Surgical modeling of Chiari-like malformation in rats: Insights from canine morphology.

BACKGROUND: Chiari-like malformation in dogs and Chiari malformation type 1 in humans are conditions characterized by a relatively small caudal cranial fossa, leading to cerebellar herniation. This study aimed to develop a rat model of Chiari-like malformation using surgical techniques based on morphological characteristics observed in dogs. METHODS: Endocranial magnetic resonance images of both normal dogs and dogs diagnosed with Chiari-like malformation were retrospectively analyzed. Measurements of the caudal cranial fossa volume, rostral and medial fossa volume, and volume index were taken. The differences in caudal cranial fossa volume and volume index between normal dogs and those diagnosed with Chiari-like malformation were then utilized to create a rat model of Chiari-like malformation through surgical intervention. The measurements were conducted on both the rat Chiari-like malformation models and normal rats, with each measurement taken twice and the mean values calculated. RESULTS: Significant differences were found between normal dogs and dogs diagnosed with Chiari-like malformation in terms of the volume of the caudal cranial fossa (27.62% reduction) and the volume index (23.36% reduction) (p<0.05). These differences were used to develop a rat model, which also showed significant reductions in both caudal cranial fossa volume (29.52%) and volume index (28.30%) compared to normal rats (p<0.05). The condition in the rat model was confirmed through magnetic resonance imaging, which revealed cerebellar herniation into the foramen magnum. CONCLUSIONS: The study successfully established a rat model of Chiari-like malformation that accurately reproduces the morphological features observed in dogs. This model potentially serves as a valuable tool for investigating the pathological mechanisms and potential therapeutic approaches for Chiari-like malformation in veterinary medicine.

Comprehensive comparative study of Chiari-like malformation in veterinary and human medicine.

This review aims to enrich our understanding of Chiari-like malformation (CLM) by combining human and veterinary insights, and providing a detailed cross-species overview. CLM is a developmental abnormality characterised by caudal displacement of the hindbrain into the foramen magnum due to an entire brain parenchymal shift caused by insufficient skull volume. This malformation leads to a progressive obstruction at the craniocervical junction, which disrupts the normal cerebrospinal fluid flow, leading to secondary syringomyelia. The clinical signs of CLM and syringomyelia include phantom scratching, head tilt, head tremor, ataxia, tetraparesis, pain, muscle atrophy, and scoliosis or torticollis. Magnetic resonance imaging remains the gold standard for diagnosing CLM, since it allows the visualisation of abnormal findings such as the caudal cerebellar herniation, caudal cerebellar compression from occipital dysplasia, and attenuated cerebrospinal fluid cisternae. Although various medical and surgical interventions, including foramen magnum decompression, can provide temporary symptomatic/clinical sign relief, current literature shows a lack of sustained long-term efficacy. Therefore, additional research is needed to evaluate the long-term effects of existing treatment strategies and to compare different techniques utilised in conjunction with foramen magnum decompression.

Sliding Microneedle - Lateral flow immunoassay strip device for highly sensitive biomarker detection in interstitial fluid.

Diabetes is a chronic disease with significant complications, necessitating regular treatment and checkups, which can be costly and time-consuming for patients. To address this, we developed the Sliding Microneedle (MN)-Lateral flow immunoassay strip (LFIAs) device that combines the advantages of MNs and LFIAs to detect IL-6, an independent biomarker for diabetes complications. This device offers rapid and highly sensitive detection of IL-6 by extracting interstitial fluid (ISF) through MNs and transferring it to LFIAs. The stainless MN, embedded in the 3D-printed Sliding MN-LFIAs device, was inserted into the skin at a 20° angle, minimizing blood contamination risk. With a filter paper attached to the MN surface, the device collected 4.65 ± 0.05 µL of ISF containing IL-6 within 90 s. The ISF was then transferred to the LFIAs using a running buffer. After a 15-min reaction, silver enhancement (SE) treatment was applied, allowing for the highly sensitive and specific detection of IL-6 at 102 pg/mL concentrations. The Sliding MN-LFIAs device successfully distinguished between normal and diabetic rat models, demonstrating its potential as an effective tool for detecting diabetes complications quickly and affordably.

Highly efficient microbial inactivation enabled by tunneling charges injected through two-dimensional electronics.

Airborne pathogens retain prolonged infectious activity once attached to the indoor environment, posing a pervasive threat to public health. Conventional air filters suffer from ineffective inactivation of the physics-separated microorganisms, and the chemical-based antimicrobial materials face challenges of poor stability/efficiency and inefficient viral inactivation. We, therefore, developed a rapid, reliable antimicrobial method against the attached indoor bacteria/viruses using a large-scale tunneling charge-motivated disinfection device fabricated by directly dispersing monolayer graphene on insulators. Free charges can be stably immobilized under the monolayer graphene through the tunneling effect. The stored charges can motivate continuous electron loss of attached microorganisms for accelerated disinfection, overcoming the diffusion limitation of chemical disinfectants. Complete (>99.99%) and broad-spectrum disinfection was achieved <1 min of attachment to the scaled-up device (25 square centimeters), reliably for 72 hours at high temperature (60°C) and humidity (90%). This method can be readily applied to high-touch surfaces in indoor environments for pathogen control.

Reconstructive surgery with an autologous bone graft in a dog with presumptive chronic non-bacterial osteomyelitis.

A 15-year-old Cocker Spaniel was referred to for the evaluation of left forelimb lameness. Radiographic and computed tomography examinations revealed osteolysis of the proximal left third, fourth and fifth metacarpal bones and pathological fractures of the proximal left fourth metacarpal bone. Histopathological examination via bone biopsy did not provide a definitive diagnosis, and the owner elected limb-sparing surgery. The fourth metacarpal bone and digits were amputated. Subsequently, autologous bone grafts were performed on the lytic area of the third and fifth metacarpal bones. The dog showed improvement in gait 7 weeks after reconstructive surgery. Chronic non-bacterial osteomyelitis (CNO) was diagnosed by exclusion. To the best of our knowledge, CNO has not been previously reported in dogs.

A Novel Passive Shoulder Exoskeleton Using Link Chains and Magnetic Spring Joints.

Work-related musculoskeletal disorders represent a major occupational disability issue, and 53.4% of these disorders occur in the back or shoulders. Various types of passive shoulder exoskeletons have been introduced to support the weight of the upper arm and work tools during overhead work, thereby preventing injuries and improving the work environment. The general passive shoulder exoskeleton is constructed with rigid links and joints to implement shoulder rotation, but there exists a challenge to align with the flexible joint movements of the human shoulder. Also, a force-generating part using mechanical springs require additional mechanical components to generate torque similar to the shoulder joint, resulting in increased overall volume and inertia to the upper arm. In this study, we propose a new type of passive shoulder exoskeleton that uses magnetic spring joint and link chain. The redundant degrees of freedom in the link chains enables to follow the shoulder joint movement in the horizontal direction, and the magnetic spring joint generates torque without additional parts in a compact form. Conventional exoskeletons experience a loss in the assisting torque when the center of shoulder rotation changed during arm elevation. Our exoskeleton minimizes the torque loss by customizing the installation height and initial angle of the magnetic spring joint. The performances of the proposed exoskeleton were verified by an electromyographic evaluation of shoulder-related muscles in overhead work and box lifting task.

Boosting the Output Performance of the MoS2 Monolayer-Based Piezoelectric Nanogenerator by Artificial Dual Strain Concentration.

Piezoelectric nanogenerators (PENGs) with molybdenum disulfide (MoS2) monolayers have been intensively studied owing to their superior mechanical durability and stability. However, the limited output performance resulting from a small active area and low strain levels continues to pose a significant challenge that should be overcome. Herein, we report a novel strategy for the epoch-making output performance of a PENG with a MoS2 monolayer by adopting the additive strain concentration concept. The simulation study indicates that strain in the MoS2 monolayer can be initially augmented by the wavy structure resulting from the prestretched poly(dimethylsiloxane) (PDMS) and is further increased through flexural deformation (i.e., bending). Based on these studies, we have developed concentrated strain-applied PENGs with MoS2 monolayers. The wavy structures effectively applied strain to the MoS2 monolayer and generated a piezoelectric output voltage and current of around 580 mV and 47.5 nA, respectively. Our innovative approach to enhancing the performance of PENGs with MoS2 monolayers through the artificial dual strain concept has led to groundbreaking results, achieving the highest recorded output voltage and current for PENGs based on two-dimensional (2D) materials, which provides unique opportunities for the 2D-based energy harvesting field and structural insight into how to improve the net strain on 2D materials.

Paper-Based Radial Flow Assay Integrated to Portable Isothermal Amplification Chip Platform for Colorimetric Detection of Target DNA.

A novel integrated detection system that introduces a paper-chip-based molecular detection strategy into a polydimethylsiloxane (PDMS) microchip and temperature control system was developed for on-site colorimetric detection of DNA. For the paper chip-based detection strategy, a padlock probe DNA (PLP)-mediated rolling circle amplification (RCA) reaction for signal amplification and a radial flow assay according to the Au-probe labeling strategy for visualization were optimized and applied for DNA detection. In the PDMS chip, the reactions for ligation of target-dependent PLP, RCA, and labeling were performed one-step under isothermal temperature in a single chamber, and one drop of the final reaction solution was loaded onto the paper chip to form a radial colorimetric signal. To create an optimal analysis environment, not only the optimization of molecular reactions for DNA detection but also the chamber shape of the PDMS chip and temperature control system were successfully verified. Our results indicate that a detection limit of 14.7 nM of DNA was achieved, and non-specific DNAs with a single-base mismatch at the target DNA were selectively discriminated. This integrated detection system can be applied not only for single nucleotide polymorphism identification, but also for pathogen gene detection. The adoption of inexpensive paper and PDMS chips allows the fabrication of cost-effective detection systems. Moreover, it is very suitable for operation in various resource-limited locations by adopting a highly portable and user-friendly detection method that minimizes the use of large and expensive equipment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13206-023-00101-7.

Tolerability, acceptability, and reproducibility of topical STAR particles in human subjects.

Topical delivery to treat dermatological disease is constrained by low skin permeability to most drugs due to the stratum corneum barrier. STAR particles containing microneedle protrusions can be topically applied on the skin to create micropores that dramatically increase skin permeability, even to water-soluble compounds and macromolecules. This study addresses the tolerability, acceptability, and reproducibility of STAR particles rubbed on the skin at multiple pressures and after multiple applications to human subjects. One-time STAR particle application at pressures between 40 and 80 kPa showed that skin microporation and erythema directly correlated with increased pressure, and 83% of subjects reported STAR particles to be comfortable at all pressures. Repeated application of STAR particles for 10 consecutive days at 80 kPa showed that skin microporation (~0.5% of skin area), erythema (low-to-moderate), and comfort with self-administration (75%) were similar over the course of the study. Comfort of sensations associated with STAR particles increased from 58% to 71% during the study, and familiarity with STAR particles increased from 12.5% to 50% of subjects reporting STAR particle application not feeling different from other skin products. This study demonstrates that topically applied STAR particles were well tolerated and highly acceptable after application at various pressures and repeated daily use. These findings further suggest that STAR particles offer a safe and reliable platform to enhance cutaneous drug delivery.

Six-month sustained delivery of anti-VEGF from in-situ forming hydrogel in the suprachoroidal space.

Patients with wet age-related macular degeneration (AMD) require intravitreal injections of bevacizumab (Bev) or other drugs, often on a monthly basis, which is a burden on the healthcare system. Here, we developed an in-situ forming hydrogel comprised of Bev and hyaluronic acid (HA) crosslinked with poly(ethylene glycol) diacrylate for slow release of Bev after injection into the suprachoroidal space (SCS) of the eye using a microneedle. Liquid Bev formulations were cleared from SCS within 5 days, even when formulated with high viscosity, unless Bev was conjugated to a high molecular-weight HA (2.6 MDa), which delayed clearance until 1 month. To extend release to 6 months, we synthesized in-situ forming Bev-HA hydrogel initially as a low-viscosity mixture suitable for injection and flow in the SCS to cover a large area extending to the posterior pole of the eye where the macula is located in humans. Within 1 h after injection, Bev and HA were crosslinked, which retained Bev for slow release as the hydrogel biodegraded. In vivo studies in the rabbit eye reported Bev release for >6 months, depending on gel formulation and Bev assay. The in-situ forming Bev-HA hydrogel was well tolerated, as assessed by clinical exam, fundus imaging, histological analysis, and intraocular pressure measurement. We conclude that Bev released from an in-situ forming hydrogel may enable long-acting treatments of AMD and other posterior ocular indications.

Sustainable Drug Release Using Nanoparticle Encapsulated Microneedles.

Microneedle (MN) is a minimally invasive drug delivery method that is directly inserted into the skin without pain to improve the efficiency of transdermal administration and is a drug delivery system used to treat various diseases. Furthermore, nanoparticle (NP)-based drug delivery methods suggest therapeutic strategies to improve drug solubility and increase drug delivery efficiency. Therefore, the drug delivery system in which NPs and MNs are integrated is a promising alternative to the existing delivery methods of poorly soluble and hydrophobic drugs and nucleic acid therapeutics. This system can increase the solubility of drugs and biocompatibility in the body and improve the therapeutic efficacy with sustained drug release. In this review, we investigated recent studies of NPs designed for drug delivery, sustained-release drug delivery MNs based on these NPs, and the applications for clinical treatments.

Biosynthesis and applications of iron oxide nanocomposites synthesized by recombinant Escherichia coli.

Recombinant Escherichia coli (E. coli) strain that produces phytochelatin (PC) and/or metallothionein (MT) can synthesize various metal nanoparticles (NPs) by reducing metal ions. Here we report in vivo biosynthesis of iron oxide nanocomposites (NCs) using recombinant E. coli. We designed a strategy of biosynthesizing iron oxide NCs by first internalizing chemically synthesized iron oxide NPs, followed by the reduction of added metal ions on the surface of internalized NPs by PC and/or MT in E. coli. For this, chemically synthesized Fe3O4 NPs were internalized by recombinant E. coli, and then, Au and Ag ions were added for the biosynthesis of AuFe3O4 and AgFe3O4 NCs, respectively. The NCs synthesized were analyzed by transmission electron microscopy, UV-vis spectrophotometry, and X-ray diffractometry to characterize their shape, optical property, and crystallinity. The Fe3O4 NPs in the biosynthesized NCs allowed easy purification of the biosynthesized NCs by applying a magnetic field. The AuFe3O4 NCs were used for enzyme-linked immunosorbent assay to detect prostate-specific antigen protein, while AgFe3O4 NCs were utilized for the antimicrobial application with low minimum inhibitory concentration. As recombinant E. coli can uptake and reduce various NPs and metal ions, biosynthesis of a wide range of NCs as new nanomaterials will be possible for diverse applications. KEY POINTS: • AuFe3O4 and AgFe3O4 nanocomposites were synthesized by recombinant E. coli. • Escherichia coli synthesized different iron oxide NCs depending on the metal ions to be added. • Biosynthesized AuFe3O4 NC was used for ELISA and AgFe3O4 NC for antimicrobial tests.

Evaluation of a Direct Reverse Transcription Loop-Mediated Isothermal Amplification Method without RNA Extraction (Direct RT-LAMP) for the Detection of Lymph Node Metastasis in Early Breast Cancer.

PURPOSE: Assessing lymph node metastasis, tumor-derived DNA, or tumor-derived RNA has previously been studied in place of immunohistochemical assay. Because a direct reverse transcription loop-mediated isothermal amplification method (direct RT-LAMP) has been previously developed in order to rapidly identify viruses in place of RNA extraction, our team hypothesized that a direct RT-LAMP assay can be employed as a substitute in order to detect tumor involvement of lymph nodes within breast cancer patients. MATERIALS AND METHODS: A total amount of 92 lymph nodes removed across 40 patients possessing breast cancer were collected at Kyungpook National University Chilgok Hospital between the months of November 2015 and February 2016. All samples were then evaluated and contrasted via both a direct RT-LAMP assay and routine histopathologic examination. RESULTS: The sensitivity and specificity of the direct RT-LAMP assay were 85.7% and 100%, respectively. The positive predictive value and negative predictive value were 100% and 94.4%, respectively. CONCLUSION: Direct RT-LAMP assay is capable of facilitating the detection of sentinel lymph node metastasis within breast cancer patients intraoperatively possessing an excellent sensitivity via a cost-effective and time-saving manner.

Precise Layer Control and Electronic State Modulation of a Transition Metal Dichalcogenide via Phase-Transition-Induced Growth.

Wafer-scale growth of transition metal dichalcogenides with precise control over the number of layers, and hence the electronic state is an essential technology for expanding the practical application of 2D materials. Herein, a new growth method, phase-transition-induced growth (PTG), is proposed for the precisely controlled growth of molybdenum disulfide (MoS2 ) films consisting of one to eleven layers with spatial uniformity on a 2 in. wafer. In this method, an energetically unstable amorphous MoSx Oy (a-MoSx Oy ) phase is effectively converted to a thermodynamically stable crystalline MoS2 film. The number of MoS2 layers is readily controlled layer-by-layer by controlling the amount of Mo atoms in a-MoSx Oy , which is also applicable for the growth of heteroatom-inserted MoS2 . The electronic states of intrinsic and Nb-inserted MoS2 with one and four layers grown by PTGare are analyzed based on their work functions. The work function of monolayer MoS2 effectively increases with the substitution of Nb for Mo. As the number of layers increases to four, charge screening becomes weaker, dopant ionization becomes easier, and ultimately the work function increases further. Thus, better electronic state modulation is achieved in a thicker layer, and in this respect, PTG has the advantage of enabling precise control over the film thickness.

Enhanced extraction of skin interstitial fluid using a 3D printed device enabling tilted microneedle penetration.

Interstitial fluid (ISF) is a body fluid that fills, surrounds cells and contains various biomarkers, but it has been challenging to extract ISF in a reliable and sufficient amount with high speed. To address the issues, we developed the tilted microneedle ISF collecting system (TMICS) fabricated by 3D printing. In this system, the microneedle (MN) was inserted at 66° to the skin by TMICS so that the MN length could be extended within a safe range of skin penetration. Moreover, TMICS incorporating three MN patches created reliable ISF collecting conditions by penetrating the skin at consistent angle and force, 4.9 N. Due to the MN length increase and the patch number expansion, the surface area of the penetrated tissue was increased, thereby confirming that ISF extraction efficiency was improved. Skin ISF was collected into the paper reservoir on the patch, and the absorbed area was converted into a volume. ISF extraction from the rat skin in vivo by TMICS was well tolerated, and the 2.9 µL of ISF was obtained within 30 s. Therefore, TMICS is promising to apply in the diagnosis of multiple biomarkers in ISF with high speed and stability.

Microneedle for transdermal drug delivery: current trends and fabrication.

Background: Transdermal delivery has the advantage of bypassing the first-pass effect and allowing sustained release of the drug. However, the drug delivery is limited owing to the barrier created by the stratum corneum. Microneedles are a transdermal drug delivery system that is painless, less invasive, and easy to self-administer, with a high drug bioavailability. Area covered: The dose, delivery rate, and efficacy of the drugs can be controlled by the microneedle design and drug formulations. This review introduces the types of microneedles and their design, materials used for fabrication, and manufacturing methods. Additionally, recent biological applications and clinical trials are introduced. Expert opinion: With advancements made in formulation technologies, the drug-loading capability of microneedles can be improved. 3D printing and digital technology contribute to the improvement of microneedle fabrication technology. However, regulations regarding the manufacture of microneedle products should be established as soon as possible to promote commercialization.

Drug-Free, Nonsurgical Reduction of Intraocular Pressure for Four Months after Suprachoroidal Injection of Hyaluronic Acid Hydrogel.

Glaucoma is the leading cause of irreversible blindness. Current treatments use drugs or surgery to reduce intraocular pressure (IOP). In this study, a drug-free, nonsurgical method is developed that lowers IOP for 4 months without requiring daily patient adherence. The approach involves expanding the suprachoroidal space (SCS) of the eye with an in situ-forming hydrogel injected using a microneedle. This study tests the hypothesis that SCS expansion increases the drainage of aqueous humor from the eye via the unconventional pathway, which thereby lowers IOP. SCS injection of a commercial hyaluronic acid (HA) hydrogel reduces the IOP of normotensive rabbits for more than 1 month and an optimized HA hydrogel formulation enables IOP reduction for 4 months. Safety assessment by clinical ophthalmic examinations indicate the treatment is well tolerated. Histopathology shows minor hemorrhage and fibrosis at the site of injection. Further analysis by ultrasound biomicroscopy demonstrates a strong correlation of IOP reduction with SCS expansion. Outflow facility measurements show no difference in pressure-dependent outflow by the conventional pathway between treated and untreated eyes, supporting the hypothesis. In conclusion, SCS expansion with an in situ-forming hydrogel can enable extended IOP reduction for treating ocular hypertension and glaucoma without drugs or surgery.

Modulating Effects of Whole-body Vibration on Cortical Activity and Gait Function in Chronic Stroke Patients.

Whole-body vibration exercise (WBVe) can provide proper somatosensory stimulation and improve muscle strength in stroke patients. This study investigated the effects of WBVe on gait function and cortical activity in patients with chronic stroke. Thirty stroke patients were randomly assigned to either the WBVe or the control group. The WBVe group received the vibration in a half-squat position for 5 minutes at an intensity of 20 Hz. The control group kept the same posture but did not receive the vibration. Cortical activity was investigated using functional near-infrared spectroscopy (fNIRS). Gait function was assessed by a 10-m walk test (10MWT), a timed up and go (TUG) test, a Fugl-Meyer Assessment, and a Tinetti Performance-Oriented Mobility Assessment (TPOMA). In group analysis of the fNIRS data, oxygenated hemoglobin concentration was significantly increased in the ipsilesional supplementary motor area, bilateral sensorimotor cortex, and contralesional prefrontal cortex in the WBVe group compared to the control group (p < 0.05). Functional assessment demonstrated a significant interaction between time and group for the 10MWT and TUG test, suggesting that the WBVe group demonstrated meaningful improvement after intervention (p < 0.05). These results suggested that WBVe modulated the cerebral cortical activities and resulted in improvement of gait function in chronic stroke patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03375346.

Collagenase injection into the suprachoroidal space of the eye to expand drug delivery coverage and increase posterior drug targeting.

Injection into the suprachoroidal space (SCS) allows drug delivery targeted to sclera, choroid, and retina. Here, we studied SCS injection formulated with collagenase to expand drug delivery coverage and increase posterior drug targeting within SCS by breaking down collagen fibrils that link sclera and choroid in the SCS. When 1 µm latex microparticles were injected with a collagenase formulation using microneedles into the SCS of rabbit eyes ex vivo and incubated at 37 °C for 4 h, microparticle delivery coverage increased from 20% to 45% and enhanced posterior drug targeting. Collagenase concentration was optimized to 0.5 mg/mL to maximize expanded posterior delivery and minimize tissue damage. Effects of collagenase injection within SCS increased and then plateaued 4 h after injection. Simultaneous injection of collagenase and microparticles had a greater effect on expanded delivery in the SCS compared to sequential injection. Collagenase injection into the SCS of rabbit eyes in vivo was also effective to expand delivery and was generally well-tolerated, showing transiently lowered IOP, but no apparent lasting adverse effects on ocular tissues such as sclera, choroid, and retina, as determined by analyzing histology, sclera tensile strength, and fundus imaging. We conclude that addition of collagenase during SCS injection can expand drug delivery coverage and increase posterior drug targeting.

Targeting drug delivery within the suprachoroidal space.

The suprachoroidal space (SCS), a potential anatomical space between the sclera and choroid, is a novel route for drug delivery targeting the chorioretinal layers of the eye. The safety and efficacy of SCS drug delivery have been shown in multiple clinical trials. Recent studies have developed methods for more precise targeting within the SCS at sites of action at the posterior pole (e.g., macula), near the limbus (e.g., ciliary body), and throughout the SCS using iontophoresis, swollen hydrogels, high-density particle emulsions, highly viscous and non-Newtonian fluids, and microstents. Here, we review novel technologies targeting the posterior, anterior, or entire SCS.