Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and surface chemistry to work as a therapeutic delivery agent and a diagnostic tool for non-invasive real-time monitoring using imaging technologies. Here, we evaluate the selective uptake of 18 nm and 80 nm sized gold nanoparticles (AuNPs) by SKOV3 (4 times higher) ovarian cancer (OC) cells (compared to OVCAR5) in vitro, quantified by inductively coupled plasma (ICP) and MARS spectral photon-counting CT imaging (MARS SPCCT). Based on in vitro analysis, pristine AuNPs (18 nm) and surface modified AuNPs (18 nm) were chosen as a contrast agent for MARS SPCCT. The chemical analysis by FTIR spectroscopy confirmed the luteinizing hormone-releasing hormone (LHRH) conjugation to the AuNPs surface. For the first time, LHRH conjugated AuNPs were used for in vitro and selective in vivo OC targeting. The ICP-MS analysis confirmed preferential uptake of LHRH modified AuNPs by organs residing in the abdominal cavity with OC nodules (pancreas: 0.46 ng mg-1, mesentery: 0.89 ng mg-1, ovary: 1.43 ng mg-1, and abdominal wall: 2.12 ng mg-1) whereas the MARS SPCCT analysis suggested scattered accumulation of metal around the abdominal cavity. Therefore, the study showed the exciting potential of LHRH conjugated AuNPs to target ovarian cancer and also as a potential contrast agent for novel SPCCT imaging technology.

Correction for 'LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research' by Dhiraj Kumar et al., J. Mater. Chem. B, 2023, 11, 1916-1928, https://doi.org/10.1039/D2TB02416K.

X-ray photon-counting detector (PCD) offers low noise, high resolution, and spectral characterization, representing a next generation of CT and enabling new biomedical applications. It is well known that involuntary patient motion may induce image artifacts with conventional CT scanning, and this problem becomes more serious with PCD due to its high detector pitch and extended scan time. Furthermore, PCD often comes with a substantial number of bad pixels, making analytic image reconstruction challenging and ruling out state-of-the-art motion correction methods that are based on analytical reconstruction. In this paper, we extend our previous locally linear embedding (LLE) cone-beam motion correction method to the helical scanning geometry, which is especially desirable given the high cost of large-area PCD. In addition to our adaption of LLE-based parametric searching to helical cone-beam photon-counting CT geometry, we introduce an unreliable-volume mask to improve the motion estimation accuracy and perform incremental updating on gradually refined sampling grids for optimization of both accuracy and efficiency. Our numerical results demonstrate that our method reduces the estimation errors near the two longitudinal ends of the reconstructed volume and overall image quality. The experimental results on clinical photon-counting scans of the patient extremities show significant resolution improvement after motion correction using our method, which reveals subtle fine structures previously hidden under motion blurring and artifacts.

Gastrointestinal (GI) tract is one of the hard-to-reach target tissues for the delivery of contrast agents and drugs mediated by nanoparticles due to its harsh environment. Herein, we overcame this barrier by designing orally ingestible probiotic vectors for 'hitchhiking' ultrasmall hafnia (HfO2) (∼1-2 nm) nanoparticles. The minute-made synthesis of these nanoparticles is accomplished through a simple reduction reaction. These nanoparticles were incubated with probiotic bacteria with potential health benefits and were non-specifically taken up due to their small size. Subsequently, the bacteria were lyophilized and packed into a capsule to be administered orally as the radiopaque contrast agents for delineating the GI features. These nano-bio-hybrid entities could successfully be utilized as contrast agents in vivo in the conventional and multispectral computed tomography (CT). We demonstrated in 'color' the accumulated nanoparticles using advanced detectors of the photon counting CT. The enhanced nano-bio-interfacing capability achieved here can circumvent traditional nanoparticle solubility and delivery problems while offering a patient friendly approach for GI imaging to replace the currently practiced barium meal.

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm 3 and 2.83 mm 3 , respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans.

The early detection of bone microdamages is crucial to make informed decisions about the therapy and taking precautionary treatments to avoid catastrophic fractures. Conventional computed tomography (CT) imaging faces obstacles in detecting bone microdamages due to the strong self-attenuation of photons from bone and poor spatial resolution. Recent advances in CT technology as well as novel imaging probes can address this problem effectively. Herein, the bone microdamage imaging is demonstrated using ligand-directed nanoparticles in conjunction with photon counting spectral CT. For the first time, Gram-scale synthesis of hafnia (HfO2) nanoparticles is reported with surface modification by a chelator moiety. The feasibility of delineating these nanoparticles from bone and soft tissue of muscle is demonstrated with photon counting spectral CT equipped with advanced detector technology. The ex vivo and in vivo studies point to the accumulation of hafnia nanoparticles at microdamage site featuring distinct spectral signal. Due to their small sub-5 nm size, hafnia nanoparticles are excreted through reticuloendothelial system organs without noticeable aggregation while not triggering any adverse side effects based on histological and liver enzyme function assessments. These preclinical studies highlight the potential of HfO2-based nanoparticle contrast agents for skeletal system diseases due to their well-placed K-edge binding energy.

Bone as a functional material could experience various stresses that could lead to microdamages. In article number 1904936, Dipanjan Pan and co-workers show that targeted hafnia nanoparticles and photon counting spectral computed tomography can detect microdamages. This advanced technology could determine signals from hafnia nanoparticles bound to the hard tissue of bone both in the ex vivo model and in vivo.

In this article, we propose a slice-based interactive segmentation of spectral CT datasets using a bag of features method. The data are acquired from a MARS scanner that divides up the X-ray spectrum into multiple energy bins for imaging. In literature, most existing segmentation methods are limited to performing a specific task or tied to a particular imaging modality. Therefore, when applying generalized methods to MARS datasets, the additional energy information acquired from the scanner cannot be sufficiently utilized. We describe a new approach that circumvents this problem by effectively aggregating the data from multiple channels. Our method solves a classification problem to get the solution for segmentation. Starting with a set of labeled pixels, we partition the data using superpixels. Then, a set of local descriptors, extracted from each superpixel, are encoded into a codebook and pooled together to create a global superpixel-level descriptor (bag of features representation). We propose to use the vector of locally aggregated descriptors as our encoding/pooling strategy, as it is efficient to compute and leads to good results with simple linear classifiers. A linear support vector machine is then used to classify the superpixels into different labels. The proposed method was evaluated on multiple MARS datasets. Experimental results show that our method achieved an average of more than 10% increase in the accuracy over other state-of-the-art methods.

Photon-counting CT offers the potential to provide new diagnostic information. In this study, we sought to determine the interplay between material identification errors, image quality indicators, and radiation doses using photon-counting spectral CT, and to determine whether this relationship is replicated in spectral CT scans of mice. Custom-built Perspex phantoms were used to measure signal-to-noise ratio (SNR) and spatial resolution, and to measure radiation dose using thermoluminescent dosimeters. A multicontrast calibration phantom containing inserts with different concentrations of gadolinium (1, 2, 4, and 8 mg/mL), hydroxyapatite rods (0, 54.3, 104.3, 211.7, 402.3, and 808.5 mg/mL) along with water and lipid was used to assess material identification errors. Image acquisition was performed using the MARS photon-counting scanner with four energy channels (30–45, 45–60, 60–78, and 78–118 keV) at four different tube currents (24, 34, 44, and $55~\mu \text{A}$ ). As increased tube current showed no significant effect on material characterization, small animal dosimetry was performed with 24- $\mu \text{A}$ tube current using two noncontrast mice and one mouse injected with gadolinium. Results demonstrated that a tube current increase from 24 to $54~\mu \text{A}$ improved the SNR and spatial resolution by <10%, gadolinium identification by <20% (for 1 mg/mL) but radiation dose increased by >160%. Imaging results of the mice showed no obvious artefacts, and the mean absorbed dose measured for the three mice was 27.3±2.4 mGy. The results suggest that the energy resolving capability of photon-counting CT maintains diagnostically relevant image quality with high levels of material discrimination at reduced radiation dose.

Crystal-related arthropathies are the result of crystal deposition in joint and periarticular soft tissues. Identification of urate crystals is mandatory to distinguish gout from other crystalline arthropathies, including calcium pyrophosphate dihydrate and basic calcium phosphate crystal deposition diseases. ACR/EULAR classification criteria for gout included dual-energy computed tomography and ultrasound with equal impact to the final score. Different diagnostic strengths of these imaging modalities depend on disease duration and scanned anatomic site. While ultrasound has been indicated as the first-choice imaging technique, especially in the early stages of the disease, dual-energy computed tomography has shown to be highly specific, allowing the detection of crystal deposits in anatomic sites not accessible by ultrasound, such as the spine. At the spinal level, MRI findings are usually nonspecific. Finally, there is preliminary evidence that at the knee, dual-energy computed tomography may discriminate calcium pyrophosphate dihydrate from basic calcium phosphate crystal deposits.

The aim is to perform qualitative and quantitative assessment of metal induced artefacts of small titanium biomaterials using photon counting spectral CT. The energy binning feature of some photon counting detectors enables the measured spectrum to be segmented into low, mid and high energy bins in a single exposure. In this study, solid and porous titanium implants submerged in different concentrations of calcium solution were scanned using the small animal MARS photon counting spectral scanner equipped with a polyenergetic X-ray source operated at 118 kVp. Five narrow energy bins (7-45 keV, 45-55 keV, 55-65 keV, 65-75 keV and 75-118 keV) in charge summing mode were utilised. Images were evaluated in the energy domain (spectroscopic images) as well as material domain (material segmentation and quantification). Results show that calcium solution outside titanium implants can be accurately quantified. However, there was an overestimation of calcium within the pores of the scaffold. This information is critical as it can severely limit the assessment of bone ingrowth within metal structures. The energy binning feature of the spectral scanner was exploited and a correction factor, based on calcium concentrations adjacent to and within metal structures, was used to minimise the variation. Qualitative and quantitative evaluation of bone density and morphology with and without titanium screw shows that photon counting spectral CT can assess bone-metal interface with less pronounced artefacts. Quantification of bone growth in and around the implants would help in orthopaedic applications to determine the effectiveness of implant treatment and assessment of fracture healing.

Images from MARS spectral CT scanners show that there is much diagnostic value from using small pixels and good energy data. MARS scanners use energy-resolving photon-counting CZT Medipix3RX detectors that measure the energy of photons on a five-point scale and with a spatial resolution of 110 microns. The energy information gives good material discrimination and quantification. The 3D reconstruction gives a voxel size of 70 microns. We present images of pre-clinical specimens, including excised atheroma, bone and joint samples, and nanoparticle contrast agents along with images from living humans. Images of excised human plaque tissue show the location and extent of lipid and calcium deposition within the artery wall. The presence of intraplaque haemorrhage, where the blood leaks into the artery wall following a rupture, has also been visualised through the detection of iron. Several clinically important bone and joint problems have been investigated including: site-specific bone mineral density, bone-metal interfaces (spectral CT reduces metal artefacts), cartilage health using ionic contrast media, gout and pseudogout crystals, and microfracture assessment using nanoparticles. Metallic nanoparticles have been investigated as a cellular marker visible in MARS images. Cell lines of different cancer types (Raji and SK-BR3) were incubated with monoclonal antibody-functionalised AuNPs (Herceptin and Rituximab). We identified and quantified the labelled AuNPs demonstrating that Herceptin-functionalised AuNPs bound to SK-BR3 breast cancer cells but not to the Raji lymphoma cells. In vivo human images show the bone microstructure. Fat, water, and calcium concentrations are quantifiable.

The purpose of the present study was to demonstrate an in vitro proof of principle that spectral photon-counting CT can measure gold-labelled specific antibodies targeted to specific cancer cells. A crossover study was performed with Raji lymphoma cancer cells and HER2-positive SKBR3 breast cancer cells using a MARS spectral CT scanner. Raji cells were incubated with monoclonal antibody-labelled gold, rituximab (specific antibody to Raji cells), and trastuzumab (as a control); HER2-positive SKBR3 breast cancer cells were incubated with monoclonal antibody-labelled gold, trastuzumab (specific antibody to HER2-positive cancer cells), and rituximab (as a control). The calibration vials with multiple concentrations of nonfunctionalised gold nanoparticles were used to calibrate spectral CT. Spectral imaging results showed that the Raji cells-rituximab-gold and HER2-positive cells-trastuzumab-gold had a quantifiable amount of gold, 5.97 mg and 0.78 mg, respectively. In contrast, both cell lines incubated with control antibody-labelled gold nanoparticles had less gold attached (1.22 mg and 0.15 mg, respectively). These results demonstrate the proof of principle that spectral molecular CT imaging can identify and quantify specific monoclonal antibody-labelled gold nanoparticles taken up by Raji cells and HER2-positive SKBR3 breast cancer cells. The present study reports the future potential of spectral molecular imaging in detecting tumour heterogeneity so that treatment can be tuned accordingly, leading to more effective personalised medicine.

This study demonstrates the translation of small-bore MARS photon-counting CT technology to live human spectral imaging within a clinical radiation dose level. We used the same spectral CT technology platform (hardware and software) for the acquisition of spectral CT data, image reconstruction, material decomposition and visualisation as used in small-bore MARS photon-counting CT. Small-bore MARS photon-counting CT has been used to produce promising results in the fields of cancer, bone and cartilage health, and cardio-vascular diseases. With the development of large-bore MARS photon-counting CT, small-animal studies can now be translated to humans, sheep, or pigs. Spectral CT data at eight energy-channels were acquired simultaneously to scan body-parts of a human volunteer. Two scans were performed, the first a part of the lower-leg, and the second of the wrist. After reconstructing the spectral CT images with voxel dimensions of 90 × 90 × 90 μm 3 , a constrained leastsquare based material decomposition was applied to estimate the density of soft-tissue components (water and fat) and bone (calcium) in each voxel. The computed tomography dose index was measured to assess the radiation dose delivered in scanning the lower-leg of a live human. The previous studies conducted on small-bore MARS photon-counting CT have indicated that spectral information is beneficial for the assessment of cancer, bone and cartilage health, and cardio-vascular diseases. This study also demonstrates that spectral information obtained with the large-bore MARS photon-counting CT provides a similar level of material information to that obtained with small-bore MARS photon-counting CT. The measured weighted computed tomography dose index for scanning the two body-parts in this study was below 5 mGy in each scan. Obtaining diagnostic quality spectral CT images of a human within a clinical radiation dose level demonstrates the potential for using large-bore MARS photon-counting CT in human clinical trials.

The aim of the present study is to show that non-invasive MARS imaging can differentiate between infected and healthy pulmonary tissue using an iodine-based contrast agent at high resolution. One C57BL/6J mouse with chronic tuberculosis (TB) was euthanized with CO 2 and the pulmonary tissue excised. The TB lungs were incubated in 3% iodine solution. Mouse pulmonary tissue free of TB was also excised and incubated in the iodine solution for control purposes. Calibration of the MARS scanner involved scanning a phantom containing four concentrations of iodine along with water (soft tissue) and lipid (fat). The calibration phantom, control, and TB infected tissue were imaged at four threshold energy levels (20, 27, 34, 45 keV) at a constant 60 kVp tube voltage and 90 μA tube current. Following analysis of the calibration phantom, material decomposition (MD) was applied to the pulmonary tissue samples and iodine to obtain material images. MARS Vision software was used to visualize the materials to produce 3D material images. TB granulomas are visible within the lung lobes due to the iodine uptake. The amount of iodine uptake can be measured in mg by analysis of the material images using MARS Vision. MARS imaging was able to better differentiate between infected and healthy tissue. The present study demonstrated non-invasive, photon-counting CT is capable of differentiating between infected and healthy tissue. Future studies will consider development of TB markers, or drug markers labelled with gold nanoparticles, to enhance the understanding of the basic biology and mechanisms underpinning TB, and its relevance to the phenomenon of persistence in the infected host during therapy.