On the generality of the finite element modeling physical fields in biological systems by the multiscale smeared concept (Kojic transport model).

The biomechanical and biochemical processes in the biological systems of living organisms are extremely complex. Advances in understanding these processes are mainly achieved by laboratory and clinical investigations, but in recent decades they are supported by computational modeling. Besides enormous efforts and achievements in this modeling, there still is a need for new methods that can be used in everyday research and medical practice. In this report, we give a view of the generality of the finite element methodology introduced by the first author and supported by his collaborators. It is based on the multiscale smeared physical fields, termed as Kojic Transport Model (KTM), published in several journal papers and summarized in a recent book (Kojic et al., 2022) [1]. We review relevant literature to demonstrate the distinctions and advantages of our methodology and indicate possible further applications. We refer to our published results by a selection of a few examples which include modeling of partitioning, blood flow, molecular transport within the pancreas, multiscale-multiphysics model of coupling electrical field and ion concentration, and a model of convective-diffusive transport within the lung parenchyma. Two new examples include a model of convective-diffusive transport within a growing tumor, and drug release from nanofibers with fiber degradation.

Kinetic Perimetry on Virtual Reality Headset.

OBJECTIVE: We present a portable automatic kinetic perimeter based on a virtual reality (VR) headset device as an innovative and alternative solution for the screening of clinical visual fields. We compared the performances of our solution with a gold standard perimeter, validating the test on healthy subjects. METHODS: The system is composed of an Oculus Quest 2 VR headset with a clicker for participant response feedback. An Android app was designed in Unity to generate moving stimuli along vectors, following a standard Goldmann kinetic perimetry approach. Sensitivity thresholds are obtained by moving centripetally three different targets (V/4e, IV/1e, III/1e) along 24 or 12 vectors from an area of non-seeing to an area of seeing and then transmitted wirelessly to a PC. A Python real-time algorithm processes the incoming kinetic results and displays the hill of vision in a two-dimensional map (isopter). We involved 21 subjects (5 males and 16 females, age range 22-73 years) for a total of 42 eyes tested with our proposed solution, and results were compared with a Humphrey visual field analyzer to test reproducibility and efficacy. RESULTS: isopters generated with the Oculus headset were in good agreement with those acquired with a commercial device (Pearson's correlation values r > 0.83 for each target). CONCLUSIONS: we demonstrate the feasibility of VR kinetic perimetry by comparing performances between our system and a clinically used perimeter in healthy subjects. SIGNIFICANCE: proposed device leads the way for a portable and more accessible visual field test, overcoming challenges in current kinetic perimetry practices.

Quantitative high-resolution 7T MRI to assess longitudinal changes in articular cartilage after anterior cruciate ligament injury in a rabbit model of post-traumatic osteoarthritis.

Objective: To demonstrate an ultra-high field (UHF) 7 â€‹T delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) protocol for quantitative post-traumatic osteoarthritis (PTOA) detection and monitoring in a rabbit anterior cruciate ligament transection (ACLT) model. Design: ACL transections were performed unilaterally in 5 rabbits (33-weeks-old, 3.5 â€‹± â€‹0.5 â€‹kg) to induce PTOA. MRI exams were performed at 7 â€‹T prior to and 2, 4, 7 and 10-weeks after ACLT using a modified dGEMRIC protocol. Voxel-based T1 and T2 maps were created over manually drawn femoral cartilage ROIs from the center of the tibial plateau to the posterior meniscus. Femoral, tibial, and patellar epiphyses were harvested 10-weeks post-surgery and processed for µCT imaging and histology. Results: Quantitative analysis revealed a 35% and 39% decrease in dGEMRIC index in the medial ACLT knee compartment 7- and 10-weeks post-surgery, respectively (p â€‹= â€‹0.009 and p â€‹= â€‹0.006) when compared to baseline. There was no significant change in the lateral ACLT compartment or in either compartment of the control knees. Visual inspection of histology confirmed PTOA in the ACLT knees. Osteophytes were found only in ACLT knees (osteophyte volume in femur: 94.53 â€‹± â€‹44.08 â€‹mm3, tibia: 29.35 â€‹± â€‹13.79 â€‹mm3, and patella: 3.84 â€‹± â€‹0.92 â€‹mm3) and were significantly larger in the medial compartments of the femur than lateral (p â€‹= â€‹0.0312). Conclusion: The dGEMRIC technique quantitatively applied at 7 â€‹T UHF-MRI demonstrates site-specific cartilage degeneration in a large animal PTOA model. This should encourage further investigation, with potential applications in drug and therapeutic animal trials as well as human studies.

Zonal Intratumoral Delivery of Nanoparticles Guided by Surface Functionalization.

Delivery of small molecules and anticancer agents to malignant cells or specific regions within a tumor is limited by penetration depth and poor spatial drug distribution, hindering anticancer efficacy. Herein, we demonstrate control over gold nanoparticle (GNP) penetration and spatial distribution across solid tumors by administering GNPs with different surface chemistries at a constant injection rate via syringe pump. A key finding in this study is the discovery of different zone-specific accumulation patterns of intratumorally injected nanoparticles dependent on surface functionalization. Computed tomography (CT) imaging performed in vivo of C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors on their flank and gross visualization of excised tumors consistently revealed that intratumorally administered citrate-GNPs accumulate in particle clusters in central areas of the tumor, while GNPs functionalized with thiolated phosphothioethanol (PTE-GNPs) and thiolated polyethylene glycol (PEG-GNPs) regularly accumulate in the tumor periphery. Further, PEG functionalization resulted in larger tumoral surface coverage than PTE, reaching beyond the outer zone of the tumor mass and into the surrounding stroma. To understand the dissimilarities in spatiotemporal evolution across the different GNP surface chemistries, we modeled their intratumoral transport with reaction-diffusion equations. Our results suggest that GNP surface passivation affects nanoparticle reactivity with the tumor microenvironment, leading to differential transport behavior across tumor zones. The present study provides a mechanistic understanding of the factors affecting spatiotemporal distribution of nanoparticles in the tumor. Our proof of concept of zonal delivery within the tumor may prove useful for directing anticancer therapies to regions of biomarker overexpression.

A novel system for measuring visual potentials evoked by passive head-mounted display stimulators.

PURPOSE: The objective of this work is to evaluate the performances of a novel integrated device, based on passive head-mounted display (HMD), for the pattern reversal visual evoked potential (PR-VEP) clinical test. METHODS: Google Cardboard® is used as passive HMD to generate the checkerboard pattern stimuli through an Android® application. Electroencephalographic signals are retrieved and processed over 20 subjects, 12 females and 8 males between 20 and 26 years. Morphological PR-VEPs and frequency response were compared with previous literature results, to test the reproducibility and the efficacy of the proposed solution. RESULTS: PR-VEPs evoked by our novel prototype showed typical triphasic waveforms in moderate agreement with those obtained with other more expensive HMDs and standard commercial devices. Statistical analysis did not highlight strong differences among the systems over the features analyzed except for the P100 amplitude and peak time (**p < 0.005). CONCLUSION: The proposed solution opens the door for a new generation of non-invasive first-level diagnostic devices of optic nerve pathologies inexpensive and easy to access.

Hyaluronate-Thiol Passivation Enhances Gold Nanoparticle Peritumoral Distribution When Administered Intratumorally in Lung Cancer.

Biofouling is the unwanted adsorption of cells, proteins, or intracellular and extracellular biomolecules that can spontaneously occur on the surface of metal nanocomplexes. It represents a major issue in bioinorganic chemistry because it leads to the creation of a protein corona, which can destabilize a colloidal solution and result in undesired macrophage-driven clearance, consequently causing failed delivery of a targeted drug cargo. Hyaluronic acid (HA) is a bioactive, natural mucopolysaccharide with excellent antifouling properties, arising from its hydrophilic and polyanionic characteristics in physiological environments which prevent opsonization. In this study, hyaluronate-thiol (HA-SH) (MW 10 kDa) was used to surface-passivate gold nanoparticles (GNPs) synthesized using a citrate reduction method. HA functionalized GNP complexes (HA-GNPs) were characterized using absorption spectroscopy, scanning electron microscopy, zeta potential, and dynamic light scattering. GNP cellular uptake and potential dose-dependent cytotoxic effects due to treatment were evaluated in vitro in HeLa cells using inductively coupled plasma-optical emission spectrometry (ICP-OES) and trypan blue and MTT assays. Further, we quantified the in vivo biodistribution of intratumorally injected HA functionalized GNPs in Lewis Lung carcinoma (LLC) solid tumors grown on the flank of C57BL/6 mice and compared localization and retention with nascent particles. Our results reveal that HA-GNPs show overall greater peritumoral distribution (** p < 0.005, 3 days post-intratumoral injection) than citrate-GNPs with reduced biodistribution in off-target organs. This property represents an advantageous step forward in localized delivery of metal nano-complexes to the infiltrative region of a tumor, which may improve the application of nanomedicine in the diagnosis and treatment of cancer.

Nanomaterials to Fight Cancer: An Overview on Their Multifunctional Exploitability.

In recent years the worldwide research community has highlighted innumerable benefits of nanomaterials in cancer detection and therapy. Nevertheless, the development of cancer nanomedicines and other bionanotechnology requires a huge amount of considerations about the interactions of nanomaterials and biological systems, since long-term effects are not yet fully known. Open issues remain the determination of the nanoparticles distributions patterns and the internalization rate into the tumor while avoiding their accumulation in internal organs or other healthy tissues. The purpose of this work is to provide a standard overview of the most recent advances in nanomaterials to fight cancer and to collect trends and future directions to follow according to some critical aspects still present in this field. Complementary to the very recent review of Wolfram and Ferrari which discusses and classifies successful clinically-approved cancer nanodrugs as well as promising candidates in the pipeline, this work embraces part of their proposed classification system based on the exploitation of multifunctionality and extends the review to peer-reviewed journal articles published in the last 3 years identified through international databases.

Effects of Surface Protein Adsorption on the Distribution and Retention of Intratumorally Administered Gold Nanoparticles.

The heterogeneous distribution of delivery or treatment modalities within the tumor mass is a crucial limiting factor for a vast range of theranostic applications. Understanding the interactions between a nanomaterial and the tumor microenvironment will help to overcome challenges associated with tumor heterogeneity, as well as the clinical translation of nanotheranostic materials. This study aims to evaluate the influence of protein surface adsorption on gold nanoparticle (GNP) biodistribution using high-resolution computed tomography (CT) preclinical imaging in C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors. LLC provides a valuable model for study due to its highly heterogenous nature, which makes drug delivery to the tumor challenging. By controlling the adsorption of proteins on the GNP surface, we hypothesize that we can influence the intratumoral distribution pattern and particle retention. We performed an in vitro study to evaluate the uptake of GNPs by LLC cells and an in vivo study to assess and quantify the GNP biodistribution by injecting concentrated GNPs citrate-stabilized or passivated with bovine serum albumin (BSA) intratumorally into LLC solid tumors. Quantitative CT and inductively coupled plasma optical emission spectrometry (ICP-OES) results both confirm the presence of particles in the tumor 9 days post-injection (n = 8 mice/group). A significant difference is highlighted between citrate-GNP and BSA-GNP groups (** p < 0.005, Tukey's multiple comparisons test), confirming that the protein corona of GNPs modifies intratumoral distribution and retention of the particles. In conclusion, our investigations show that the surface passivation of GNPs influences the mechanism of cellular uptake and intratumoral distribution in vivo, highlighting the spatial heterogeneity of the solid tumor.

Pattern-Reversal Visual Evoked Potential on Smart Glasses.

OBJECTIVE: This paper presents an integrated device, based on smart glasses, for the pattern-reversal visual evoked potential (PR-VEP) clinical test. METHODS: Smart glasses are used to generate the checkerboard changing pattern, with its related red fixation point through an Android application. Electroencephalographic signals, for monitoring the stimulus generated by PR-VEP, were amplified close to the scalp and then transmitted wirelessly to a PC. A MATLAB real-time algorithm processed the incoming signals to extract the final PR-VEP signal. METHODS: In total, 40 eyes (from 20 subjects, 12 males and 8 females between 24 and 28 years old) were tested and results were compared, with a commercial device for VEP clinical exam, to test the reproducibility and the efficacy of the proposed solution. RESULTS: PR-VEPs generated by smart glasses showed typical triphasic waveforms: We observed promising results and components in moderate agreement with those obtained using commercial PR-VEP recorder, with potential for improvements after further refinement works. SIGNIFICANCE: The proposed device leads the way for a portable and low-cost solution.