bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the Impact of Social Support on Mental Health Among Elderly in West Health Center of Tehran, Iran
Authors:   West Health Center of Tehran, Iran University of Medical Science, Tehran, Iran., Aghajani Tahereh , Solhi Mahnaz ,   School of Public Health, Iran University of Medical Science, Tehran, Iran., Forughan Mahshid ,   University of Social welfare and Rehabilitation, Tehran, Iran., Ezattifard Akram ,   West Health Center of Tehran, Iran University of Medical Science, Tehran, Iran., Ghahremanzadeh Neda ,   School of Public Health, Iran University of Medical Science, Tehran, Iran., Rezaei Fateme ,   Isfahan University of Medical Science, Tehran, Iran., Dargahi Hossein ,   School of Public Health, Health Information Management, Tehran University of Medical Science, Tehran, Iran.
Published: November 2024

Introduction: Increasing of elderly people in all countries, including Iran, is accompanied by economic, social, and healthcare challenges. Therefore, assessing the needs of the elderly is essential in every community. One of the factors affecting the mental health of elderly is the special attention paid to the social support of these people. Therefore, this research was aimed to explore the impact of social support on mental health among elderly in the west health center of Tehran, Iran.
Methodology: This was descriptive- analytical research conducted on over 60 years old elderly covering by west health center of Tehran resident of municipal areas of 9, 18, 21, 22 at 2021-2022. The sample size was assigned by Krejcie & Morgan table including 351 people regarding response rate of 85% completed 300 questionnaires. The research tools were GHQ-28 and social support assessment. The descriptive results showed by descriptive statistics, and analytical results reported by Pearson regression coefficient, linear regression, independent T and K2 by SPSS software version 26 on a significant level of 0.05.
Result: The average of mental health equal 37.5(10.1) among male elderly and 37.1(12) among female elderly and also social support among male elderly equal 47.6(7.8) were and 48.6(7.5) among female were undesired. Also, there was significant and negative regression between mental health and social support of elderly people. Furthermore, with decreased of one- point in the total social support score, the average of mental health well- being is exported to increase by 30% which means that we are going to see reduction in the number of elderly response who have mental health problems.
Conclusion: Increasing social and emotional support for the elderly is a key part of the welfare of this group of people in the community, which showed provided by governments through the support of family, friends, and other means, including welfare, rehabilitation services, financial, and counselling.
Milk production of goats with different tone of the autonomic nervous system
Authors: Boychuk B. I. , Karpovskyi V. I. , Gutyj B. V. , Hryshchuk I. A. , Hryshchuk A. V.
Published: November 2024

The active development of goat breeding is rapidly moving from small enterprises to large farms. This development is ensured by the rapid growth of demand for these products for ordinary consumers and people looking for an alternative to cow's milk. Therefore, a significant amount of effort is being made to improve the yield of dairy products from goats. This is because this farm cannot rapidly increase the number of livestock, and the demand for this product is constantly growing. Our study aimed to establish the dependence of the autonomic nervous system tone on the indicators of goat milk production. To form the experimental groups of animals, a variational pulse oscillometric study was used to calculate the following indicators: mode (Mo), mode amplitude (AMo), variation range (∆x), autonomic rhythm index (ARI), autonomic balance index (ABI), and tension index (TI). Subsequently, three experimental groups of animals were formed according to the tone of autonomic nervous regulation using the Baevsky method: sympathotonics, normotonics, and vagotonics. Statistical analysis of the results and calculation of Student's t-test to establish correlation and one-factor analysis of variance between milk production and autonomic nervous regulation tone were performed using Microsoft Excel. According to the results of the study, it was found that the highest milk production was determined in the experimental group of normotonics 1058 ± 9.76 l/year (P < 0.001), and the lowest in sympathotonics 845.5 ± 27.71 l/year (P < 0.001). Also, according to the initial data's statistical processing results, a correlation was established between milk production indicators and the tone of autonomic nervous regulation. Thus, the experimental group of normotonics had a correlation r = (-0.649) (P < 0.001), sympathotonics r = (-0.572) (P < 0.001), and vagotonics r = 0.865 (P < 0.001), which is confirmed by one - factor analysis of variance.
Distribution of chronic latent gynecological pathologies in dairy cows
Authors: Sidashova S. O. , Gutyj B. V. , Shnaider V. L. , Todoriuk V. B.
Published: November 2024

The purpose of the research and production research in four breeding dairy farms of the industrial type was to establish the prevalence of chronic latent inflammatory processes of the reproductive organs, which lead to the loss of generative resources of dairy breeds of cattle. Analytical, structural-comparative, and statistical methods were used to perform the research tasks. The research data were obtained through a comprehensive examination of cows of the main milking herd (n = 552) and groups of culled cows due to numerous ineffective inseminations (n = 116), namely, ultrasound scanning of the tissues and uterine cavity and differential palpation of the fallopian tubes and gonads. Experimentally under in vivo conditions, it was established that compared to cows of the leading dairy herd in the culled group, the prevalence of symptoms of chronic latent endometritis was 33.93 % higher on average (P < 0.05) with significant fluctuations in different herds (from 12.06 to 67.51 %). A considerable spread of multiorgan gynecological pathology was established, namely the spread of chronic adhesive salpingitis, the symptoms of which in dairy cows were on average 39.40 % (with fluctuations of 7.18–83.65 %), which significantly increased among culled cows: +30, 77 % (in different farms from 52.17 to 90.00 %), which indicated the chronicity of long-term inflammatory processes in the endometrium and the area of the ciliated epithelium of the oviducts, which lead to chronic irreversible infertility (P < 0.01). An innovative methodological approach to improving diagnostics requires the introduction of innovations in the practical training methods of zoo-veterinary specialists and the requirements for preserving the generative and secretory functions of the reproductive organs of cows in gynecological therapy schemes.
Hypocalcaemia in pregnant and lactating goats (distribution, etiology, diagnostic methods)
Authors: Hotsuliak M. M. , Sakhniuk V. V.
Published: November 2024

The article presents the results of studies on the prevalence, etiology, and methods of diagnosing hypocalcemia in pregnant and lactating goats of Zaanen, Alpine, Nubian, and Lamancha dairy breeds of 1–4 years of age, with a productivity of 750–1050 kg per lactation. Subclinical hypocalcemia was diagnosed in 45,3 % of goats, including 44,0 % of lactating goats (75–90 and 120–140 days of gestation) and 46,3 % of lactating animals (0–2; 15–25 and 50–60 days after lambing). Clinically expressed hypocalcaemia was diagnosed in 5,2 % of goats in the first 24–48 hours after lambing. The following clinical signs characterized the subclinical course of hypocalcemia: a) slight depression of the general condition; b) decreased body weight (BCS 1,5–2,0); c) decreased appetite; d) incisor shakiness; e) hypotension of the foregut; f) unsteady gait; g) muscle tremors; h) lactation and isolated cases of mastitis and metritis in lactating goats in the first days after lambing. It has been established that the leading causes of hypocalcemia in goats are, first of all, violations of the feeding regime and diet structure during pregnancy and lactation. The role of the nutritional factor lies in the unbalanced and insufficient feeding of animals, in particular, the deficiency of macro- (Ca, P and their ratio, Mg), microelements (Zn, Cu, I), a pronounced deficiency of vitamins A and D, as well as the lack of motivation and insufficient natural insolation of animals. In addition, goats' diets often noted a lack of metabolic energy, dry matter, crude fat, and a deficiency of readily fermentable sugar and starch carbohydrates. In the studied goats with liver pathology and functional renal failure (hepatorenal syndrome), the development of secondary hypocalcaemia was diagnosed.
DEFINING CORPORATE SOCIAL RESPONSIBILITY (CSR) PRACTICES: A MULTIDIMENSIONAL FRAMEWORK OF COMPLIANCE, STAKEHOLDER ENGAGEMENT, STRATEGIC VALUE, AND CULTURAL SENSITIVITY
Authors:   Sumy National Agrarian University, Zhang Yang
Published: November 2024

Purpose: This study aims to establish a comprehensive framework for defining Corporate Social Responsibility
(CSR) practices, recognizing the multi-layered approaches that companies adopt to meet legal standards, address
stakeholder expectations, create strategic value, and align with cultural norms. The paper explores how distinct CSR
models contribute unique perspectives that shape the broader understanding and implementation of CSR in corporate contexts. Design/methodology/approach: The study synthesizes insights from academic literature, categorizing CSR practices into four core approaches: compliance-oriented, stakeholder-centered, strategic value-driven,
and culturally-embedded. Each model is examined for its defining attributes and practical implications, highlighting
the diversity of CSR practices across industries and cultural contexts. Findings: Results indicate that CSR practices serve different purposes depending on the company’s strategic objectives and socio-cultural setting. Compliance-oriented CSR is reactive and legally driven, primarily focused on regulatory adherence. Stakeholder-centered
CSR emphasizes ethical responsibility to various stakeholders. Strategic value-driven CSR integrates social goals
with business strategy, enhancing corporate reputation and risk management. Lastly, culturally-embedded CSR
reflects local norms and national policies, particularly in non-Western contexts. Research limitations/implications:
This conceptual framework, while broad, may require further empirical validation across specific industries and regions to capture the full extent of CSR practices. Practical implications: Understanding the varied dimensions of
CSR can guide corporations in choosing a balanced approach that aligns with their objectives, stakeholder expectations, and cultural setting. Originality/value: This study provides a holistic view of CSR practices, advocating for
an integrative approach that balances compliance, stakeholder interests, strategic goals, and cultural relevance for
sustainable corporate responsibility.
Descrição epidemiológica dos pacientes com tuberculose pulmonar em hospital pediátrico referência do Sul do Brasil – um estudo retrospectivo de dez anos
Authors: Farias Ana Carolina , Guimarães Arthur Santos , Navarini Izabella Geórgia Formento , Carvalho Emanuela Rocha
Published: November 2024

Este estudo visa descrever as características epidemiológicas dos pacientes com tuberculose pulmonar atendidos em hospital pediátrico referência de Santa Catarina, Brasil, 2011-2022. Tratou-se de estudo observacional e descritivo dos casos de tuberculose pulmonar com dados presentes em prontuário, em que foram analisadas variáveis epidemiológicas e demográficas, com posterior análise descritiva e percentual. Dentre os 42 pacientes incluídos no estudo, houve prevalência do sexo feminino, de cor branca, com idade entre 11 e 15 anos. O caso fonte foi identificado em 71,4% dos casos, com predomínio do contato intradomiciliar. Houve maior número de casos de tuberculose entre pré-adolescentes do sexo feminino, de cor branca com caso fonte identificável.  Logo, são imprescindíveis medidas de saúde pública que visem identificar e tratar precocemente os contatos de pacientes diagnosticados com tuberculose pulmonar.
Multifunctional perfluorocarbon nanoemulsions for cancer therapy and imaging
Authors: Fernandes Donald A. , Fernandes Dennis D. , Li Yuchong , Wang Yan , Zhang Zhenfu , Rousseau Dérick , Gradinaru Claudiu C. , Kolios Michael C.
Published: November 2024

Nanotechnology provides a promising platform for drug-delivery in medicine. Nanostructured materials can be designed with desired superparamagnetic or fluorescent properties in conjunction with biochemically functionalized moieties (i.e., antibodies, peptides, and small molecules) to actively bind to target sites. These multifunctional properties make them suitable agents for multimodal imaging, diagnosis, and therapy. Perfluorohexane nanoemulsions (PFH-NEs) are novel drug-delivery vehicles and contrast agents for ultrasound and photoacoustic imaging of cancer in vivo, offering higher spatial resolution and deeper penetration of tissue when compared to conventional optical techniques. Compared to other theranostic agents, our PFH-NEs are one of the smallest of their kind (<100 nm), exhibit minimal aggregation, long-term stability at physiological conditions, and provide a noninvasive cancer imaging and therapy alternative for patients. Here, we show, using high-resolution imaging and correlative techniques, that our PFH-NEs, when in tandem with silica-coated gold nanoparticles (scAuNPs), can be used as a drug-loaded therapeutic via endocytosis and as a multimodal imaging agent for photoacoustic, ultrasound, and fluorescence imaging of tumor growth.
In Vitro Studies of Multifunctional Perfluorocarbon Nanoemulsions for Cancer Therapy and Imaging
Authors: Fernandes Donald A. , Fernandes Dennis D. , Gradinaru Claudiu
C. , Kolios Michael C.
Published: November 2024

Nanoparticles are attractive agents for cancer therapy because of two unique properties. First is their ability to accumulate in tumor tissue. This is due in part to their unique pharmacokinetics allowing minimal renal filtration and evading uptake by the reticuloendothelial system. Second is their high surface-to-volume ratios for carrying various sensors, therapeutics and targeting species for passive or active targeting of cancer cells.

Perfluorocarbon nanoemulsions are a unique class of theranostic agents which are able to solubilize a wide variety of therapeutic agents, at the same time have optical properties for tumor detection using various imaging modalities. Perfluorocarbon (PFC) nanoemulsions allow for a range of functions in vivo because of their biological inertness, high stability, and reduced cytotoxicity. Like many other nanoparticles, the nanoemulsions can be designed to have various targeting ligands on their surface to direct them to various biomarkers associated with cancer. It can at the same time carry a variety of extrinsic imaging agents such as chromophores for fluorescence imaging or use its intrinsic physical properties such as its density or ability to vaporize upon expansion for ultrasound and photoacoustic imaging. Its phase transition from a liquid droplet to a microbubble can be accomplished by either directly providing energy using acoustic waves or indirectly through the use of optical absorbers (i.e. gold nanoparticles) which can transfer energy as heat to PFC nanodroplets. This work will study the effect of perfluorocarbon nanoemulsions in breast cancer cell lines (i.e. MCF-7, MDA-MB 231) and will quantify nanodroplet and nanoparticle uptake and co-diffusion using various fluorescence techniques (i.e. dual color fluorescence correlation spectroscopy and total internal reflection fluorescence microscopy) to determine their efficacy as theranostic agents.
Label-Free Analysis of Red Blood Cell Storage Lesions Using Imaging Flow Cytometry
Authors: Pinto Ruben N. , Sebastian Joseph A. , J. Parsons Michael , Chang Tim C. , Turner Tracey R. , Acker Jason P. , Kolios Michael C.
Published: November 2024

Deleterious changes, collectively termed as storage lesions, alter the characteristics of red blood cell (RBC) morphology during in vitro storage. Due to gradual loss of cellular membrane, RBCs lose their original biconcave disk shape and begin a process of spherical deformation that is characterized by well-defined morphological criteria. At the spheroechinocyte stage, the structure of RBC is irreversibly damaged and lacks the elasticity necessary to efficiently deliver oxygen. Quantifying the prevalence of spheroechinocytes could provide an important morphological measure of the quality of stored blood products. Unlike the conventional RBC morphology characterization assay involving light microscopy, we introduce a label-free assay using imaging flow cytometry (IFC). The technique captures 100,000 images of a sample and calculates a relative measure of spheroechinocyte population in a fraction of the time required by the conventional method. A comparative method study, measuring a morphological index for 11 RCC units through storage, found that the two techniques measured similar trends with IFC reporting the metric at an average of 3.9% higher. We monitored 18 RCC units between Weeks 1 and 6 of storage and found that the spheroechinocyte population increased by an average of 26.2%. The large (3.5-64.1%) variation between the units' spheroechinocyte population percentage at Week 1 suggests a possible dependence of blood product quality on donor characteristics. Given our method's ability to rapidly monitor large samples and refine morphological characterization beyond conventional methods, we believe our technique offers good potential for studying the underlying relationships between RBC morphology and blood storage lesions. © 2019 International Society for Advancement of Cytometry.
Integrating Therapeutic Ultrasound With Nanosized Drug Delivery Systems in the Battle Against Cancer
Authors: Kashkooli Moradi , Jakhmola Anshuman , A Ferrier Graham , Hornsby Tyler K. , Tavakkoli Jahangir (Jahan) , Kolios Michael C.
Published: November 2024

Controlled, localized, and timely activation of nanosized drug delivery systems (NSDDSs), using an external stimulus such as therapeutic ultrasound (TUS), can improve the efficacy of cancer treatments compared to either conventional chemotherapy methods or passive NSDDSs alone. Specifically, TUS induces thermal and mechanical effects that trigger drug release from NSDDSs and overcomes drug delivery barriers in tumor microenvironments to allow nanoparticle drug carriers to penetrate more deeply into tumor tissue while minimizing side effects. This review highlights recent advancements, contemplates future prospects, and addresses challenges in using TUS-mediated NSDDSs for cancer treatment, encompassing preclinical and clinical applications.
In vivo photoacoustic assessment of the oxygen saturation changes in the human radial artery: a preliminary study associated with age
Authors: Bok Taehoon , Hysi Eno , Kolios Michael C.
Published: November 2024

Significance: We demonstrate the potential of probing the sO2 change under blood flow in vivo using photoacoustic (PA) imaging and sheds light on the complex relationship between RBC aggregation and oxygen delivery.

Aim: To conduct in vivo assessments of the sO2 in the radial artery of healthy volunteers and simultaneously probe the relation between the sO2 and hemodynamic behavior such as red blood cell (RBC) aggregation.

Approach: The effects of PA-based measurements of blood hemodynamics were studied as a function of the subjects' age (20s, 30s, and 40s). The pulsatile blood flow in the human radial artery of 12 healthy subjects was imaged in the 700 to 900 nm optical wavelength range using a linear array-based PA system.

Results: The PA power when blood velocity is minimum (Pamax) was larger than the one attained at maximum blood velocity (Pamin), consistent with predictions based on the cyclical variation of RBC aggregation during pulsatile flow. The difference between Pamin and Pamax at 800 nm (ΔPa800) increased with age (1.7, 2.2, and 2.6 dB for age group of 20s, 30s, and 40s, respectively). The sO2 computed from Pamax was larger than the one from Pamin.

Conclusions: The ΔPa800 increased with participant age. The ΔPa800 metric could be a surrogate of noninvasively monitoring the age-induced changes in RBC aggregation. The sO2 change during a cycle of pulsatile blood flow also increased with age, demonstrating that RBC aggregation can affect the sO2 change.
Photoacoustic Imaging of Cancer Treatment Response: Early Detection of Therapeutic Effect from Thermosensitive Liposomes
Authors: May Jonathan
P. , Hysi Eno , Wirtzfeld Lauren A. , Undzys Elijus , Li Shyh-Dar , Kolios Michael C.
Published: November 2024

Imaging methods capable of indicating the potential for success of an individualized treatment course, during or immediately following the treatment, could improve therapeutic outcomes. Temperature Sensitive Liposomes (TSLs) provide an effective way to deliver chemotherapeutics to a localized tumoral area heated to mild-hyperthermia (HT). The high drug levels reached in the tumor vasculature lead to increased tumor regression via the cascade of events during and immediately following treatment. For a TSL carrying doxorubicin (DOX) these include the rapid and intense exposure of endothelial cells to high drug concentrations, hemorrhage, blood coagulation and vascular shutdown. In this study, ultrasound-guided photoacoustic imaging was used to probe the changes to tumors following treatment with the TSL, HaT-DOX (Heat activated cytoToxic). Levels of oxygen saturation (sO2) were studied in a longitudinal manner, from 30 min pre-treatment to 7 days post-treatment. The efficacious treatments of HT-HaT-DOX were shown to induce a significant drop in sO2 (>10%) as early as 30 min post-treatment that led to tumor regression (in 90% of cases); HT-Saline and non-efficacious HT-HaT-DOX (10% of cases) treatments did not show any significant change in sO2 at these timepoints. The changes in sO2 were further corroborated with histological data, using the vascular and perfusion markers CD31 and FITC-lectin. These results allowed us to further surmise a plausible mechanism of the cellular events taking place in the TSL treated tumor regions over the first 24 hours post-treatment. The potential for using photoacoustic imaging to measure tumor sO2 as a surrogate prognostic marker for predicting therapeutic outcome with a TSL treatment is demonstrated.
Optical coherence tomography spectral analysis for detecting apoptosis in vitro and in vivo
Authors: Farhat Golnaz , Giles Anoja , Kolios Michael C. , Czarnota Gregory J.
Published: November 2024

Apoptosis is a form of programmed cell death characterized by a series of predictable morphological changes at the subcellular level, which modify the light-scattering properties of cells. We present a spectroscopic optical coherence tomography (OCT) technique to detect changes in subcellular morphology related to apoptosis in vitro and in vivo. OCT data were acquired from acute myeloid leukemia (AML) cells treated with cisplatin over a 48-h period. The backscatter spectrum of the OCT signal acquired from the cell samples was characterized by calculating its in vitro integrated backscatter (IB) and spectral slope (SS). The IB increased with treatment duration, while the SS decreased, with the most significant changes occurring after 24 to 48 h of treatment. These changes coincided with striking morphological transformations in the cells and their nuclei. Similar trends in the spectral parameter values were observed in vivo in solid tumors grown from AML cells in mice, which were treated with chemotherapy and radiation. Our results provide a strong foundation from which future experiments may be designed to further understand the effect of cellular morphology and kinetics of apoptosis on the OCT signal and demonstrate the feasibility of using this technique in vivo.
Phase Change Nanoemulsions for Cancer Therapy and Imaging
Authors: Fernandes Donald
A. , Fernandes Dennis D. , Wang Yan J. , Li Yuchong , Gradinaru Claudiu
C. , Rousseau Dérick , Kolios Michael C.
Published: November 2024

Much of the biological therapeutics currently available struggle to function as effective drug delivery vehicles due in part to their poor stability, solubility, and permeability across barriers such as the tight junctions between endothelial cells in tumor vasculature. Given this understanding, there is currently a significant interest in designing nanocarriers (< 100 nm in diameter) which are able to increase the bioavailability of drugs. In particular, much attention has been focused on nanoemulsions whose liposome-like structure protects drugs against physico-chemical and enzymatic degradation and charged surface favors drug adsorption. One novel class of nanoemulsions called perfluorocarbon (PFC) emulsions are of particular interest because they can be used both for delivering drugs and imaging tumors. In this work we show that nanoemulsions with a PFC core and Zonyl FSP surfactant shell can be produced using an oil-in-water technique via sonication. This technique is successful in producing PFC emulsions that are on average 50 nm in diameter with long-term stability at physiological conditions, as determined by Electron Microscopy, Fluorescence Correlation Spectroscopy and Dynamic Light Scattering. Using laser excitation, these nanoemulsions can vaporize into microbubbles in the presence of silica coated gold nanoparticles for efficient drug release and imaging using high contrast imaging modalities such as photoacoustic microscopy. Taken together, the size and stability of these PFC nanodroplets make them cost effective drug delivery vehicles suitable for efficient internalization by cancer cell lines.
The role of primary and secondary delays in the effective resonance frequency of acoustically interacting microbubbles
Authors: Haghi Hossein , Kolios Michael C.
Published: November 2024

Acoustically excited microbubbles (MBs) are known to be nonlinear oscillators with complex dynamics. This has enabled their use in a wide range of applications from medicine to industry and underwater acoustics. To better utilize their potential in applications and possibly invent new ones a comprehensive understanding of their dynamics is required. In this work, we explore the effect of bubble-bubble interactions on the resonance frequency of MB suspensions. MBs oscillate in response to an external acoustic wave and since bubbles in a cluster are at different locations compared to the excitation source, they are excited at different times. In this work we refer to these delays as primary delays. Interactions between the scattered pressure fields from adjacent bubbles have also been shown to alter the dynamics of MBs that exist within clusters. These secondary waves generated by MBs reach MBs in their proximity at different times that depend on their spatial location in the cluster. Here we refer to these delays as secondary delays. Inclusion of the secondary delays modifies the class of the differential equations governing the oscillations of interacting MBs in a cluster from ordinary differential equations to neutral delay differential equations. Previous work has not considered the all the delays associated with the bubble distances when modeling the interactions between bubbles. In this work we investigate the effect of both the primary and secondary delays on the effective resonance frequency of MB clusters. It is shown that primary delays cause spreading the resonance frequency of identical MBs within a range where the closest MB to the acoustic source exhibits the lowest resonance frequency and the furthest MB resonates at the highest frequency. This range has been shown to be up to 0.12 MHz for the examples investigated in this work. The effect of secondary delays is shown to be very significant. In the absence of secondary delays, the ordinary differential equation model predicts a decrease of up to 26% in the resonance frequency of 4 identical interacting MBs as the inter-bubble distances are decreased. However, we show that inclusion of the secondary delays result in the increase of the resonance frequency of MBs if they are situated close to each other. This increase is shown to be significant and for the case of 4 identical interacting MBs we show an increase of 58% in the resonance frequency.
Probing Red Blood Cell Morphology Using High-Frequency Photoacoustics
Authors: Strohm Eric M. , Berndl Elizabeth S. L. , Kolios Michael C.
Published: November 2024

A method that can rapidly quantify variations in the morphology of single red blood cells (RBCs) using light and sound is presented. When irradiated with a laser pulse, an RBC absorbs the optical energy and emits an ultrasonic pressure wave called a photoacoustic wave. The power spectrum of the resulting photoacoustic wave contains distinctive features that can be used to identify the RBC size and morphology. When particles 5-10 μm in diameter (such as RBCs) are probed with high-frequency photoacoustics, unique periodically varying minima and maxima occur throughout the photoacoustic signal power spectrum at frequencies >100 MHz. The location and distance between spectral minima scale with the size and morphology of the RBC; these shifts can be used to quantify small changes in the morphology of RBCs. Morphological deviations from the normal biconcave RBC shape are commonly associated with disease or infection. Using a single wide-bandwidth transducer sensitive to frequencies between 100 and 500 MHz, we were able to differentiate healthy RBCs from irregularly shaped RBCs (such as echinocytes, spherocytes, and swollen RBCs) with high confidence using a sample size of just 21 RBCs. As each measurement takes only seconds, these methods could eventually be translated to an automated device for rapid characterization of RBC morphology and deployed in a clinical setting to help diagnose RBC pathology.
Fluence-matching technique using photoacoustic radiofrequency spectra for improving estimates of oxygen saturation
Authors: Fadhel Muhannad N. , Hysi Eno , Assi Hisham , Kolios Michael C.
Published: November 2024

Photoacoustic (PA) signals encode information about the optical absorption and spatial distribution of absorbing chromophores as well as the light distribution in the medium. The wavelength dependence of the latter affects the accuracy in chromophore quantification, including estimations of oxygen saturation (sO2) with depth. We propose the use of the ratio of the PA radiofrequency (RF) spectral slopes (SS) at different optical wavelengths to generate frequency filters which can be used to match the fluence profiles across separate images generated with different optical wavelengths.

Proof-of-principle experiments were carried on a plastic tube with blood of a known oxygenation inserted into a porcine tissue. The algorithm was tested in-vivo in the hind leg of six CD1 mice, each under three different breathing conditions (100 % O2, room air and 100 % CO2). Imaging was done using the VevoLAZR system at the wavelengths 720 and 870 nm. The SS was calculated from the linear fit of the ratio of the photoacoustic RF power spectra at the two wavelengths. An ultrasound frequency filter was designed and applied to each segmented PA signal in the frequency domain and inversely transformed into the time domain to correct for the differences in the fluence profiles at both wavelengths. Linear spectral unmixing was used to estimate sO2 before and after applying the ultrasound frequency filter.

The estimated blood sO2 in the plastic tube for the porcine tissue experiment improved by 10.3% after applying the frequency filter when compared to the sO2 measured by a blood gas analyzer. For the in-vivo mouse experiments, the applied sO2 correction was 2.67, 1.33 and -3.33% for every mm of muscle tissue for mice breathing 100% O2, room air and 100% CO2, respectively. The approach presented here provides a new approach for fluence matching that can potentially improve the accuracy of sO2 estimates by removing the fluence depth dependence at different optical wavelengths.
The dance of the nanobubbles: detecting acoustic backscatter from sub-micron bubbles using ultra-high frequency acoustic microscopy
Authors: Moore Michael
J. , Bodera Filip , Hernandez Christopher , Rostam Shirazi Niloufar , Abenojar Eric , Exner Agata A. , Kolios Michael C.
Published: November 2024

Nanobubbles have gained attention for their use as highly stable ultrasound (US) contrast agents, but assessment of individual nanobubble size remains a challenge. Current sizing techniques require either extensive sample preparation or depend on assumed values of nanobubble density that are not well characterized. An US based approach would be desirable; however, probing individual nanobubbles using US transducers at clinical frequencies is not feasible due to the comparatively long acoustic wavelengths employed. Here we present a technique which can be used to estimate nano- or microbubble size by virtue of the amount of motion detected in an M-Mode image acquired using an acoustic microscope equipped with a 200 MHz transducer. A sample of a bubble-containing solution is incorporated into a phantom composed of molten agarose. The solidified agarose gel contains pores with well-defined sizes dictated by the agarose concentration. Bubbles in the gel matrix that are smaller in diameter than the gel pore size are capable of undergoing stochastic motion which manifests as intensity fluctuations in M-Mode images. Conversely, bubbles which are larger than the agarose pores become trapped and produce static M-Mode intensity patterns. In this study, agarose gels with concentrations ranging from 0.25% to 1.25% (mean pore sizes ranging from 2.68 μm to 0.34 μm) were loaded with either nanobubbles (mean diameter 0.326 μm) or microbubbles (mean diameter 2.71 μm) and imaged at 200 MHz. In the nanobubble loaded gels, M-Mode fluctuations were clearly visible up to a gel concentration of 1% (pore size of 0.39 μm). In contrast, the microbubble loaded gels exhibited minimal M-Mode fluctuation even at agarose concentrations of 0.25% (2.68 μm pore size). Autocorrelation curves generated from the M-Mode data demonstrated a clear trend of curve flattening (loss of motion) when the pore size was comparable to mean bubble diameter, indicating that individual bubbles trapped in the agarose pores are the main source of acoustic backscatter. In the future, decay parameters extracted from the autocorrelation curves could potentially be used as indicators of mean bubble diameter for bubble populations of unknown size.
Ultrasound-mediated nano-sized drug delivery systems for cancer treatment: Multi-scale and multi-physics computational modeling
Authors: Moradi Kashkooli Farshad , Hornsby Tyler K. , Kolios Michael C. , Tavakkoli Jahangir (Jahan)
Published: November 2024

Computational modeling enables researchers to study and understand various complex biological phenomena in anticancer drug delivery systems (DDSs), especially nano-sized DDSs (NSDDSs). The combination of NSDDSs and therapeutic ultrasound (TUS), that is, focused ultrasound and low-intensity pulsed ultrasound, has made significant progress in recent years, opening many opportunities for cancer treatment. Multiple parameters require tuning and optimization to develop effective DDSs, such as NSDDSs, in which mathematical modeling can prove advantageous. In silico computational modeling of ultrasound-responsive DDS typically involves a complex framework of acoustic interactions, heat transfer, drug release from nanoparticles, fluid flow, mass transport, and pharmacodynamic governing equations. Owing to the rapid development of computational tools, modeling the different phenomena in multi-scale complex problems involved in drug delivery to tumors has become possible. In the present study, we present an in-depth review of recent advances in the mathematical modeling of TUS-mediated DDSs for cancer treatment. A detailed discussion is also provided on applying these computational models to improve the clinical translation for applications in cancer treatment. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Sink or float? Characterization of shell-stabilized bulk nanobubbles using a resonant mass measurement technique
Authors: Hernandez Christopher , Abenojar Eric C. , Hadley Judith , de Leon Al Christopher , Coyne Robert , Perera Reshani , Gopalakrishnan Ramamurthy , Basilion James P. , Kolios Michael C. , Exner Agata A.
Published: November 2024

Nano-sized shell-stabilized gas bubbles have applications in various fields ranging from environmental science to biomedical engineering. A resonant mass measurement (RMM) technique is demonstrated here as a new and only method capable of simultaneously measuring the size and concentration of buoyant and non-buoyant particles in a nanobubble sample used as a next-generation ultrasound contrast agent.
Anti-HER2 PLGA-PEG polymer nanoparticle containing gold nanorods and paclitaxel for laser-activated breast cancer detection and therapy
Authors: Wang Yanjie , Pasternak Maurice , Sathiyamoorthy Krishnan , Kolios Michael C.
Published: November 2024

Phase-transition nanoparticles have been identified as effective theragnostic, anti-cancer agents. However, non-selective delivery of these agents results in inaccurate diagnosis and insufficient treatment. In this study, we report on the development of targeted phase-transition polymeric nanoparticles (NPs) for the imaging and treatment of breast cancer cell lines over-expressing human epidermal growth factor receptor 2 (HER2). These NPs contain a perfluorohexane liquid interior and gold nanorods (GNRs) stabilized by biodegradable and biocompatible copolymer PLGA-PEG. Water-insoluble therapeutic drug Paclitaxel (PAC) and fluorescent dye were encapsulated into the PLGA shell. The NP surfaces were conjugated to HER2-binding agent, Herceptin, to actively target HER2-positive cancer cells. We evaluated the potential of using these NPs as a photoacoustic contrast agent. The efficacy of cancer cell treatment by laser-induced vaporization and stimulated drug release were also investigated. The results showed that our synthesized PLGA-PEG-GNRs (mean diameter 285 ± 29 nm) actively targeted HER2 positive cells with high efficacy. The laser-induced vaporization caused more damage to the targeted cells versus PAC-only and negative controls. This agent may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer.
Structurally random Fourier domain compressive sampling and frequency domain beamforming for ultrasound imaging
Authors: Foroozan Foroohar , Yousefi Rozhin , Sadeghi Parastoo , Kolios Michael C.
Published: November 2024

Advances in ultrasound technology have fueled the emergence of Point-Of-Care Ultrasound (PoCU) imaging, including improved ease-of-use, superior image quality, and lower cost ultrasound. One of the approaches that can make the adoption of PoCU universal is to make the data acquisition module as simple as a "stethoscope" while further processing and image construction can be done using cloud-based processors. Toward this goal, we use Structurally Random Matrices (SRM) for compressive sensing of ultrasound data, Fourier sparsifying matrix for recovery in 1D, and frequency domain approach for 2D ultrasound image reconstruction. This approach is demonstrated through wire phantom and in vivo carotid arteries data from ultrasound system using 25%, 12.5%, and 6.25% of the full data rate and ultrasound images of similar perceived quality quantified by Structural Similarity Index Metric (SSIM).
Properties of cells through life and death - an acoustic microscopy investigation
Authors: M Pasternak Maurice , Strohm Eric M. , Berndl Elizabeth SL , Kolios Michael C.
Published: November 2024

Current methods to evaluate the status of a cell are largely focused on fluorescent identification of molecular biomarkers. The invasive nature of these methods - requiring either fixation, chemical dyes, genetic alteration, or a combination of these - prevents subsequent analysis of samples. In light of this limitation, studies have considered the use of physical markers to differentiate cell stages. Acoustic microscopy is an ultrahigh frequency (>100 MHz) ultrasound technology that can be used to calculate the mechanical and physical properties of biological cells in real-time, thereby evaluating cell stage in live cells without invasive biomarker evaluation. Using acoustic microscopy, MCF-7 human breast adenocarcinoma cells within the G1, G2, and metaphase phases of the proliferative cell cycle, in addition to early and late programmed cell death, were examined. Physical properties calculated include the cell height, sound speed, acoustic impedance, cell density, adiabatic bulk modulus, and the ultrasonic attenuation. A total of 290 cells were measured, 58 from each cell phase, assessed using fluorescent and phase contrast microscopy. Cells actively progressing from G1 to metaphase were marked by a 28% decrease in attenuation, in contrast to the induction of apoptosis from G1, which was marked by a significant 81% increase in attenuation. Furthermore late apoptotic cells separated into 2 distinct groups based on ultrasound attenuation, suggesting that presently-unidentified sub-stages may exist within late apoptosis. A methodology has been implemented for the identification of cell stages without the use of chemical dyes, fixation, or genetic manipulation.
Pickering Bubbles as Dual-Modality Ultrasound and Photoacoustic Contrast Agents
Authors: De Leon Al , Wei Peiran , Bordera Filip , Wegierak Dana , McMillen Madelyn , Yan David , Hemmingsen Christina , Kolios Michael C. , Pentzer Emily B. , Exner Agata A.
Published: November 2024

Microbubbles (MBs) stabilized by particle surfactants (i.e., Pickering bubbles) have better thermodynamic stability compared to MBs stabilized by small molecules as a result of steric hindrance against coalescence, higher diffusion resistance, and higher particle desorption energy. In addition, the use of particles to stabilize MBs that are typically used as an ultrasound (US) contrast agent can also introduce photoacoustic (PA) properties, thus enabling a highly effective dual-modality US and PA contrast agent. Here, we report the use of partially reduced and functionalized graphene oxide as the sole surfactant to stabilize perfluorocarbon gas bubbles in the preparation of a dual-modality US and PA agent, with high contrast in both imaging modes and without the need for small-molecule or polymer additives. This approach offers an increase in loading of the PA agent without destabilization and increased thickness of the MB shell compared to traditional systems, in which the focus is on adding a PA agent to existing MB formulations.
Pharmacokinetic Modeling of the Second-Wave Phenomenon in Nanobubble-Based Contrast-Enhanced Ultrasound
Authors: Chen Chuan , Perera Reshani , Kolios Michael C. , Wijkstra Hessel , Exner Agata A. , Mischi Massimo , Turco Simona
Published: November 2024

With a typical 100-500 nm diameter, nanobubbles are a promising new-generation ultrasound contrast agent that paves ways for several applications, such as efficient drug delivery, molecular imaging, and assessment of vascular permeability. Due to their unique physical properties, nanobubbles exhibit distinct in vivo pharmacokinetics. We have shown that the first pass of the nanobubble bolus is usually accompanied by the appearance of a second bolus (wave) within a time range of about 15 minutes. Such phenomenon, to the best of our knowledge, has never been observed with conventional microbubbles and smaller molecular contrast agents used in MRI and CT. In a previous study, we showed the potential of this phenomenon in supporting cancer diagnosis. This study focuses on developing a new compartmental pharmacokinetic model that can be used to interpret the second-wave phenomenon. With this model, we can analyze more in-depth the roles of several physiological factors affecting the characteristics of the second-wave phenomenon.
Pharmacokinetic modeling of PSMA-targeted nanobubbles for quantification of extravasation and binding in mice models of prostate cancer
Authors: Chen Chuan , Perera Reshani , Kolios Michael C. , Wijkstra Hessel , Mischi Massimo , Exner Agata A. , Turco Simona
Published: November 2024

Purpose

Contrast-enhanced ultrasound (CEUS) by injection of microbubbles (MBs) has shown promise as a cost-effective imaging modality for prostate cancer (PCa) detection. More recently, nanobubbles (NBs) have been proposed as novel ultrasound contrast agents. Unlike MBs, which are intravascular ultrasound contrast agents, the smaller diameter of NBs allows them to cross the vessel wall and target specific receptors on cancer cells such as the prostate-specific membrane antigen (PSMA). It has been demonstrated that PSMA-targeted NBs can bind to the receptors of PCa cells and show a prolonged retention effect in dual-tumor mice models. However, the analysis of the prolonged retention effect has so far been limited to qualitative or semi-quantitative approaches.

Methods

This work introduces two pharmacokinetics models for quantitative analysis of time–intensity curves (TICs) obtained from the CEUS loops. The first model is based on describing the vascular input by the modified local density random walk (mLDRW) model and independently interprets TICs from each tumor lesion. Differently, the second model is based on the reference-tissue model, previously proposed in the context of nuclear imaging, and describes the binding kinetics of an indicator in a target tissue by using a reference tissue where binding does not occur.

Results

Our results show that four estimated parameters, β, β/λ, β+/β−, for the mLDRW-input model, and γ for the reference-based model, were significantly different (p-value <0.05) between free NBs and PSMA-NBs. These parameters estimated by the two models demonstrate different behaviors between PSMA-targeted and free NBs.

Conclusions

These promising results encourage further quantitative analysis of targeted NBs for improved cancer diagnostics and characterization.
Laser-Activatible PLGA Microparticles for Image-Guided Cancer Therapy In Vivo
Authors: Sun Yang , Wang Yanjie , Niu Chengcheng , Strohm Eric M. , Zheng Yuanyi , Ran Haitao , Huang Rongzhong , Zhou Di , Gong Yuping , Wang Zhigang , Wang Dong , Kolios Michael C.
Published: November 2024

Poly(lactide-co-glycolic acid) (PLGA) particles are biocompatible and bio­degradable, and can be used as a carrier for various chemotherapeutic drugs, imaging agents and targeting moieties. Micrometer-sized PLGA particles were synthesized with gold nanoparticles and DiI dye within the PLGA shell, and perfluorohexane liquid (PFH) in the core. Upon laser irradiation, the PLGA shell absorbs the laser energy, activating the liquid core (liquid conversion to gas). The rapidly expanding gas is expelled from the particle, resulting in a microbubble; this violent process can cause damage to cells and tissue. Studies using cell cultures show that PLGA particles phagocytosed by single cells are consistently vaporized by laser energies of 90 mJ cm−2, resulting in cell destruction. Rabbits with metastasized squamous carcinoma in the lymph nodes are then used to evaluate the anti-cancer effects of these particles in the lymph nodes. After percutaneous injection of the particles and upon laser irradiation, through the process of optical droplet vaporization, ultrasound imaging shows a significant increase in contrast in comparison to the control. Histology and electron microscopy confirm damage with disrupted cells throughout the lymph nodes, which slows the tumor growth rate. This study shows that PLGA particles containing PFC liquids can be used as theranostic agents in vivo.