Trojan Horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment.

Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. However, targeted delivery of nanotheranostics is hindered by several biological barriers. Here, we report the development of a dual size/charge- transformable, Trojan-Horse nanoparticle (pPhD NP) for delivery of ultra-small, full active pharmaceutical ingredients (API) nanotheranostics with integrated dual-modal imaging and trimodal therapeutic functions. pPhD NPs exhibit ideal size and charge for drug transportation. In tumour microenvironment, pPhD NPs responsively transform to full API nanotheranostics with ultra-small size and higher surface charge, which dramatically facilitate the tumour penetration and cell internalisation. pPhD NPs enable visualisation of biodistribution by near-infrared fluorescence imaging, tumour accumulation and therapeutic effect by magnetic resonance imaging. Moreover, the synergistic photothermal-, photodynamic- and chemo-therapies achieve a 100% complete cure rate on both subcutaneous and orthotopic oral cancer models. This nanoplatform with powerful delivery efficiency and versatile theranostic functions shows enormous potentials to improve cancer treatment

The Integration of Positron Emission Tomography With Magnetic Resonance Imaging

A number of laboratories and companies are currently exploring the development of integrated imaging systems for magnetic resonance imaging (MRI) and positron emission tomography (PET). Scanners for both preclinical and human research applications are being pursued. In contrast to the widely distributed and now quite mature PET/computed tomography technology, most PET/MRI designs allow for simultaneous rather than sequential acquisition of PET and MRI data. While this offers the possibility of novel imaging strategies, it also creates considerable challenges for acquiring artifact-free images from both modalities. This paper discusses the motivation for developing combined PET/MRI technology, outlines the obstacles in realizing such an integrated instrument, and presents recent progress in the development of both the instrumentation and of novel imaging agents for combined PET/MRI studies. The performance of the first-generation PET/MRI systems is described. Finally, a range of possible biomedical applications for PET/MRI are outlined

A Human-derived Dual MRI/PET Reporter Gene System with High Translational Potential for Cell Tracking

Purpose: Reporter gene imaging has been extensively used to longitudinally report on whole-body distribution and viability of transplanted engineered cells. Multi-modal cell tracking can provide complementary information on cell fate. Typical multi-modal reporter gene systems often combine clinical and preclinical modalities. A multi-modal reporter gene system for magnetic resonance imaging (MRI) and positron emission tomography (PET), two clinical modalities, would be advantageous by combining the sensitivity of PET with the high-resolution morphology and non-ionizing nature of MRI. Procedures: We developed and evaluated a dual MRI/PET reporter gene system composed of two human-derived reporter genes that utilize clinical reporter probes for engineered cell detection. As a proof-of-concept, breast cancer cells were engineered to co-express the human organic anion transporter polypeptide 1B3 (OATP1B3) that uptakes the clinical MRI contrast agent gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), and the human sodium iodide symporter (NIS) which uptakes the PET tracer, [18F] tetrafluoroborate ([18F] TFB). Results: T1-weighted MRI results in mice exhibited significantly higher MRI signals in reporter-gene-engineered mammary fat pad tumors versus contralateral naïve tumors (p \u3c 0.05). No differences in contrast enhancement were observed at 5 h after Gd-EOB-DTPA administration using either intravenous or intraperitoneal injection. We also found significantly higher standard uptake values (SUV) in engineered tumors in comparison to the naïve tumors in [18F]TFB PET images (p \u3c 0.001). Intratumoral heterogeneity in signal enhancement was more conspicuous in relatively higher resolution MR images compared to PET images. Conclusions: Our study demonstrates the ability to noninvasively track cells engineered with our human-derived dual MRI/PET reporter system, enabling a more comprehensive evaluation of transplanted cells. Future work is focused on applying this tool to track therapeutic cells, which may one day enable the broader application of cell tracking within the healthcare system

Penta-Modal Imaging Platform with OCT- Guided Dynamic Focusing for Simultaneous Multimodal Imaging

Complex diseases, such as Alzheimer’s disease, are associated with sequences of changes in multiple disease-specific biomarkers. These biomarkers may show dynamic changes at specific stages of disease progression. Thus, testing/monitoring each biomarker may provide insight into specific disease-related processes, which can result in early diagnosis or even development of preventive measures. Obtaining a comprehensive information of biological tissues requires imaging of multiple optical contrasts, which is not typically offered by a single imaging modality. Thus, combining different contrast mechanisms to achieve simultaneous multimodal imaging is desirable. However, this process is highly challenging due to specific optical and hardware requirements for each optical imaging system. The objective of this dissertation is to develop a novel Penta-modal optical imaging system integrating photoacoustic microscopy (PAM), optical coherence tomography (OCT), optical Doppler tomography (ODT), OCT angiography (OCTA) and confocal fluorescence microscopy (CFM) in one platform providing comprehensive structural, functional, and molecular information of living biological tissues. The system can simultaneously image different biomarkers with a large field-of-view (FOV) and high-speed imaging. The large FOV and the high imaging speed is achieved by combining optical and mechanical scanning mechanisms. To compensate for an uneven surface of biological samples, which result in images with non-uniform resolution and low signal to noise ratio (SNR), we further develop a novel OCT-guided surface contour scanning methodology, a technique for adjusting objective lens focus to follow the contour of the sample surface, to provide a uniform spatial resolution and SNR across the region of interest (ROI). The imaging system was tested by imaging phantoms, ex vivo biological samples, and in vivo. The OCT-guided surface contour scanning methodology was utilized for imaging a leaf of purple queen plant, which resulted in a significant contrast improvement of 41% and 38% across a large imaging area for CFM and PAM, respectively. The nuclei and cells walls were also clearly observed in both images. In an in vivo imaging of the Swiss Webster mouse ear, our multimodal imaging system was able to provide images with uniform resolution in an FOV of 10 mm x 10 mm with an imaging time of around 5 minutes. In addition to measuring the blood flow in the mouse ear, the system also successfully imaged mouse ear blood vessels, sebaceous glands, as well as several tissue structures. We further conducted a comparative study of OCTA for rodent retinal imaging by evaluating the performance of three OCTA algorithms, namely the phase variance (PV), improved speckle contrast (ISC), and optical microangiography (OMAG). It was concluded that the OMAG algorithm provided statistically significant higher mean values of BVD and VPI compared to the ISC algorithm (0.27±0.07 vs. 0.24±0.05 for BVD; 0.09±0.04 and 0.08±0.04 for VPI), while no statistically significant difference was observed for VDI and VCI among the algorithms. Results showed that both the ISC and OMAG algorithms are more robust than PV, and they can reveal similar vasculature features. Lastly, we utilized the proposed imaging system to monitor, for the first time, the invasion process of malaria parasites in the mosquito midgut. The system shows a promising potential to detect parasite motion as well as structural changes inside the mosquito midgut. The multimodal imaging system outlined in this dissertation can be useful in a variety of applications thanks to the specific optical contrast offered by each employed modality, including retinal and brain imaging

Autonomous Applied Robotics: Ultrasound-Based Robot-Assisted Needle Insertion System Concept and Development

Ultrasound (US) is a popular imaging modality for image-guided minimally invasive surgery (MIS), enabling the faster and more reliable execution of numerous procedures, such as biopsy, electrode placement and vessel cannulation. Blood vessel cannulation is a common, routine intervention, e.g., for blood oxygen level testing. Yet, in particular cases, when the vessel is located deep or veins less stable (with the loss of subcutaneous tissue), it is hard to complete it without US assistance. In this paper, we present a solution for US-guided, robot-assisted needle insertion for vein cannulation. We developed an image-guided system to aid needle insertion via active targeting and anatomy-relevant positioning, together with safeguarding features, such as a kinematically enforced Remote Center of Motion (RCM) mechanism. The proposed system comprises a portable US transducer mounted on a KUKA iiwa collaborative robot, a custom designed needle insertion mechanism with adjacent controllers. The US and needle insertion mechanism are attached to the robot through a 3D printed custom designed mounting part with integrated force sensor. The robot arm is responsible for moving the needle to target position with impedance control. The needle insertion mechanism allows the manipulation of the needle along 3 axes. The mechanism was designed for near-surface vein cannulation with an RCM kinematic structure to avoid damage to the vein. The developed system was tested with different types of gelatin phantoms. Vein deformation and tissue motion was examined during US imaging. The control loop of our system is supplemented with vein deformation tissue model and US-based visual servoing

Monitoring mouse brain perfusion with hybrid magnetic resonance optoacoustic tomography

Progress in brain research critically depends on the development of next-generation multi-modal imaging tools capable of capturing transient functional events and multiplexed contrasts noninvasively and concurrently, thus enabling a holistic view of dynamic events in vivo. Here we report on a hybrid magnetic resonance and optoacoustic tomography (MROT) system for murine brain imaging, which incorporates an MR-compatible spherical matrix array transducer and fiber-based light illumination into a 9.4 T small animal scanner. An optimized radiofrequency coil has further been devised for whole-brain interrogation. System's utility is showcased by acquiring complementary angiographic and soft tissue anatomical contrast along with simultaneous dual-modality visualization of contrast agent dynamics in vivo

A dual-modal CT/US kidney phantom model for image-guided percutaneous renal access

Percutaneous renal access (PRA) is a crucial step in some minimally invasive kidney interventions. During this step, the surgeon inserts a needle through the skin until the kidney target site using fluoroscopy and ultrasound imaging. Recently, new concepts of enhanced image-guided interventions have been introduced in these interventions. However, their validation remains a challenging task. Phantom models have been presented to solve such challenge, using realistic anatomies in a controlled environment. In this work, we evaluate the accuracy of a porcine kidney phantom for validation of novel dual-modal computed tomography (CT)/ultrasound (US) image-guided strategies for PRA. A porcine kidney was combined with a tissue mimicking material (TMM) and implanted fiducial markers (FM). While the TMM mimics the surrounding tissues, the FM are used to accurately assess the registration errors between the US and CT images, providing a valid ground-truth. US and CT image acquisitions of the phantom model were performed and the FM were manually selected on both images. A rigid alignment was performed between the selected FM, presenting a root-mean-square error of 1.1 mm. Moreover, the kidney was manually segmented, presenting volumes of 203 ml and 238 ml for CT and US, respectively. The initial results are promising on achieving a realistic kidney phantom model to develop new strategies for PRA, but further work to improve the manufacturing process and to introduce motion and anatomical artifacts in the phantom is still required.This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project NORTE-01-0145-FEDER-000013, supported by the NORTE 2020, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). J. Gomes-Fonseca, A. Miranda, P. Morais, and S. Queirós were funded by FCT under the Ph.D. grants PD/BDE/113597/2015, SFRH/BD/52059/ 2012, SFRH/BD/95438/2013, and SFRH/BD/93443/2013, respectively.info:eu-repo/semantics/publishedVersio