Multi-physics simulations for investigating the effect of electrode conditions on transscleral ocular iontophoresis for particulate drug delivery into ocular tissues.

Purpose: Transscleral ocular iontophoresis has been proposed to deliver charged particulate drugs to ocular tissues effectively by transmitting a weak electrical current through the sclera. The electric fields formed are influenced by the electrode conditions, thus affecting the amount of particulate drugs delivered to the ocular tissues via iontophoresis. Computational simulation is widely used to simulate drug concentrations in the eye; therefore, reflecting the characteristics of the drugs in living tissues to the simulations is important for a more precise estimation of drug concentration. In this study, we investigated the effect of electrode conditions (location and size) on the efficacy of transscleral iontophoresis. Methods: We first determined the simulation parameters based on the comparison of the amount of drug in the sclera in the simulation and in vivo experimental results. The injection of the negatively charged nanoparticles into the cul-de-sac of the lower eyelid was simulated. The active electrode (cathode) was attached to the skin immediately above the injection site, while the return electrode (anode) was placed over the eyebrow. The drug concentration distribution in the eye, based on either the location or size of each electrode, was evaluated using the finite element method with the estimated simulation parameters. Results: Our results indicate that drug permeability varies depending on the location and the size of the electrodes. Conclusion: Our findings demonstrate that the determination of optimal electrode conditions is necessary to enhance the effectiveness of transscleral iontophoresis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00359-2.

Fe-Porphyrin Cross-Linked Hydrogel for Reactive Oxygen Species Scavenging and Oxygen Generation in Diabetic Wounds.

Healing chronic diabetic wounds is challenging because of excessive reactive oxygen species (ROS) and hypoxia in the wound microenvironment. To address this issue, we propose a hydrogel wound dressing composed of polyethylene glycol (PEG) cross-linked with a biomimetic catalase, Fe-containing porphyrin (FeP) (i.e., FeP hydrogel). The immobilized FeP can serve as a catalyst for both ROS scavenging and O2 generation. The properties of the hydrogels were optimized by varying the composition ratios of the two constituent materials based on their mechanical properties and catalytic activity. Our in vitro cell experiments revealed that the FeP-80 hydrogel enhanced the proliferation and migration of keratinocytes and dermal fibroblasts and promoted the expression of angiogenic growth factors in keratinocytes. When tested with an in vivo diabetic chronic wound model, the FeP-80 hydrogel promoted wound healing by facilitating re-epithelialization, promoting angiogenesis, and suppressing inflammation, compared with other control groups.

Neutrophil extracellular traps promote ΔNp63+ basal cell hyperplasia in chronic rhinosinusitis.

BACKGROUND: Neutrophil extracellular traps (NETs) are observed in chronic rhinosinusitis (CRS), although their role remains unclear. OBJECTIVES: This study aimed to investigate the influence of NETs on the CRS epithelium. METHODS: Forty-five sinonasal biopsy specimens were immunofluorescence-stained to identify NETs and p63+ basal stem cells. Investigators treated human nasal epithelial cells with NETs and studied them with immunofluorescence staining, Western blotting, and quantitative real-time PCR. NET inhibitors were administered to a murine neutrophilic nasal polyp model. RESULTS: NETs existed in tissues in patients with CRS with nasal polyps, especially in noneosinophilic nasal polyp tissues. p63+ basal cell expression had a positive correlation with the release of NETs. NETs induced the expansion of Ki-67+p63+ cells. We found that ΔNp63, an isoform of p63, was mainly expressed in the nasal epithelium and controlled by NETs. Treatment with deoxyribonuclease (DNase) I or Sivelestat (NET inhibitors) prevented the overexpression of ΔNp63+ epithelial stem cells and reduced polyp formation. CONCLUSIONS: These results reveal that NETs are implicated in CRS pathogenesis via basal cell hyperplasia. This study suggests a novel possibility of treating CRS by targeting NETs.

Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Chromophoric cerium oxide nanoparticle-loaded sucking disk-type strip sensor for optical measurement of glucose in tear fluid.

BACKGROUND: Noninvasive monitoring of tear glucose levels can be convenient for patients to manage their diabetes mellitus. However, there are issues with monitoring tear glucose levels, such as the invasiveness of some methods, the miniaturization, inaccuracy, or the high cost of wearable devices. To overcome the issues, we newly designed a sucking disk-type (SD) strip biosensor that can quickly suck tear fluid and contains cerium oxide nanoparticle (CNP) that causes a unique color change according to the glucose level of the tear without complicated electronic components. METHODS: The SD strip biosensor composed of three distinct parts (tip, channel, and reaction chamber) was designed to contain the sensing paper, onto which tear fluid can be collected and delivered. The sensing paper treated with CNP/APTS (aminopropyltriethoxysilane) /GOx (glucose oxidase) was characterized. Then we carried out the reliability of the SD strip biosensor in the diabetic rabbit animals. We quantitatively analyzed the color values of the SD strip biosensor through the colorimetric analysis algorithm. RESULTS: We contacted the inferior palpebral conjunctiva (IPC) of a diabetic rabbit eye using an SD strip biosensor to collect tears without eye irritation and successfully verified the performance and quantitative efficacy of the sensor. An image processing algorithm that can optimize measurement accuracy is developed for accurate color change measurement of SD strip biosensors. The validation tests show a good correlation between glucose concentrations measured in the tear and blood. CONCLUSION: Our findings demonstrate that the CNP-embedded SD strip biosensor and the associated image processing can simply monitor tear glucose to manage diabetes mellitus.

Microneedles coated with composites of phenylboronic acid-containing polymer and carbon nanotubes for glucose measurements in interstitial fluids.

A microneedle (MN) sensor coated with a sensing composite material was proposed for measuring glucose concentrations in interstitial fluid (ISF). The sensing composite material was prepared by blending a polymer containing glucose-responsive phenylboronic acid (PBA) moieties (i.e., polystyrene-block-poly(acrylic acid-co-acrylamidophenylboronic acid)) with conductive carbon nanotubes (CNTs). The polymer exhibited reversible swelling behavior in response to glucose concentrations, which influenced the distribution of the embedded CNTs, resulting in sensitive variations in electrical percolation, even when coated onto a confined surface of the MN in the sensor. We varied the ratio of PBA moieties and the loading amount of CNTs in the sensing composite material of the MN sensor and tested them in vitro using an ISF-mimicking gel with physiological glucose concentrations to determine the optimal sensitivity conditions. When tested in animal models with varying blood glucose concentrations, the MN sensor coated with the selected sensing material exhibited a strong correlation between the measured electrical currents and blood glucose concentrations, showing accuracy comparable to that of a glucometer in clinical use.

Fe-containing metal-organic framework with D-penicillamine for cancer-specific hydrogen peroxide generation and enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is based on the production of cytotoxic reactive oxygen species, such as hydroxyl radicals (•OH). Thus, CDT can be advantageous when it is cancer-specific, in terms of efficacy and safety. Therefore, we propose NH2-MIL-101(Fe), a Fe-containing metal-organic framework (MOF), as a carrier of Cu (copper)-chelating agent, d-penicillamine (d-pen; i.e., the NH2-MIL-101(Fe)/d-pen), as well as a catalyst with Fe-metal clusters for Fenton reaction. NH2-MIL-101(Fe)/d-pen in the form of nanoparticles was efficiently taken into cancer cells and released d-pen in a sustained manner. The released d-pen chelated Cu that is highly expressed in cancer environments and this produces extra H2O2, which is then decomposed by Fe in NH2-MIL-101(Fe) to generate •OH. Therefore, the cytotoxicity of NH2-MIL-101(Fe)/d-pen was observed in cancer cells, not in normal cells. We also suggest a formulation of NH2-MIL-101(Fe)/d-pen combined with NH2-MIL-101(Fe) loaded with the chemotherapeutic drug, irinotecan (CPT-11; NH2-MIL-101(Fe)/CPT-11). When intratumorally injected into tumor-bearing mice in vivo, this combined formulation exhibited the most prominent anticancer effects among all tested formulations, owing to the synergistic effect of CDT and chemotherapy.

Implantable device with magnetically rotating disk for needle-free administrations of emergency drug.

Prompt administration of first-aid drugs can save lives during medical emergencies such as anaphylaxis and hypoglycemia. However, this is often performed by needle self-injection, which is not easy for patients under emergency conditions. Therefore, we propose an implantable device capable of on-demand administration of first-aid drugs (i.e., the implantable device with a magnetically rotating disk [iMRD]), such as epinephrine and glucagon, via a noninvasive simple application of the magnet from the outside skin (i.e., the external magnet). The iMRD contained a disk embedded with a magnet, as well as multiple drug reservoirs that were sealed with a membrane, which was designed to rotate at a precise angle only when the external magnet was applied. During this rotation, the membrane on a designated single-drug reservoir was aligned and torn to expose the drug to the outside. When implanted in living animals, the iMRD, actuated by an external magnet, delivers epinephrine and glucagon, similar to conventional subcutaneous needle injections.

Implantable device actuated by manual button clicks for noninvasive self-drug administration.

Self-injectable therapy has several advantages in the treatment of metabolic disorders. However, frequent injections with needles impair patient compliance and medication adherence. Therefore, we develop a fully implantable device capable of on-demand administration of self-injection drugs via noninvasive manual button clicks on the outer skin. The device is designed to infuse the drug only at the moment of click actuation, which allows for an accurate and reproducible drug infusion, and also prevents unwanted drug leakage. Using a mechanical means of drug infusion, this implantable device does not contain any electronic compartments or batteries, making it compact, and semi-permanent. When tested in animals, the device can achieve subcutaneous injection-like pharmacokinetic and pharmacodynamic effects for self-injection drugs such as exenatide, insulin, and glucagon.

Metal-organic framework for biomimetic nitric oxide generation and anticancer drug delivery.

The potential therapeutic implications of nitric oxide (NO) have drawn a great deal of interest for reversing multidrug resistance (MDR) in cancer; however, previous strategies utilized unstable or toxic NO donors often oxidized by the excessive addition of reactive oxygen species, leading to unexpected side effects. Therefore, this study proposed a metal-organic framework (MOF), Porous coordination network (PCN)-223-Fe, to be loaded with a biocompatible NO donor, L-arginine (L-arg; i.e., PCN-223-Fe/L-arg). This specific MOF possesses a ligand of Fe-porphyrin, a biomimetic catalyst. Thus, with PCN-223-Fe/L-arg, L-arg was released in a sustained manner, which generated NO by a catalytic reaction between L-arg and Fe-porphyrin in PCN-223-Fe. Through this biomimetic process, PCN-223-Fe/L-arg could generate sufficient NO to reverse MDR at the expense of hydrogen peroxide already present and highly expressed in cancer environments. For treatment of MDR cancer, this study also proposed PCN-223-Fe loaded with an anticancer drug, irinotecan (CPT-11; i.e., PCN-223-Fe/CPT-11), to be formulated together with PCN-223-Fe/L-arg. Owing to the synergistic effect of reversed MDR by NO generation and sustained release of CPT-11, this combined formulation exhibited a higher anticancer effect on MDR cancer cells (MCF-7/ADR). When intratumorally injected in vivo, coadministration of PCN-223-Fe/L-arg and PCN-223-Fe/CPT-11 greatly suppressed tumor growth in nude mice bearing MDR tumors.

Evaluation of Paste-Type Micronized Acellular Dermal Matrix for Soft Tissue Augmentation: Volumetric and Histological Assessment in a Mouse Model.

BACKGROUND: A biological injectable material, paste-type micronized acellular dermal matrix (ADM), has been proven effective in wound healing by filling defects through tissue replacement. This study aimed to compare the efficacy of paste-type micronized ADM on soft tissue augmentation with that of the conventional fillers in animal experiments. METHODS: Two distinct paste-type micronized ADMs, which were mixed with distilled water (mADM) and gelatin (mADM+GEL), respectively, were compared with conventional fillers, hyaluronic acid (HA) and polymethyl methacrylate (COL+PMMA). Thus, four different types of fillers were each injected into the dorsum of nude mice to compare the volume retention and biocompatibility. During the 8-week experimental period, ultrasound and computed tomography (CT) images were obtained for volumetric analysis. Histological evaluation was performed using hematoxylin and eosin and CD 31 staining. RESULTS: According to the CT images at week 8, the mADM and mADM+GEL showed a higher volume persistence rate of 113.54% and 51.12%, compared with 85.09% and 17.65% for HA and COL+PMMA, respectively. The 2-week interval ultrasound images revealed that the mADM showed a volume increase in width rather than in height, and an increase in height for HA did not vary much. Histological analysis showed marked fibrous invasion and neovascularization with the mADM and mADM+GEL compared to that of the conventional fillers. CONCLUSIONS: Paste-type micronized ADM showed soft tissue augmentation with similar effectiveness to that of conventional fillers. Therefore, paste-type micronized ADM has potential as an alternative material for a soft tissue filler in tissue replacement. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma.

Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.

Feasibility of epidural temporal interference stimulation for minimally invasive electrical deep brain stimulation: simulation and phantom experimental studies.

Objective. Temporal interference stimulation (TIS) has shown the potential as a new method for selective stimulation of deep brain structures in small animal experiments. However, it is challenging to deliver a sufficient temporal interference (TI) current to directly induce an action potential in the deep area of the human brain when electrodes are attached to the scalp because the amount of injection current is generally limited due to safety issues. Thus, we propose a novel method called epidural TIS (eTIS) to address this issue; in this method, the electrodes are attached to the epidural surface under the skull.Approach. We employed finite element method (FEM)-based electric field simulations to demonstrate the feasibility of eTIS. We first optimized the electrode conditions to deliver maximum TI currents to each of the three different targets (anterior hippocampus, subthalamic nucleus, and ventral intermediate nucleus) based on FEM, and compared the stimulation focality between eTIS and transcranial TIS (tTIS). Moreover, we conducted realistic skull-phantom experiments for validating the accuracy of the computational simulation for eTIS.Main results. Our simulation results showed that eTIS has the advantage of avoiding the delivery of TI currents over unwanted neocortical regions compared with tTIS for all three targets. It was shown that the optimized eTIS could induce neural action potentials at each of the three targets when a sufficiently large current equivalent to that for epidural cortical stimulation is injected. Additionally, the simulated results and measured results via the phantom experiments were in good agreement.Significance. We demonstrated the feasibility of eTIS, facilitating more focalized and stronger electrical stimulation of deep brain regions than tTIS, with the relatively less invasive placement of electrodes than conventional deep brain stimulation via computational simulation and realistic skull phantom experiments.

Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Micro-textured silicone-based implant fabrication using electrospun fibers as a sacrificial template to suppress fibrous capsule formation.

Conventionally, macro-textured surfaces comprising several hundred micrometer-sized patterns are used to minimize silicone-based breast implant complications, including capsular contracture. However, because of the recent cases of breast implant-associated anaplastic large cell lymphoma from macro-textured implants, there is a strong demand for nano- or micro-textured silicone implants with dimensions smaller than sub-micrometers. Herein, we propose a simple and cost-effective topographical surface modification strategy for silicone-based implants. Several hundred nanometer to sub-micrometer wide groove-type micro-textures were fabricated on a polydimethylsiloxane surface using electrospun polyvinylpyrrolidone fibers as a sacrificial template. The aligned and randomly oriented micro-textures were prepared by controlling the electrospun fiber orientation. In vitro experiments demonstrated that the micro-textured polydimethylsiloxane was cytocompatible and suppressed differentiation of fibroblasts into myofibroblasts. Importantly, the aligned micro-texture promoted the polarization of macrophages into the anti-inflammatory M2 phenotype. Long-term in vivo studies established that the micro-textures potently suppressed various factors affecting foreign body reactions by downregulating profibrotic cytokine gene expression and reducing the fibroblast and myofibroblast counts, the cells playing important roles in the immune response. Thus, the thickness and collagen density of fibrous capsules were decreased, demonstrating that the micro-textured surface effectively inhibited capsular contracture. Although the aligned micro-textures contributed to the polarization of macrophages to the M2 phenotype both in vitro and in vivo, foreign body reaction by both the aligned and randomly oriented micro-textures are similar.

Magnetically actuating implantable pump for the on-demand and needle-free administration of human growth hormone.

A bolus of human growth hormone (hGH) is often prescribed for the treatment of growth hormone deficiency, which requires frequent injections in current clinical settings. This painful needle-involved delivery often results in poor patient compliance, leading to low medication adherence and poor clinical outcomes. Therefore, we propose a magnetically actuating implantable pump (MAP) that can infuse an accurate dose of hGH only at the time of non-invasive magnet application from the skin. The MAP herein could reproducibly infuse 20.6 ±â€¯0.9 µg hGH per actuation without any leak at times without actuation. The infused amount increased proportionally with an increase in the number of actuations. When the MAP was implanted and actuated with a magnet in animals with growth hormone deficiency for 21 days, the profiles of plasma hGH concentration and insulin-like growth factor (IGF)-1, as well as changes in body weight, were similar to those observed in animals treated with conventional subcutaneous hGH injections. Therefore, we anticipate that the MAP fabricated in this study can be a non-invasive alternative to administer hGH without repeated and frequent needle injections.

Iontophoretic ocular delivery of latanoprost-loaded nanoparticles via skin-attached electrodes.

Prolonged drug efficacy to reduce the number of administrations is a key factor in the successful treatment of glaucoma through topical drug delivery to the eye. Therefore, we propose a new strategy for iontophoretic ocular delivery of drug-loaded nanoparticles. Considering safety and convenience, our strategy is involved with topical administration of the drug-loaded nanoparticles followed by their permeation into the eye tissues via noninvasive iontophoresis, using the skin-attached electrodes. Thus, those nanoparticles stayed longer in the eye, and during this period, the drug was released in a sustained manner, thereby prolonging drug exposure even with one-time treatment. The nanoparticles were made of poly(lactic-co-glycolic acid) (PLGA), which were loaded with a glaucoma drug, latanoprost. We varied the size of the nanoparticles at 100, 200, 300, and 500 nm and sought to find the optimum size under the fixed conditions for iontophoresis proposed in this work (4 mA; 30 min). Even with iontophoresis through the skin-attached electrodes, the nanoparticles were indeed deposited in the eye tissues, where with an increase in particle size, drug release was more sustained, but fewer particles could permeate into the eye tissues. Because of these two competing factors, iontophoretic delivery of the 300-nm particles exhibited the most prolonged drug efficacy in vivo for more than 7 days, and showed an approximately 23-fold increase in drug efficacy compared with that of Xalatan®, a commercially available eye drop of latanoprost developed for once-a-day administration every day. STATEMENT OF SIGNIFICANCE: To treat glaucoma, conventional eye drops are often prescribed; however, they often require multiple daily administrations due to rapid preocular clearance. To resolve this, we suggest a noninvasive iontophoretic ocular delivery of latanoprost-loaded PLGA nanoparticles using the skin-attached electrodes. Even with iontophoresis via the skin-attached electrodes, the nanoparticles can indeed be deposited into the eye tissues. However, with an increase in particle size, fewer particles can permeate into the eye tissues, although drug release is more sustained. Therefore, the particles with a size of 300 nm show the optimal in vivo delivery profile in this work, where the drug efficacy can be extended for more than 7 days with a single administration.

Microchannel-embedded implantable device with fibrosis suppression for prolonged controlled drug delivery.

For the prolonged, controlled delivery of systemic drugs, we propose an implantable drug-delivery chip (DDC) embedded with pairs of a microchannel and drug-reservoir serving as a drug diffusion barrier and depot, respectively. We pursued a DDC for dual drugs: a main-purpose drug, diclofenac (DF), for systemic exposure, and an antifibrotic drug, tranilast (TR), for local delivery. Thus, the problematic fibrotic tissue formation around the implanted device could be diminished, thereby less hindrance in systemic exposure of DF released from the DDC. First, we separately prepared DDCs for DF or TR delivery, and sought to find a proper microchannel length for a rapid onset and sustained pattern of drug release, as well as the required drug dose. Then, two distinct DDCs for DF and TR delivery, respectively, were assembled to produce a Dual_DDC for the concurrent delivery of DF and TR. When the Dual_DDC was implanted in living rats, the DF concentration in blood plasma did not drop significantly in the later periods after implantation relative to that in the early periods before fibrotic tissue formation. When the Dual_DDC was implanted without TR, there was a significant decrease in the blood plasma DF concentration as the time elapsed after implantation. Biopsied tissues around the Dual_DDC exhibited a significant decrease in the fibrotic capsule thickness and collagen density relative to the Dual_DDC without TR, owing to the effect of the local, sustained release of the TR.

Synergistic Effect of Whitlockite Scaffolds Combined with Alendronate to Promote Bone Regeneration.

BACKGROUND: Due to the increasing aging of society, the number of patients suffering from senile diseases is increasing. Patients suffering from osteoporosis, which is a representative senile disease, take a long time to recover from fractures, and the resulting mortality rate is very high. Alendronate (Ald), which is widely used as a treatment for osteoporosis, alleviates osteoporosis by inhibiting osteoclasts. In addition, whitlockite (WH) promotes the osteogenic differentiation of bone cells and improves bone regeneration. Therefore, we intended to bring about a synergistic effect by using these substances together. METHODS: In this study, a scaffold composed of gelatin/heparin was fabricated and applied to effectively use WH and Ald together. A scaffold was constructed using gelatin and heparin was used to effectively utilize the cations released from WH. In addition, it formed a porous structure for effective bone regeneration. In vitro and in vivo osteoclast inhibition, osteogenic differentiation, and bone regeneration were studied using the prepared scaffolds. RESULTS: The inhibition of osteoclast was much higher when WH and Ald were applied in combination rather than individually. The highest level of osteogenic differentiation was observed when both substances were applied simultaneously. In addition, when applied to bone regeneration through the mouse calvarial defect model, combined treatment showed excellent bone regeneration. CONCLUSION: Therefore, this study showed the synergistic effect of WH and Ald, and it is suggested that better bone regeneration is possible by applying this treatment to bones with fractures that are difficult to regenerate.

In-vivo estimation of tissue electrical conductivities of a rabbit eye for precise simulation of electric field distributions during ocular iontophoresis.

Precise estimation of electrical conductivity of the eyes is important for the accurate analysis of electric field distributions in the eyes during ocular iontophoresis. In this study, we estimated the tissue electrical conductivities of a rabbit eye, which has been widely employed for neuro-ophthalmological experiments, through an in vivo experiment for the first time. Electrical potentials were measured at multiple locations on the skin, while weak currents were transmitted into the skin via two surface electrodes attached to the skin around the eye. A finite element model was constructed to calculate the electric potentials at the measurement locations. The conductivity values of different tissues were then estimated using an optimization procedure to minimize the difference between the measured and calculated electric potentials. The accuracy of the estimated tissue conductivity values of the rabbit eye was validated by comparing the measured and calculated electric potential values for different electrode montages. Further multi-physical analyses of iontophoretic drug delivery to the rabbit eye showed a significant influence of the conductivity profile on the resultant particle distribution. Overall, our results provide an important reference for the tissue electrical conductivity values of the rabbit eye, which could be further utilized for designing new medical devices for delivering electric fields to the eyes, such as transorbital and transscleral electrical stimulations.