Mechanical properties play a critical role in regulating ovarian function, yet their spatial variation within intact tissue remains poorly understood due to the limitations of conventional mechanical testing techniques. Confocal Brillouin microscopy offers a non-contact and label-free approach for mapping mechanical properties of the intact ovarian tissue without perturbing tissue structure. In fresh ovarian tissue, Brillouin images reveal spatial heterogeneity in mechanical properties across follicles, surrounding stroma, and fluid-filled regions, suggesting underlying differences in cellular organization and extracellular matrix composition. These measurements capture both inter- and intra-follicular variations, providing insight into regional differences in mechanical properties within and between follicles. This chapter outlines the principles of Brillouin microscopy and its application to fresh ovarian tissue, highlighting its capability to resolve microscale mechanical variations in situ. This method provides a foundation for understanding the role of mechanical properties in ovarian function, with potential applications in disease models and reproductive health research.

Advanced in vivo imaging modalities, such as magnetic resonance imaging (MRI), are essential research tools to effectively detect tumors in preclinical mouse models. MRI provides detailed anatomical information on tumor location and size. However, this imaging modality is expensive and time-consuming. To overcome this access barrier without compromising imaging quality, a multianimal MRI protocol was implemented. This protocol uses a four-chamber bed insert to obtain high-resolution multianimal anatomical MRI scans within a single acquisition session. Simultaneously imagining multiple mice reduces the time and cost of this procedure. This protocol describes a multianimal MRI workflow designed to increase the efficiency of tumor detection and longitudinal tumor monitoring in a genetically engineered Kras-driven, p53-deleted (KPC) mouse model of pancreatic ductal adenocarcinoma. This well-established clinically relevant KPC model has provided invaluable insight into the molecular mechanisms underlying pancreatic carcinogenesis, tumor progression, and treatment resistance. As proof-of-concept, this protocol is applied to validate the therapeutic benefit of the standard-of-care chemotherapeutic agent gemcitabine in the KPC model. Future applications of this MRI-guided preclinical study design are briefly discussed to evaluate the therapeutic efficacy of combination therapies.

Objective: The implantation of neural probes is critical for precise recording and stimulation of target neurons. However, the implantation of rigid neural probes, involves risks such as tissue damage and foreign body reactions, which can lead to probe failure and irreversible brain injury. Previous studies have employed force response and crack formation during probe insertion to understand the mechanical dynamics of implantation. While many researchers have explored the impact of different probe parameters on the implantation and long-term biological responses, the study of mechanical parameters during insertion remains incomplete. In particular, there are ongoing debates surrounding the quantitative impact of insertion speed on potential tissue damage. This study investigates the interaction effects of insertion speed, insertion depth, and probe geometry parameters on insertion force and insertion-induced damage during probe implantation. Tungsten and boron-doped diamond (BDD) probes were used as representative examples in this research. Peak insertion force and crack size were quantitatively evaluated in both agarose hydrogels and brain tissues, taking insertion direction and relatively wide speed range into account. Our results revealed a previously unreported fourth-order relationship between insertion speed and peak force within a certain insertion depth range, which can be understood as a Taylor-series approximation of the underlying rate- and state-dependent friction behavior within the experimental velocity regime. Meanwhile, crack analysis further showed an inverse relationship between crack size and insertion speed. These findings offer valuable insights into the mechanics of probe implantation with the goal of further improving the safety and reliability of neural implants.

Pancreatic islet transplantation is a promising cell replacement therapy for patients with type 1 diabetes (T1D), an autoimmune disease that destroys insulin-producing islet β cells. However, the shortage of donor pancreatic islets significantly limits the widespread use of this strategy as a routine therapy. Pluripotent stem cell-derived insulin-producing islet organoids present a promising alternative β cell source for T1D patients. One critical challenge is the lack of vascularization in islet organoids, making it essential to investigate vascularized transplantation sites to support their survival. Brown adipose tissue (BAT) is well vascularized and secretes active cytokines, facilitating islet organoid survival. Thus, BAT represents a promising transplantation site for islet organoids, making it an ideal location to support cell replacement therapies and improve treatment approaches for T1D. Here, we describe the methods for transplanting human-induced pluripotent stem cell (iPSC)-derived islet organoids into the BAT of a mouse model.

Background Fat taste impairment has been implicated in visceral lipid accumulation and insulin resistance, with emerging evidence linking it to the oral microbiota. However, the role and mechanisms of the oral microbiota in this process remain unclear.Objective We aimed to explore the manifestations of Prevotella in fat taste, visceral lipid accumulation and insulin sensitivity, as well as to elucidate the mechanism involved.Design We characterized the oral microbiota in humans with fat taste impairment, visceral lipid accumulation and insulin resistance, as well as in catch-up fat rats. Fat taste sensitivity, serum biochemistry and tissue morphology were assessed in rats colonized orally with Prevotella to explore potential mechanisms.Results Reduced fat taste sensitivity correlated with visceral lipid accumulation and insulin resistance in both individuals and rats. Prevotella was enriched in individuals and rats with low fat taste sensitivity. Additionally, rats with visceral lipid accumulation and insulin resistance were associated with lower proliferation in taste buds and inhibition in Hedgehog (Hh) signaling. Prevotella colonization downregulated the Hh signaling, fat taste impairment, visceral lipid accumulation and insulin resistance, whereas Hh pathway agonist supplementation mitigated these effects.Conclusions Oral microbiota and fat taste impairment are associated with visceral lipid accumulation and insulin resistance, and Prevotella may play a vital role in fat taste impairment, visceral lipid accumulation and insulin resistance by downregulating the Hh signaling in taste buds.

The integration of Positron emission tomography (PET) with Magnetic resonance imaging (MRI) combines the functional imaging capabilities of PET with the high-resolution anatomical detail of MRI, creating a synergistic platform for advanced diagnostic imaging and image-guided therapies. Central to the success of this dual-modality system is the development of specialized PET/MRI dual-modality probes, particularly those capable of simultaneous functionality, which present significant technical challenges in synthesis and applications. This review explores the advancements in PET/MRI probe development, summarizes the current applications, and highlights the critical challenges in translating PET/MRI probes from experimental research to clinical applications, offering insights into the future direction of this transformative imaging technology. EVIDENCE LEVEL: 5. TECHNICAL EFFICACY: Stage 1.

Diabetic kidney disease (DKD) has become a major cause of chronic kidney disease and end-stage renal disease. Numerous studies have indicated that exosomal miRNAs play a crucial role in the pathophysiological processes of DKD. We screened differentially expressed miRNAs in urinary exosomes from patients with DKD using the GEO database and performed PCR validation both in patients who were pathologically diagnosed and clinically diagnosed. We assessed the clinical diagnostic value of urinary exosomal miRNAs using ROC curves, analyzed the correlation between miRNAs and clinical indicators, predicted the target genes using the miRTarBase database and explored the potential signaling pathways involved through functional enrichment analysis. Screening results showed that the expression of miR-136-5p was significantly elevated in the DKD group compared to the DM group, with significance maintained in validation samples. The sensitivity and specificity of miR-136-5p for diagnosing DKD were 72.2% and 78.4%, respectively, with an area under the curve of 0.722. Additionally, the expression of miR-136-5p was positively correlated with UACR, urea nitrogen, cystatin C, chronic kidney disease progression risk stratification indicators, and negatively correlated with eGFR. 152 target genes of miR-136-5p were predicted and enriched in 25 pathways, including insulin secretion, cAMP signaling pathway, and sphingolipid signaling pathway.

Microrobots hold immense potential in biomedical applications, including drug delivery, disease diagnostics, and minimally invasive surgeries. However, two key challenges hinder their clinical translation: achieving scalable and precision fabrication, and enabling non-invasive imaging and tracking within deep biological tissues. Magnetic particle imaging (MPI), a cutting-edge imaging modality, addresses these challenges by detecting the magnetization of nanoparticles and visualizing superparamagnetic nanoparticles (SPIONs) with sub-millimeter resolution, free from interference by biological tissues. This capability makes MPI an ideal tool for tracking magnetic microrobots in deep tissue environments. In this study, "TriMag" microrobots are introduced: 3D-printed microrobots with three integrated magnetic functionalities-magnetic actuation, magnetic particle imaging, and magnetic hyperthermia. The TriMag microrobots are fabricated using an innovative method that combines two-photon lithography for 3D printing biocompatible hydrogel structures with in situ chemical reactions to embed the hydrogel scaffold with Fe3O4 nanoparticles for good MPI contrast and CoFe2O4 nanoparticles for efficient magnetothermal heating. This approach enables scalable, precise fabrication of helical magnetic hydrogel microrobots. The resulting TriMag microrobots, with the synergistic effects of Fe3O4 and CoFe2O4 nanoparticles, demonstrate efficient magnetic actuation for controlled movement, precise imaging via MPI for imaging and tracking in biological fluid and organs, including porcine eye and mouse stomach, and magnetothermal heating for tumor ablation in a mouse model. By combining these capabilities, the fabrication and imaging approach provides a robust platform for non-invasive monitoring and manipulation of microrobots for transformative applications in medical treatment and biological research.

Pulmonary fibrosis (PF) is a progressive and chronic lung disease characterized by repeated alveolar epithelial injury that leads to excessive extracellular matrix deposition, resulting in tissue thickening, scarring, and impaired gas exchange, leading to respiratory dysfunction. In the United States, around 50,000 new cases are reported annually, with patients facing serious complications such as pneumothorax, pulmonary hypertension, respiratory failure, and an increased risk of lung cancer. Current therapeutic options are limited in efficacy and primarily aim to slow disease progression. Cell therapy has emerged as a promising intervention, offering the potential to regenerate damaged lung tissue, modulate inflammation, and improve pulmonary function. However, the effectiveness of these therapies depends significantly on the ability to monitor the distribution, survival, and integration of transplanted cells within the host lungs. Magnetic Particle Imaging (MPI) is a novel, non-invasive, preclinical imaging modality that utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as tracers. MPI offers high sensitivity, specificity, and no background signal, allowing for real-time and quantitative tracking of labeled cells in vivo. In this study, we investigated the use of MPI for monitoring human distal lung epithelial progenitor cells transplanted into the lungs of immunocompromised mice. Cells were labeled with varying SPION concentrations to optimize the signal, confirmed by immunostaining and iron quantification. After intratracheal instillation, 2D MPI scans were acquired to track the spatial distribution of transplanted cells. Longitudinal imaging over 2 weeks enabled visualization of cell integration and retention within lung tissue. Successful instillation exhibited MPI signals in both left and right lungs, which decreased (~65%) over time. Mice were subsequently sacrificed for histological validation. This study demonstrates the utility of MPI for noninvasive, longitudinal tracking of cell therapy in pulmonary fibrosis, and pivots around the intricate techniques utilized during the procedures.

In recent years, magnetic particle imaging (MPI) has emerged as a promising imaging technique depicting high sensitivity and spatial resolution. It originated in the early 2000s where it proposed a new approach to challenge the low spatial resolution achieved by using relaxometry in order to measure the magnetic fields. MPI presents 2D and 3D images with high temporal resolution, non-ionizing radiation, and optimal visual contrast due to its lack of background tissue signal. Traditionally, the images were reconstructed by the conversion of signal from the induced voltage by generating system matrix and X-space based methods. Because image reconstruction and analyses play an integral role in obtaining precise information from MPI signals, newer artificial intelligence-based methods are continuously being researched and developed upon. In this work, we summarize and review the significance and employment of machine learning and deep learning models for applications with MPI and the potential they hold for the future. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 1.

Citation: Li S, Dou H, Wang P and Shang H (2024) Editorial: Novel insights into the comorbidities and mortality in patients with diabetes. Front. Endocrinol. 15:1406131. doi: 10.3389/fendo.2024.1406131

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging of the lung is demonstrated. Shape anisotropy proves to be a critical parameter for increasing signal intensity and resolution and exceeding those properties of conventional spherical nanoparticles. The 0D nanoparticles exhibit a 2-fold increase, while the 1D nanorods have a > 5-fold increase in signal intensity when compared to VivoTrax. Newly designed 1D nanorods displayed high signal intensities and excellent resolution in lung images. A spatiotemporal lung imaging study in mice revealed that this tracer offers new opportunities for monitoring disease and guiding intervention.

Background:Transplantation of human-induced pluripotent stem cell (hiPSC)-derived islet organoids is a promising cell replacement therapy for type 1 diabetes (T1D). It is important to improve the efficacy of islet organoids transplantation by identifying new transplantation sites with high vascularization and sufficient accommodation to support graft survival with a high capacity for oxygen delivery.Methods:A human-induced pluripotent stem cell line (hiPSCs-L1) was generated constitutively expressing luciferase. Luciferase-expressing hiPSCs were differentiated into islet organoids. The islet organoids were transplanted into the scapular brown adipose tissue (BAT) of nonobese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice as the BAT group and under the left kidney capsule (KC) of NOD/SCID mice as a control group, respectively. Bioluminescence imaging (BLI) of the organoid grafts was performed on days 1, 7, 14, 28, 35, 42, 49, 56, and 63 posttransplantation.Results:BLI signals were detected in all recipients, including both the BAT and control groups. The BLI signal gradually decreased in both BAT and KC groups. However, the graft BLI signal intensity under the left KC decreased substantially faster than that of the BAT. Furthermore, our data show that islet organoids transplanted into streptozotocin-induced diabetic mice restored normoglycemia. Positron emission tomography/MRI verified that the islet organoids were transplanted at the intended location in these diabetic mice. Immunofluorescence staining revealed the presence of functional organoid grafts, as confirmed by insulin and glucagon staining.Conclusions:Our results demonstrate that BAT is a potentially desirable site for islet organoid transplantation for T1D therapy.

There are limited options for primary prevention of breast cancer (BC). Experimental procedures to locally prevent BC have shown therapeutic efficacy in animal models. To determine the suitability of FDA-approved iodine-containing and various metal-containing (bismuth, gold, iodine, or tantalum) preclinical nanoparticle-based contrast agents for image-guided intraductal (ID) ablative treatment of BC in rodent models, we performed a prospective longitudinal study to determine the imaging performance, local retention and systemic clearance, safety profile, and compatibility with ablative solution of each contrast agent. At least six abdominal mammary glands (>3 female FVB/JN mice and/or Sprague-Dawley rats, 10–11 weeks of age) were intraductally injected with commercially available contrast agents (Omnipaque® 300, Fenestra® VC, MVivoTM Au, MVivoTM BIS) or in-house synthesized tantalum oxide (TaOx) nanoparticles. Contrast agents were administered at stock concentration or diluted in 70% ethanol (EtOH) and up to 1% ethyl cellulose (EC) as gelling agent to assess their compatibility with our image-guided ablative procedure. Mammary glands were serially imaged by microCT for up to 60 days after ID delivery. Imaging data were analyzed by radiologists and deep learning to measure in vivo signal disappearance of contrast agents. Mammary glands and major organs were ultimately collected for histopathological examination. TaOx-containing solutions provided best imaging performance for nitid visualization of ductal tree immediately after infusion, low outward diffusion (<1 day) and high homogeneity. Of all nanoparticles, TaOx had the highest local clearance rate (46% signal decay as stock and 36% as ablative solution 3 days after ID injection) and exhibited low toxicity. TaOx-containing ablative solution with 1% EC caused same percentage of epithelial cell death (88.62% ± 7.70% vs. 76.38% ± 9.99%, p value = 0.089) with similar minimal collateral damage (21.56 ± 5.28% vs. 21.50% ± 7.14%, p value = 0.98) in mouse and rat mammary glands, respectively. In conclusion, TaOx-nanoparticles are a suitable and versatile contrast agent for intraductal imaging and image-guided ablative procedures in rodent models of BC with translational potential to humans.

ObjectiveInsulin plays a central role in the regulation of energy and glucose homeostasis, and insulin resistance (IR) is widely considered as the “common soil” of a cluster of cardiometabolic disorders. Assessment of insulin sensitivity is very important in preventing and treating IR-related disease. This study aims to develop and validate machine learning (ML)-augmented algorithms for insulin sensitivity assessment in the community and primary care settings.MethodsWe analyzed the data of 9358 participants over 40 years old who participated in the population-based cohort of the Hubei center of the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals). Three non-ensemble algorithms and four ensemble algorithms were used to develop the models with 70 non-laboratory variables for the community and 87 (70 non-laboratory and 17 laboratory) variables for the primary care settings to screen the classifier of the state-of-the-art. The models with the best performance were further streamlined using top-ranked 5, 8, 10, 13, 15, and 20 features. Performances of these ML models were evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPR), and the Brier score. The Shapley additive explanation (SHAP) analysis was employed to evaluate the importance of features and interpret the models.ResultsThe LightGBM models developed for the community (AUROC 0.794, AUPR 0.575, Brier score 0.145) and primary care settings (AUROC 0.867, AUPR 0.705, Brier score 0.119) achieved higher performance than the models constructed by the other six algorithms. The streamlined LightGBM models for the community (AUROC 0.791, AUPR 0.563, Brier score 0.146) and primary care settings (AUROC 0.863, AUPR 0.692, Brier score 0.124) using the 20 top-ranked variables also showed excellent performance. SHAP analysis indicated that the top-ranked features included fasting plasma glucose (FPG), waist circumference (WC), body mass index (BMI), triglycerides (TG), gender, waist-to-height ratio (WHtR), the number of daughters born, resting pulse rate (RPR), etc.ConclusionThe ML models using the LightGBM algorithm are efficient to predict insulin sensitivity in the community and primary care settings accurately and might potentially become an efficient and practical tool for insulin sensitivity assessment in these settings.

Supplementary Fig. S1. Viability of 4T1, SUM149PT and SUM159PT breast cancer cells treated with MN-anti-miR10b and low-dose doxorubicin.

Supplementary Fig. S6. Gross anatomical features of mice treated with MN-anti-miR10b and doxorubicin.