and followed-up for more than 1 year were enrolled. We measured stored plasma for CRP every 3 months. Elevation of CRP was defined as greater than or equal to 5 mg/L and persistent elevation of CRP as elevated CRP levels that lasted longer than 6 months. Serum albumin, cholesterol, lipoprotein(a), and plasma fibrinogen were measured at 3 months after the start of CAPD. Twenty-six patients showed an elevation of CRP for more than 6 months during the follow-up period. Twenty-eight patients showed positive findings on thallium SPECT. Coronary angiography showed significant stenosis (narrowing of the diameter more than 50%) in 23 of the 25 patients studied. Seventeen (65%) of 26 patients who had an elevated CRP level for longer than 6 months had positive thallium SPECT. The presence of diabetes, albumin, fibrinogen, and the presence of a persistent elevation of CRP were different between the patients with positive (n = 28) or negative thallium SPECT (n = 45). A multivariate logistic regression analysis showed that a persistent elevation of CRP is the only predictor of positive thallium SPECT (P = 0.002). There was a tendency of association, although it was not statistically significant, between the persistence of CRP elevation and the severity of IHD (P = 0.066). Three of 9 patients who had a persistent elevation of CRP and a negative thallium SPECT had a history of cerebral infarction or peripheral vascular disease. Therefore, 77% (20/26) of an elevated CRP level that lasted longer than 6 months can be explained by the presence of IHD or other atherosclerotic vascular disease. In conclusion, a persistent elevation of CRP level in patients with CAPD was strongly associated with IHD. For patients who have a persistent elevation of CRP without an apparent cause, we recommend a workup for IHD or other atherosclerotic cardiovascular disease.