Implementing new computational methods for the study of JCT and SC inner wall basement membrane biomechanics and hydrodynamics.

PURPOSE: The conventional aqueous outflow pathway, which includes the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and the inner wall endothelium of Schlemm's canal (SC), regulates intraocular pressure (IOP) by controlling the aqueous humor outflow resistance. Despite its importance, our understanding of the biomechanics and hydrodynamics within this region remains limited. Fluid-structure interaction (FSI) offers a way to estimate the biomechanical properties of the JCT and SC under various loading and boundary conditions, providing valuable insights that are beyond the reach of current imaging techniques. METHODS: In this study, a normal human eye was fixed at a pressure of 7 mm Hg, and two radial wedges of the TM tissues, which included the SC inner wall basement membrane and JCT, were dissected, processed, and imaged using 3D serial block-face scanning electron microscopy (SBF-SEM). Four different sets of images were used to create 3D finite element (FE) models of the JCT and inner wall endothelial cells of SC with their basement membrane. The outer JCT portion was carefully removed as the outflow resistance is not in that region, leaving only the SCE inner wall and a few µm of the tissue, which does contain the resistance. An inverse iterative FE algorithm was then utilized to calculate the unloaded geometry of the JCT/SC complex at an aqueous humor pressure of 0 mm Hg. Then in the model, the intertrabecular spaces, pores, and giant vacuole contents were replaced by aqueous humor, and FSI was employed to pressurize the JCT/SC complex from 0 to 15 mm Hg. RESULTS: In the JCT/SC complex, the shear stress of the aqueous humor is not evenly distributed. Areas proximal to the inner wall of SC experience larger stresses, reaching up to 10 Pa, while those closer to the JCT undergo lower stresses, approximately 4 Pa. Within this complex, giant vacuoles with or without I-pore behave differently. Those without I-pores experience a more significant strain, around 14%, compared to those with I-pores, where the strain is roughly 9%. CONCLUSIONS: The distribution of aqueous humor wall shear stress is not uniform within the JCT/SC complex, which may contribute to our understanding of the underlying selective mechanisms in the pathway.

In-silico study of drug delivery to atherosclerosis in the human carotid artery using metal-organic frameworks based on adhesion of nanocarriers.

This study investigates nanocarriers (NCs) for drug delivery targeting carotid artery atherosclerosis. This targeted drug delivery mechanism is based on ligand-receptor bindings facilitated by coating NCs with P-selectin aptamers, which exhibit high affinities for P-selectin plaque receptors. Recognizing the significant advantages of metal-organic frameworks (MOFs), such as their high drug-loading percentages, we chose them as nanocarriers for this research. Our evaluation considers critical factors: NC surface density (the number of attached nanocarriers per unit of plaque area), toxicity (percentage of NCs missing the target), and efficient drug transfer to plaque tissue. Employing molecular dynamics (MD) for drug loading calculations via van der Waals interactions and computational fluid dynamics (CFD) for toxicity, surface density, and drug transfer assessments, we achieve a comprehensive analysis. A cardiac cycle-based metric guides optimal MOF release conditions, establishing an ideal dosage of 600 NCs per cycle. MOF-801 exhibits outstanding drug delivery performance, particularly in plaque targeting. While a magnetic field enhances NC adhesion, its impact on drug transfer is limited, emphasizing the need for further optimization in magnetic targeting for NC-based therapies. This study provides crucial insights into NC drug delivery performance in carotid artery atherosclerosis, advancing the field of targeted drug delivery for atherosclerosis treatment.

A curved expansion-contraction microfluidic structure for inertial based separation of circulating tumor cells from blood samples.

The rare presence of circulating tumor cells (CTCs) in the bloodstream has made their recording and separation one of the major challenges in the recent decade. Inertia-based microfluidic systems have received more attention in CTCs separation due to their feasibility and low cost. In this research, an inertial microfluidic system is proposed using a curved expansion-contraction array (CEA) microchannel to separate CTCs from white blood cells (WBCs). First, the optimal flow rate of the proposed microfluidic device was determined to maximize the separation efficiency of the target cells (CTCs) from the non-target ones (WBCs). Then, the efficiency and purity of the straight and curved-CEA microchannels were assessed. The experimental results indiated that the proposed system (curved-CEA microchannel) can offer the highest efficiency (-80.31%) and purity (-91.32%) at the flow rate of -7.5 ml/min, exhibiting ∼11.48% increment in the efficiency compared to its straight peer.

Novel bilayer coating on gentamicin-loaded titanium nanotube for orthopedic implants applications.

Fabricating a multifunctional orthopedic implant which prevents post-surgery infection is highly desirable in advanced materials applications. However, designing an antimicrobial implant, which simultaneously promotes a sustained drug release and satisfactory cell proliferation, remains a challenge. The current study presents a drug-loaded surface-modified titanium nanotube (TNT) implant with different surface chemistry which was developed to investigate the effect of surface coating on drug release, antimicrobial activity, and cell proliferation. Accordingly, sodium alginate and chitosan were coated on the surface of TNT implants with different coating orders through layer-by-layer assembly. The coatings' swelling ratio and degradation rate were around 613% and 75%, respectively. The drug release results showed that surface-coatings prolonged the releasing profile for about 4 weeks. Chitosan coated TNTs demonstrated greater inhibition zone at 16.33mm compared with the other samples where no inhibition zone was observed. However, chitosan and alginate coated TNTs exhibited smaller inhibition zones at 48.56mm and 43.28mm, respectively, compared to bare TNT, which can be attributed to the coatings preventing the antibiotic burst release. Higher viability of cultured osteoblast cells was observed for chitosan-coated TNT as the top layer compared to the bare TNT at 12.18%, indicating improved bioactivity of TNT implants when the chitosan has the most contact with cells. Coupled with the cell viability assay, molecular dynamics (MD) simulations were carried out by placing collagen and fibronectin near the considered substrates. In agreement with cell viability results, MD simulations also indicated that chitosan had the highest adsorption energy approximately 60Kcal/mol. In summary, the proposed bilayer chitosan-coated drug-loaded TNT implant with chitosan and sodium alginate coating as the top and the bottom layers, respectively, can be a potential candidate for orthopedic applications in the light of its bacterial biofilm prevention, better osteoconductivity, and providing an adequate drug release profile.

Targeted drug delivery of magnetic microbubble for abdominal aortic aneurysm: an in silico study.

Targeted drug delivery (TDD) to abdominal aortic aneurysm (AAA) using a controlled and efficient approach has recently been a significant challenge. In this study, by using magnetic microbubbles (MMBs) under a magnetic field, we investigated the MMBs performance in TDD to AAA based on the amount of surface density of MMBs (SDMM) adhered to the AAA lumen. The results showed that among the types of MMBs studied in the presence of the magnetic field, micromarkers are the best type of microbubble with a -[Formula: see text] increase in SDMM adhered to the critical area of AAA. The results show that applying a magnetic field causes the amount of SDMM adhered to the whole area of AAA to increase -[Formula: see text] times compared to the condition in which the magnetic field is absent. This optimal and maximum value occurs for Definity MMBs with - 3.3 µm diameter. Applying a magnetic field also increases the adhesion surface density by - [Formula: see text], - [Formula: see text], and -[Formula: see text] times for the Micromarker, Optison, and Sonovue microbubbles, respectively, relative to the condition in which the magnetic field is absent. It was shown that using MBBs under magnetic field has the best performance in delivery to AAA for patients with negative inlet blood flow. Also, we have exposed that in an efficient TDD to AAA using MMBs, decreasing the density of MMBs increases drug delivery efficiency and performance. When density is - [Formula: see text], there is the highest difference (about - 75%) between the SDMM adhered to AAA in the presence of a magnetic field and in the absence of a magnetic field.

Modeling of an Ultrasound System in Targeted Drug Delivery to Abdominal Aortic Aneurysm: A Patient-Specific in Silico Study Based on Ligand-Receptor Binding.

Targeted drug delivery methods have shown a significant impact on enhancing drug delivery efficiency and reducing drug side effects. While various stimuli have been used to promote the drug delivery process, applying ultrasound (US) waves to control drug particles through the human body, noninvasively, has drawn the scientist's attention. However, microcarriers delivery reaches the aneurysmal artery by US waves that exert volumetric forces on blood, and drug carriers, which can therefore affect blood flow patterns and movement pathways of drug carriers, have not yet been studied. In this study, we developed a 3-D patient-specific model of abdominal aortic aneurysm (AAA) to evaluate the effect of US waves in enhancing the drug-containing microbubbles (MBs) adhered on the AAA lumen through ligand-receptor binding. Thus, a focused US (FUS) transducer with a resonance frequency of ~1.1 MHz was added to the geometry. Then, the surface density of MBs (SDM) adhered on the AAA lumen was calculated at peak acoustic pressure of ~1.1, ~2.2, and ~4.3 MPa. Results indicated that increasing the US pressure had a significant impact on improving the MBs adhered to the intended wall, whereby US waves with the maximum pressure of ~4.3 MPa could enhance ~1- [Formula: see text] MBs adhesion ~98% relative to not using the waves. While US waves have the advantage of more SDM adhered to the whole artery wall, they adversely affect the SDM adhered on the critical wall of the abdominal aorta. Furthermore, when the US strength goes up, a reduction occurs in the SDM adhered. This reduction is higher for smaller MBs, which is the mentioned MBs' size and US strength reduced SDM adhesion by about ~50% relative to systemic injection. Therefore, it can be concluded that drug delivery using the US field increases the SDM adhered to the whole AAA wall and decreases the SDM adhered to the critical wall of AAA.

Targeted pulmonary drug delivery in coronavirus disease (COVID-19) therapy: A patient-specific in silico study based on magnetic nanoparticles-coated microcarriers adhesion.

Since the beginning of the COVID-19 pandemic, nearly most confirmed cases develop respiratory syndromes. Using targeted drug delivery by microcarriers is one of the most important noteworthy methods for delivering drugs to the involved bronchi. This study aims to investigate the performance of a drug delivery that applies microcarriers to each branch of the lung under the influence of a magnetic field. The results show that by changing the inlet velocity from constant to pulsatile, the drug delivery performance to the lungs increases by ∼31%. For transferring the microcarriers to the right side branches (LUL and LLL), placing the magnet at zero height and ∼30° angle yields the best outcome. Also, the microcarriers' delivery to branch LUL improves by placing the magnet at LUL-LLL bifurcation and the angle of ∼30°. It was observed that dense (9300[kgm3]) microcarriers show the best performance for delivering drugs to LLL and RLL&RML branches. Also, low-density (1000[kgm3]) microcarriers are best for delivering drugs to LUL and RUL branches. The findings of this study can improve our understanding of different factors, such as inlet velocity, the magnet's position, and the choice of microcarrier - that affect drug delivery to the infected parts of the lung.

Drug delivery performance of nanocarriers based on adhesion and interaction for abdominal aortic aneurysm treatment.

Targeted drug delivery using nanocarriers (NCs) is one of the novel techniques that has recently been used to improve drug delivery to the Abdominal aortic aneurysm (AAA) disease. The purpose of this study is to evaluate the surface density of NCs (SDNC) adhered via ligand-receptor binding to the inner wall of AAA. For this purpose, fluid-structure interaction (FSI) analysis was first performed for the patient-specific and ideal AAA models. Then, by injecting NCs into the aortic artery, the values of SDNC adhered to and interacted with AAA wall were obtained. Two types of NCs, liposomes, and solid particles in four different diameters, were used to investigate the effect of the diameter and the type of NCs on the drug delivery. Additionally, the effect of the number of the injected NCs to the artery on the values of SDNC adhered to and interacted with AAA wall was investigated. The simulation results showed that the interaction and adhesion values of SDNC for Liposome nanoparticles were higher than the ones for the solid particles. Furthermore, as the diameter of NCs increases, the values of SDNC adhered to AAA wall increase, but the values of SDNC interacted with the inner wall of AAA decrease. In the low number of inserted NCs in the artery (1000 NCs), the interaction and adhesion values of SDNC were very slight, and by increasing the number of NCs inserted into the artery, the drug delivery was improved. By examining different AAA models, it was found that the complexity of the shape of AAA has a minor effect on the pattern of increase or decrease of the values of SDNC adhered to and interacted with AAA wall.This study's findings can improve the understanding of NCs design and propose the appropriate amount of their injection into various AAA models.

Targeted Drug Delivery of Microbubble to Arrest Abdominal Aortic Aneurysm Development: A Simulation Study Towards Optimized Microbubble Design.

Abdominal aortic aneurysm (AAA) is an irreversible bulge in the artery with higher prevalence among the elderlies. Increase of the aneurysm diameter by time is a fatal phenomenon which will lead to its sidewall rupture. Invasive surgical treatments are vital in preventing from AAA development. These approaches however have considerable side effects. Targeted drug delivery using microbubbles (MBs) has been recently employed to suppress the AAA growth. The present study is aimed to investigate the surface adhesion of different types of drug-containing MBs to the inner wall of AAA through ligand-receptor binding, using fluid-structure interaction (FSI) simulation by using a patient CT-scan images of the vascular system. The effect of blood flow through AAA on MBs delivery to the intended surface was also addressed. For this purpose, the adherence of four types of MBs with three different diameters to the inner surface wall of AAA was studied in a patient with 40-mm diameter aneurysm. The effects of the blood mechanical properties on the hematocrit (Hct) percentage of patients suffering from anemia and diabetes were studied. Moreover, the impact of variations in the artery inlet velocity on blood flow was addressed. Simulation results demonstrated the dependency of the surface density of MBs (SDM) adhered on the AAA lumen to the size and the type of MBs. It was observed that the amount of SDM due to adhesion on the AAA lumen for one of the commercially-approved MBs (Optison) with a diameter of 4.5 µm was higher than the other MBs. Furthermore, we have shown that the targeted drug delivery to the AAA lumen is more favorable in healthy individuals (45% Hct) compared to the patients with diabetes and anemia. Also, it was found that the targeted drug delivery method using MBs on the patients having AAA with complicated aneurysm shape and negative inlet blood flow velocity can be severely affected.

Effects of Tamsulosin and Tolterodine on double J stent-related symptoms: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: Ureteral double J stent are routinely applied for urologic patients although stent-related symptoms are common. Several attempts have been reported to minimize these symptoms. OBJECTIVE: To compare Tolterodine, Tamsulosin, and placebo effects on double J stent-related symptoms. MATERIAL AND METHOD: In all, 125 patients (82 males and 43 females) with double J stent were randomly divided into three groups (group 1, n: 42, group2, n: 40 and group 3, n: 43). Each patient randomly received one pack of drug in different colors by a nurse unaware of the content to take Tamsulosin 0.4 mg before sleep (MODALUSINE), Tolterodine 2 mg twice a day or placebo once daily (capsules filled with starch): group 1 received placebo, group 2 Tamsulosin and group 3 Tolterodine for 1 month in a double-blind manner. Ureteral stent-related morbidity indices which analyzed include urinary symptom, pain, general health, quality of work and sex scores. All of indices measured by Ureteral Symptom Score Questionnaire for first and fourth weeks after drug consumption and the first week after double J stent removal (labeled as w1, w4, and w5, respectively). RESULT: The mean age was 44.8 years (range: 15-83 years). There was no statistically significant difference in background characteristics between groups (p value > 0.05). The most important and statistically significant results were Tolterodine-reduced urinary symptom score (p value = 0.001) and improved general health score (p value = 0.007) of the fourth week. The pain score in groups of Tamsulosin and Tolterodine significantly reduced between weeks 4 and 1 and 5 and 1 (both with the p value < 0.05), but in other indices, there was no significant difference between them. CONCLUSION: According to our results, we suggest Tolterodine to minimize stent-related urinary symptom and improve general health in patients with double J stent.