18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET), combined with compartmental modeling, is a powerful non-invasive imaging method for assessing cellular metabolism. However, classical two- and three-tissue compartment models assume homogeneous [18F]FDG distribution within the tissue, which needs justification, and the definition and interpretation of rate constants across these models is not always consistent. To address these issues, we develop a finite difference solver to simulate [18F]FDG transport and metabolism within a 1 mm3 tissue volume, representing the smallest volume resolvable by PET. Our simulations reveal sub-millimeter heterogeneity in [18F]FDG distribution and show that the measured PET signal is dependent not only on cellular metabolic activity but also on interstitial [18F]FDG diffusivity, vascular permeability, and vascular architecture. We further demonstrate that our finite-difference simulation reduces to a three-tissue compartment model when interstitial [18F]FDG concentration is homogeneous. Furthermore, this simplified model itself reduces to the two-tissue compartment model when vascular permeability is sufficiently high. This work quantitatively links vascular permeability, vascular architecture, cellular uptake kinetics, [18F]FDG diffusivity, and acquisition time. It also unifies the two- and three-tissue compartment models and identifies their applicable regimes. These findings deepen our understanding of [18F]FDG transport kinetics and enhance the interpretability of dynamic [18F]FDG-PET imaging.

Abstract Gadolinium-based nanoparticles (GdNP) are sub-5 nm particles designed for radiosensitization and MRI contrast enhancement. The high atomic number of Gd (Z = 64) enables efficient X-ray absorption and dose deposition within tumors, with tumor accumulation facilitated by the enhanced permeability and retention effect. Previous clinical trials have provided preliminary evidence for the safety and potential therapeutic benefit of intravenous GdNP in patients with cervical cancer and brain metastases. To improve tumor specificity, we conjugated GdNP with pH-low insertion peptide (pHLIP), which targets the acidic tumor microenvironment through pH-dependent membrane insertion. Previous work demonstrated that pHLIP conjugated to GdNP enhanced gadolinium uptake and radiosensitization in vitro. In vitro experiments were performed with cultured A549 human lung adenocarcinoma cells at pH 6.2 (tumor-like) and pH 7.4 (physiologic) conditions. Clonogenic assays and ICP-MS analysis revealed that while pHLIP-GdNP (0.17 mM dose) did not significantly alter cell survival, it increased intracellular gadolinium levels by approximately 18-fold under acidic conditions compared to unconjugated GdNP. In vivo, mice bearing subcutaneously implanted A549 tumors received 10 Gy X-ray irradiation with or without unconjugated GdNP or pHLIP-GdNP pretreatment (300 mg/kg; n = 7 mice/group). All irradiated groups exhibited significant tumor growth delay compared to controls (P < 0.013), but no additional radiosensitization was observed in the nanoparticle-treated cohorts, despite Gd accumulation in the tumor. MRI T1 mapping demonstrated shortened T1 relaxation times following GdNP administration, with greater reduction following pHLIP-GdNP injection, indicating enhanced contrast agent delivery. These findings suggest that pHLIP conjugation improves gadolinium uptake and MRI visibility but does not enhance radiotherapeutic efficacy under current conditions. Departing from previous work, this study used a simpler covalent bond to conjugate pHLIP to GdNP rather than a disulfide bridge, which may explain the decreased efficacy. Reintroducing the disulfide linkage might be critical, as it allows the conjugate to remain stable in circulation while releasing nanoparticle cargo upon insertion into acidic tumor cells, potentially increasing therapeutic efficacy. Citation Format: Jessica Wen, Yuwei Xue, Wu Liu, Guillem Pratx, . pH-targeted gadolinium-based nanoparticles for enhanced radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5815.

This report summarizes changes in federal research funding to the medical physics community between FY24 and FY25. By linking the AAPM membership database with NIH RePORTER records, we quantified the distribution of NIH funding for projects led by AAPM researchers. Although total NIH funding to AAPM members remained relatively stable across the two years, the composition of that funding shifted substantially. Competing (new and renewal) awards declined 50%, driven largely by an 80% collapse in new R01 grants from the National Cancer Institute (NCI). In contrast, noncompeting continuation awards increased by 10%, following a shift in how NIH funds multi-year projects. These changes occurred in the context of widespread disruptions to NIH review and grantmaking, including delayed study sections and more stringent administrative requirements. Federal funding is essential to sustaining innovation, supporting early-stage investigators, and ensuring that patients receive the best possible care. The trends identified here raise concerns about the long-term vitality and stability of the medical physics research pipeline.

Efficient and reproducible intracellular delivery is critical for manufacturing next generation cell therapies. Mechanoporation employs mechanical forces, including shear loading, adhesion, and compressive strain, to transiently permeabilize cell membranes and enable cargo transport. However, the influence of microsecond-scale unsteady forces and the origins of variability in delivery and viability remain insufficiently characterized. Here, we performed a parametric investigation of microfluidic mechanoporation using parallelized channel designs of varied widths to systematically modulate pre-compression shear loading and strain rates under constant volumetric flow. Narrow channels were found to promote a more uniform pre-constriction loading and compressive dynamics, leading to improved reproducibility of delivery outcomes. High-speed video analysis revealed greater cell focusing and computational fluid dynamics (CFD) confirmed higher pre-constriction shear loading rates and higher asymmetric biaxial forces prior to ridges, yielding a substantial improvement in delivery efficiency in both adherent B16F10 melanoma cells and suspended T-cells. Modulating cell-surface adhesion by adjusting surface chemistry showed that adhesive coatings slightly increase delivery efficiency at the expense of viability. Changing cell stiffness with pharmacological softening caused a decline in delivery efficiency. These trends indicate that mechanoporation outcomes are governed more strongly by the kinetics of loading dictated by fluid-driven acceleration and strain rate rather than by absolute strain or adhesion magnitude. Principal component and multivariate analyses identified two significant predictors of delivery and viability: strain rate and Basset-Boussinesq history (BBH) forces. Both predictors were consistently elevated in narrow multichannel architectures that showed higher delivery and lower viability. Together, these findings demonstrate that narrow channel designs establish a geometry-driven acceleration regime characterized by elevated strain rates and BBH forces that enhances delivery efficiency while imposing a viability tradeoff.

Thermally activated delayed fluorescence (TADF) materials possess exceptional photophysical properties. Organic scintillators utilizing TADF materials have shown great promise for applications requiring efficient radio-luminescence, owing to their high quantum efficiency and tunable emission properties. Previous studies demonstrated that polymer dots (P-dots) doped with TADF materials exhibit radio-luminescence under hard X-ray and electron beam excitation. However, the TADF materials used in these experiments were limited to limited color options, restricting their utility and hindering the exploration of multicolor radio-luminescence necessary for advanced applications. In this study, we successfully achieved multicolor radio-luminescence-blue, yellow, and red-by developing P-dots doped with TADF materials that emit across the visible spectrum. This breakthrough was demonstrated under excitation by hard X-rays, gamma rays, and electron beams. The ability to realize multicolor radio-luminescence is crucial, as it enables enhanced spatial and spectral resolution, which is vital for applications such as high-precision bio-imaging and multimodal sensing.

Replicating the in vitro properties of tissue barriers-such as the blood-brain barrier, gut, skin, lung, kidney, retina, nasal epithelium, and placenta-is crucial for many applications, including drug screening, studying molecular transport, drug delivery, and disease modeling in preclinical studies. Organ-on-a-chip (OoC) platforms are advanced three-dimensional (3D) in vitro models that aim to replicate various aspects of organ functionality within microfluidic systems by providing microenvironments akin to native tissue. When used to model the interface between two different tissue compartments, OoC technology offers a promising platform for more accurately replicating the physiology and pathophysiology of various tissue barriers in the body. This review focuses on the state-of-the-art biomimetic tissue barrier models, ranging from two-channel tissue barrier-on-a-chip systems with a thin porous membrane to hydrogel-based membrane models. Specifically, it explores the engineering of tissue barrier-on-a-chip platforms, highlighting various fabrication techniques for microfluidic chips and membranes, as well as methods for functional characterization of the engineered tissue barriers. Additionally, we discuss the development of organ-specific barrier models and multi-organ-on-a-chip systems for studying inter-organ communication. Finally, we highlight the current challenges in the field and future directions in advancing tissue barrier modeling using OoC technology.

Compartment models are widely used in fields such as epidemiology and biomedicine to describe the exchange of uniformly distributed materials between interconnected compartments. However, their application in biological fluids is limited by the assumption of infinitely large diffusivity, especially in environments such as tumors or subcutaneous tissue, where diffusion is considerably lower. To address this, we develop a diffusion-aware compartment model that maintains the simplicity of traditional compartment models while offering greater accuracy. We conducted experiments on the uptake of ^{18}F-fluorodeoxyglucose (FDG), a radionuclide, by cells grown in culture plates and found a good agreement between the measured and predicted cellular radioactivity. We identify two critical dimensionless parameters that compare the amount of FDG (i) replenished by diffusion and (ii) available in the culture medium to the amount of FDG taken up by cells. We demonstrate that the diffusion-aware compartment model reduces to the three-compartment model when FDG diffusion is fast relative to cellular uptake, and it further simplifies to the two-compartment model when sufficient FDG is available in the culture medium. The semianalytic solutions of the diffusion-aware compartment model can be easily extended to study other scenarios, such as drug transport and bubble growth dynamics.

Senescent cells promote osteoarthritis progression through the secretion of inflammatory mediators. Preclinical studies have identified senescence-associated beta-galactosidase (β-gal) as a biomarker of senescence, but in vivo detection remains challenging. Here, we evaluated whether a β-gal responsive gadolinium (Gd) chelate can non-invasively detect β-gal expressing senescent cells with standard clinical magnetic resonance imaging (MRI) technology in vitro, ex vivo, and in vivo in porcine joints. In vitro studies showed that senescent mesenchymal stromal cells (MSCs) exhibited significant MRI signal enhancement upon incubation with the β-gal responsive Gd-chelate compared to viable control cells. In vivo, intraarticular injection of the probe into pig knee joints revealed its retention and activation by senescent cells in cartilage defects, evidenced by a significant increase in R1 relaxation rate. MRI-based senescent cell detection holds promise for identifying patients amenable to senolytic therapies, tailoring treatment plans, and monitoring therapy response in real-time.

Most solid tumors contain regions of hypoxia that pose a significant challenge to the efficacy of radiation therapy. This study introduces a novel 3D lung tumor-on-a-chip (ToC) model designed to replicate the hypoxic tumor microenvironment in vitro while also providing a platform for clinically relevant interventions such as radiotherapy and positron emission tomography (PET) imaging. To simulate the heterogeneous oxygen distribution found in tumors, the ToC model incorporates an oxygen gradient achieved through a straightforward chemical oxygen scavenging system. A unique innovation of this device is the integration of a thin scintillator plate, which enables high-resolution radioluminescence microscopy imaging of tumor metabolism under hypoxia and normoxia conditions using clinically approved PET tracers such as fluorodeoxyglucose (FDG). The response of this hypoxic model to radiation therapy (10 Gy X-ray) demonstrated ∼4-fold higher radioresistance compared to the normoxic ToC model, as assessed by colony formation potential. Additionally, DNA damage observed in the normoxic ToC model was ∼5-fold higher than that in the hypoxic model. Furthermore, the metabolic consumption of glucose was found to mirror the localization of hypoxia, validating the use of this biomarker for planning radiation therapy. The integration of high-resolution radionuclide imaging within ToC models enables on-chip PET imaging and facilitates oncology research and discovery, offering innovative capabilities for the preclinical testing of novel cancer therapies in a clinically relevant environment.

Radiation therapy (RT) precisely targets tumors with ionizing radiation, aiming to achieve local control while minimizing collateral damage to surrounding healthy tissues. Radiation research is often carried out in animal models, but these suffer from ethical issues, high cost of operation, low throughput, and low correlation to responses in humans. The advent of microfluidic organ-on-a-chip (OoC) technology offers a promising alternative to precisely and reproducibly model the physiology of different tissues in a laboratory setting. Furthermore, organ-on-a-chip models can be constructed from patient-specific tissues to tailor therapies while enabling fine control over relevant microenvironmental factors. In this review, we highlight emerging research at the intersection of radiation biology and microphysiological models, with a focus on the unique capabilities enabled by these advanced technologies.

Nanoparticles are highly efficient vectors for ferrying contrast agents across cell membranes, enabling ultra-sensitive in vivo tracking of single cells with positron emission tomography (PET). However, this approach must be fully characterized and understood before it can be reliably implemented for routine applications. We developed a Langmuir adsorption model that accurately describes the process of labeling mesoporous silica nanoparticles (MSNP) with 68Ga. We compared the binding efficiency of three different nanoparticle systems by fitting the model to experimental data. We then chose the MSNP with the highest affinity for 68Ga to study uptake and efflux kinetics in cancer cells. After intracardiac injection of 50–100 cells in mice, PET imaging was performed to test the effectiveness of cellular radiolabeling. We found that highly porous mesoporous nanoparticles (d = 100 nm) with MCM-41 pore structures can achieve radiolabeling efficiency > 30 GBq/mg using 68Ga, without the need for any chelator. These 68Ga conjugated particles showed strong serum stability in vitro. In mice, the 68Ga-MSNPs predominantly accumulated in the liver with a high signal-to-background ratio and no bladder signal, indicating excellent stability of the labeled nanoparticles in vivo. Additionally, these MSNPs were efficiently taken up by B16F10 and MDA-MB-231 cancer cells, as confirmed by confocal imaging, flow cytometry analysis, and gamma counting. Finally, cardiac injection of < 100 68Ga-MSNP-labeled cells allowed PET/CT tracking of these cells in various organs in mice. We characterized the critical parameters of MSNP-mediated direct cellular radiolabeling to improve the use of these nanoparticles as cellular labels for highly sensitive preclinical PET imaging.

In this study, we introduce a unique doubly porous three-dimensional scaffold designed to mimic the morphological characteristics of human trabecular bone tissue closely. The scaffolds were fabricated through the thermal modification (TM) of polyacrylonitrile, featuring imprinted pores of the appropriate size to facilitate the ingrowth and proliferation of human osteoblasts throughout the entire pore volume created by a primary porogen, sodium chloride. The resulting material exhibits a dual porous morphological structure, in which adjustable larger pores support cellular ingrowth into the scaffold, while smaller pores, created using succinonitrile as a secondary porogen, enhance the diffusion of oxygen and nutrients to the developing cells. To enhance the material's mechanical properties, we introduced a secondary interpenetrating network (IPN) based on chitosan. Two cross-linking agents were investigated: the widely utilized glutaraldehyde and its non-toxic alternative, genipin. Incorporating the secondary IPN led to a significant improvement in the mechanical characteristics of the scaffold. Our findings indicate that the developed material is non-cytotoxic, and its chemical composition and morphological structure actively promote the adhesion and proliferation of the human osteosarcoma cell line SAOS-2, underscoring the scaffold's potential for applications in bone tissue engineering.

Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([18F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [18F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [18F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [18F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [18F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [18F]FDG uptake could potentially obfuscate the interpretation of [18F]FDG-PET scans in patients who have recently undergone radiation therapy.

Successful bone tissue engineering involves managing several important parameters, such as the design of intercommunicating porous structures, pore sizes, and the material and mechanical suitability of the material. In our work, we focused on the preparation of a synthetic scaffold that morphologically mimics the structure of human trabecular bone. The scaffolds were fabricated through the thermal modification (TM) of polyacrylonitrile. The scaffold strength was supported by a crosslinked chitosan supporting network. The prepared scaffold has imprinted pores of the appropriate size to facilitate the ingrowth and proliferation of human osteoblasts throughout the entire pore volume created by a primary porogen, sodium chloride. The resulting material has a dual porous morphological structure, in which adjustable larger pores support cellular ingrowth into the scaffold, whereas smaller pores, created using succinonitrile (SCN) as a secondary porogen, increase the diffusion of oxygen and nutrients to developing cells. The mechanical properties of the scaffold were promoted by the use of a secondary interpenetrating network (IPN) based on chitosan. The incorporation of secondary IPNs led to a significant improvement in the mechanical characteristics of the scaffold. Two crosslinking agents were used: the widely utilized glutaraldehyde (GA) and its green, nontoxic alternative, genipin (GEN).The current study introduces a synthetic scaffold that effectively mimics the structure of human trabecular bone, providing a conducive environment for osteoblast proliferation and ingrowth. We incorporated a dual porous morphology and a secondary IPN based on chitosan and found that the scaffold exhibited improved mechanical properties and nutrient diffusion capabilities. This research highlights the potential of these scaffolds for major advancements in bone tissue engineering, demonstrating their noncytotoxic nature and ability to support the adhesion and proliferation of the human osteosarcoma cell line SAOS-2. The described scaffold preparation technique may offer distinct advantages over current high-end methods such as 3D printing. The primary benefit lies in its very simple instrumentation, which enables the creation of a complex trabecular bone morphology with both macro- and microporosity in the bulk, which is still challenging for common 3D printers. Additionally, IPN with chitosan can be postmodified, substantially expanding the potential applications of these scaffolds.

Positron emission tomography (PET) is one of the most sensitive whole-body molecular imaging techniques available in the clinic, able to detect picomolar levels of probe. As such, it was recently demonstrated that PET could also be used to track single radiolabeled cells in small animals. In this protocol, we present detailed procedures for radiolabeling cells using mesoporous silica nanoparticles (MSNs) and for tracking these cells in real time using in vivo PET. This includes static imaging of single cells as well as dynamic tracking of moving cells directly from the list-mode data. The protocol provides detailed instructions and examples for each step.

Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts and integrins have been proposed as targets for imaging of pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics and proteomics of human surgical samples are applied to select PDAC targets. We find that selected cancer cell surface markers are spatially correlated and provide specific cancer localization, whereas the spatial correlation between cancer markers and immune-related or fibroblast markers is low. Claudin-4 expression increases similar to 16 fold in cancer as compared with normal pancreas, and tight junction localization confers low background for imaging in normal tissue. We develop a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to similar to 25% injected activity per cubic centimeter (IA/cc) in metastases and similar to 18% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets.

In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of the method, we tracked the fate of more than 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

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