Gelatin-Based Liver Phantoms for Training Purposes: A Cookbook Approach.

Background: Patients with liver pathology benefit from image-guided interventions. Training for interventional procedures is recommended to be performed on liver phantoms until a basic proficiency is reached. In the last 40 years, several attempts have been made to develop materials to mimic the imaging characteristics of the human liver in order to create liver phantoms. There is still a lack of accessible, reproducible and cost-effective soft liver phantoms for image-guided procedure training. Methods: Starting from a CT-scan DICOM file, we created a 3D-printed liver mold using InVesalius (Centro de Tecnologia da informação Renato Archer CTI, InVesalius 3 open-source software, Campinas, Brazil) for segmentation, Autodesk Fusion 360 with Netfabb (Autodesk software company, Fusion 360 2.0.19426 with Autodesk Netfabb Premium 2023.0 64-Bit Edition, San Francisco, CA, USA) for 3D modeling and Stratasys Fortus 380 mc 3D printer (Stratasys 3D printing company, Fortus 380 mc 3D printer, Minneapolis, MN, USA). Using the 3D-printed mold, we created 14 gelatin-based liver phantoms with 14 different recipes, using water, cast sugar and dehydrated gelatin, 32% fat bovine milk cream with intravenous lipid solution and technical alcohol in different amounts. We tested all these phantoms as well as ex vivo pig liver and human normal, fatty and cirrhotic liver by measuring the elasticity, shear wave speed, ultrasound attenuation, CT-scan density, MRI signal intensity and fracture force. We assessed the results of the testing performed, as well as the optical appearance on ultrasound, CT and MRI, in order to find the best recipe for gelatin-based phantoms for image-guided procedure training. Results: After the assessment of all phantom recipes, we selected as the best recipe for transparent phantoms one with 14 g of gelatin/100 mL water and for opaque phantom, the recipes with 25% cream. Conclusions: These liver gelatin-based phantom recipes are an inexpensive, reproducible and accessible alternative for training in image-guided and diagnostic procedures and will meet most requirements for valuable training.

Switchable LED-based laparoscopic multispectral system for rapid high-resolution perfusion imaging.

Significance: Multispectral imaging (MSI) is an approach for real-time, quantitative, and non-invasive tissue perfusion measurements. Current laparoscopic systems based on mosaic sensors or filter wheels lack high spatial resolution or acceptable frame rates. Aim: To develop a laparoscopic system for MSI-based color video and tissue perfusion imaging during gastrointestinal surgery without compromising spatial or temporal resolution. Approach: The system was built with 14 switchable light-emitting diodes in the visible and near-infrared spectral range, a 4K image sensor, and a 10 mm laparoscope. Illumination patterns were created for tissue oxygenation and hemoglobin content monitoring. The system was calibrated to a clinically approved laparoscopic hyperspectral system using linear regression models and evaluated in an occlusion study with 36 volunteers. Results: The root mean squared errors between the MSI and reference system were 0.073 for hemoglobin content, 0.039 for oxygenation in deeper tissue layers, and 0.093 for superficial oxygenation. The spatial resolution at a working distance of 45 mm was 156 µm. The effective frame rate was 20 fps. Conclusions: High-resolution perfusion monitoring was successfully achieved. Hardware optimizations will increase the frame rate. Parameter optimizations through alternative illumination patterns, regression, or assumed tissue models are planned. Intraoperative measurements must confirm the suitability during surgery.

Development and optimisation of in vitro sonodynamic therapy for glioblastoma.

Sonodynamic therapy (SDT) is currently on critical path for glioblastoma therapeutics. SDT is a non-invasive approach utilising focused ultrasound to activate photosensitisers like 5-ALA to impede tumour growth. Unfortunately, the molecular mechanisms underlying the therapeutic functions of SDT remain enigmatic. This is primarily due to the lack of intricately optimised instrumentation capable of modulating SDT delivery to glioma cells in vitro. Consequently, very little information is available on the effects of SDT on glioma stem cells which are key drivers of gliomagenesis and recurrence. To address this, the current study has developed and validated an automated in vitro SDT system to allow the application and mapping of focused ultrasound fields under varied exposure conditions and setup configurations. The study optimizes ultrasound frequency, intensity, plate base material, thermal effect, and the integration of live cells. Indeed, in the presence of 5-ALA, focused ultrasound induces apoptotic cell death in primary patient-derived glioma cells with concurrent upregulation of intracellular reactive oxygen species. Intriguingly, primary glioma stem neurospheres also exhibit remarkably reduced 3D growth upon SDT exposure. Taken together, the study reports an in vitro system for SDT applications on tissue culture-based disease models to potentially benchmark the novel approach to the current standard-of-care.

Ultrasound-induced cavitation renders prostate cancer cells susceptible to hyperthermia: Analysis of potential cellular and molecular mechanisms.

Background: Focused ultrasound (FUS) has become an important non-invasive therapy for prostate tumor ablation via thermal effects in the clinic. The cavitation effect induced by FUS is applied for histotripsy, support drug delivery, and the induction of blood vessel destruction for cancer therapy. Numerous studies report that cavitation-induced sonoporation could provoke multiple anti-proliferative effects on cancer cells. Therefore, cavitation alone or in combination with thermal treatment is of great interest but research in this field is inadequate. Methods: Human prostate cancer cells (LNCap and PC-3) were exposed to 40 s cavitation using a FUS system, followed by water bath hyperthermia (HT). The clonogenic assay, WST-1 assay, and Transwell® invasion assay, respectively, were used to assess cancer cell clonogenic survival, metabolic activity, and invasion potential. Fluorescence microscopy using propidium iodide (PI) as a probe of cell membrane integrity was used to identify sonoporation. The H2A.X assay and Nicoletti test were conducted in the mechanism investigation to detect DNA double-strand breaks (DSBs) and cell cycle arrest. Immunofluorescence microscopy and flow cytometry were performed to determine the distribution and expression of 5α-reductase (SRD5A). Results: Short FUS shots with cavitation (FUS-Cav) in combination with HT resulted in, respectively, a 2.2, 2.3, and 2.8-fold decrease (LNCap) and a 2.0, 1.5, and 1.6-fold decrease (PC-3) in the clonogenic survival, cell invasiveness and metabolic activity of prostate cancer cells when compared to HT alone. FUS-Cav immediately induced sonoporation in 61.7% of LNCap cells, and the combination treatment led to a 1.4 (LNCap) and 1.6-fold (PC-3) increase in the number of DSBs compared to HT alone. Meanwhile, the combination therapy resulted in 26.68% of LNCap and 31.70% of PC-3 with cell cycle arrest in the Sub-G1 phase and 35.37% of PC-3 with cell cycle arrest in the G2/M phase. Additionally, the treatment of FUS-Cav combined with HT block the androgen receptor (AR) signal pathway by reducing the relative Type I 5α-reductase (SRD5A1) level to 38.28 ± 3.76% in LNCap cells, and decreasing the relative Type III 5α-reductase 3 (SRD5A3) level to 22.87 ± 4.88% in PC-3 cells, in contrast, the relative SRD5A level in untreated groups was set to 100%. Conclusion: FUS-induced cavitation increases the effects of HT by interrupting cancer cell membranes, inducing the DSBs and cell cycle arrest, and blocking the AR signal pathway of the prostate cancer cells, with the potential to be a promising adjuvant therapy in prostate cancer treatment.

Evaluation of a Developed MRI-Guided Focused Ultrasound System in 7 T Small Animal MRI and Proof-of-Concept in a Prostate Cancer Xenograft Model to Improve Radiation Therapy.

Focused ultrasound (FUS) can be used to physiologically change or destroy tissue in a non-invasive way. A few commercial systems have clinical approval for the thermal ablation of solid tumors for the treatment of neurological diseases and palliative pain management of bone metastases. However, the thermal effects of FUS are known to lead to various biological effects, such as inhibition of repair of DNA damage, reduction in tumor hypoxia, and induction of apoptosis. Here, we studied radiosensitization as a combination therapy of FUS and RT in a xenograft mouse model using newly developed MRI-compatible FUS equipment. Xenograft tumor-bearing mice were produced by subcutaneous injection of the human prostate cancer cell line PC-3. Animals were treated with FUS in 7 T MRI at 4.8 W/cm2 to reach ~45 °C and held for 30 min. The temperature was controlled via fiber optics and proton resonance frequency shift (PRF) MR thermometry in parallel. In the combination group, animals were treated with FUS followed by X-ray at a single dose of 10 Gy. The effects of FUS and RT were assessed via hematoxylin-eosin (H&E) staining. Tumor proliferation was detected by the immunohistochemistry of Ki67 and apoptosis was measured by a TUNEL assay. At 40 days follow-up, the impact of RT on cancer cells was significantly improved by FUS as demonstrated by a reduction in cell nucleoli from 189 to 237 compared to RT alone. Inhibition of tumor growth by 4.6 times was observed in vivo in the FUS + RT group (85.3%) in contrast to the tumor volume of 393% in the untreated control. Our results demonstrated the feasibility of combined MRI-guided FUS and RT for the treatment of prostate cancer in a xenograft mouse model and may provide a chance for less invasive cancer therapy through radiosensitization.

Alternative intraoperative optical imaging modalities for fluorescence angiography in gastrointestinal surgery: spectral imaging and imaging photoplethysmography.

INTRODUCTION: Intraoperative near-infrared fluorescence angiography with indocyanine green (ICG-FA) is a well-established modality in gastrointestinal surgery. Its main drawback is the application of a fluorescent agent with possible side effects for patients. The goal of this review paper is the presentation of alternative, non-invasive optical imaging methods and their comparison with ICG-FA. MATERIAL AND METHODS: The principles of ICG-FA, spectral imaging, imaging photoplethysmography (iPPG), and their applications in gastrointestinal surgery are described based on selected published works. RESULTS: The main applications of the three modalities are the evaluation of tissue perfusion, the identification of risk structures, and tissue segmentation or classification. While the ICG-FA images are mainly evaluated visually, leading to subjective interpretations, quantitative physiological parameters and tissue segmentation are provided in spectral imaging and iPPG. The combination of ICG-FA and spectral imaging is a promising method. CONCLUSIONS: Non-invasive spectral imaging and iPPG have shown promising results in gastrointestinal surgery. They can overcome the main drawbacks of ICG-FA, i.e. the use of contrast agents, the lack of quantitative analysis, repeatability, and a difficult standardization of the acquisition. Further technical improvements and clinical evaluations are necessary to establish them in daily clinical routine.

Spectral Similarity Measures for In Vivo Human Tissue Discrimination Based on Hyperspectral Imaging.

PROBLEM: Similarity measures are widely used as an approved method for spectral discrimination or identification with their applications in different areas of scientific research. Even though a range of works have been presented, only a few showed slightly promising results for human tissue, and these were mostly focused on pathological and non-pathological tissue classification. METHODS: In this work, several spectral similarity measures on hyperspectral (HS) images of in vivo human tissue were evaluated for tissue discrimination purposes. Moreover, we introduced two new hybrid spectral measures, called SID-JM-TAN(SAM) and SID-JM-TAN(SCA). We analyzed spectral signatures obtained from 13 different human tissue types and two different materials (gauze, instruments), collected from HS images of 100 patients during surgeries. RESULTS: The quantitative results showed the reliable performance of the different similarity measures and the proposed hybrid measures for tissue discrimination purposes. The latter produced higher discrimination values, up to 6.7 times more than the classical spectral similarity measures. Moreover, an application of the similarity measures was presented to support the annotations of the HS images. We showed that the automatic checking of tissue-annotated thyroid and colon tissues was successful in 73% and 60% of the total spectra, respectively. The hybrid measures showed the highest performance. Furthermore, the automatic labeling of wrongly annotated tissues was similar for all measures, with an accuracy of up to 90%. CONCLUSION: In future work, the proposed spectral similarity measures will be integrated with tools to support physicians in annotations and tissue labeling of HS images.

Design and validation of a medical robotic device system to control two collaborative robots for ultrasound-guided needle insertions.

The percutaneous biopsy is a critical intervention for diagnosis and staging in cancer therapy. Robotic systems can improve the efficiency and outcome of such procedures while alleviating stress for physicians and patients. However, the high complexity of operation and the limited possibilities for robotic integration in the operating room (OR) decrease user acceptance and the number of deployed robots. Collaborative systems and standardized device communication may provide approaches to overcome named problems. Derived from the IEEE 11073 SDC standard terminology of medical device systems, we designed and validated a medical robotic device system (MERODES) to access and control a collaborative setup of two KUKA robots for ultrasound-guided needle insertions. The system is based on a novel standard for service-oriented device connectivity and utilizes collaborative principles to enhance user experience. Implementing separated workflow applications allows for a flexible system setup and configuration. The system was validated in three separate test scenarios to measure accuracies for 1) co-registration, 2) needle target planning in a water bath and 3) in an abdominal phantom. The co-registration accuracy averaged 0.94 ± 0.42 mm. The positioning errors ranged from 0.86 ± 0.42 to 1.19 ± 0.70 mm in the water bath setup and from 1.69 ± 0.92 to 1.96 ± 0.86 mm in the phantom. The presented results serve as a proof-of-concept and add to the current state of the art to alleviate system deployment and fast configuration for percutaneous robotic interventions.

Comparison of image registration methods for combining laparoscopic video and spectral image data.

Laparoscopic procedures can be assisted by intraoperative modalities, such as quantitative perfusion imaging based on fluorescence or hyperspectral data. If these modalities are not available at video frame rate, fast image registration is needed for the visualization in augmented reality. Three feature-based algorithms and one pre-trained deep homography neural network (DH-NN) were tested for single and multi-homography estimation. Fine-tuning was used to bridge the domain gap of the DH-NN for non-rigid registration of laparoscopic images. The methods were validated on two datasets: an open-source record of 750 manually annotated laparoscopic images, presented in this work, and in-vivo data from a novel laparoscopic hyperspectral imaging system. All feature-based single homography methods outperformed the fine-tuned DH-NN in terms of reprojection error, Structural Similarity Index Measure, and processing time. The feature detector and descriptor ORB1000 enabled video-rate registration of laparoscopic images on standard hardware with submillimeter accuracy.

[Artificial intelligence and hyperspectral imaging for image-guided assistance in minimally invasive surgery]. / Künstliche Intelligenz und hyperspektrale Bildgebung zur bildgestützten Assistenz in der minimal-invasiven Chirurgie.

BACKGROUND: Intraoperative imaging assists surgeons during minimally invasive procedures. Hyperspectral imaging (HSI) is a noninvasive and noncontact optical technique with great diagnostic potential in medicine. The combination with artificial intelligence (AI) approaches to analyze HSI data is called intelligent HSI in this article. OBJECTIVE: What are the medical applications and advantages of intelligent HSI for minimally invasive visceral surgery? MATERIAL AND METHODS: Within various clinical studies HSI data from multiple in vivo tissue types and oncological resections were acquired using an HSI camera system. Different AI algorithms were evaluated for detection and discrimination of organs, risk structures and tumors. RESULTS: In an experimental animal study 20 different organs could be differentiated with high precision (> 95%) using AI. In vivo, the parathyroid glands could be discriminated from surrounding tissue with an F1 score of 47% and sensitivity of 75%, and the bile duct with an F1 score of 79% and sensitivity of 90%. Furthermore, ex vivo tumor tissue could be successfully detected with an area under the receiver operating characteristic (ROC) curve (AUC) larger than 0.91. DISCUSSION: This study demonstrates that intelligent HSI can automatically and accurately detect different tissue types. Despite great progress in the last decade intelligent HSI still has limitations. Thus, accurate AI algorithms that are easier to understand for the user and an extensive standardized and continuously growing database are needed. Further clinical studies should support the various medical applications and lead to the adoption of intelligent HSI in the clinical routine practice.

Focused Ultrasound Treatment of a Spheroid In Vitro Tumour Model.

Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS effects at the cellular level is still missing. New techniques are commonly tested in vitro on two-dimensional (2D) monolayer cancer cell culture models. The 3D tumour model-spheroid-is mainly utilised to mimic solid tumours from an architectural standpoint. It is a promising method to simulate the characteristics of tumours in vitro and their various responses to therapeutic alternatives. This study aimed to evaluate the effects of FUS on human prostate and glioblastoma cancer tumour spheroids in vitro. The experimental follow-up enclosed the measurements of spheroid integrity and growth kinetics, DNA damage, and cellular metabolic activity by measuring intracellular ATP content in the spheroids. Our results showed that pulsed FUS treatment induced molecular effects in 3D tumour models. With the disruption of the spheroid integrity, we observed an increase in DNA double-strand breaks, leading to damage in the cancer cells depending on the cancer cell type.

Evaluating different methods of MR-based motion correction in simultaneous PET/MR using a head phantom moved by a robotic system.

BACKGROUND: Due to comparatively long measurement times in simultaneous positron emission tomography and magnetic resonance (PET/MR) imaging, patient movement during the measurement can be challenging. This leads to artifacts which have a negative impact on the visual assessment and quantitative validity of the image data and, in the worst case, can lead to misinterpretations. Simultaneous PET/MR systems allow the MR-based registration of movements and enable correction of the PET data. To assess the effectiveness of motion correction methods, it is necessary to carry out measurements on phantoms that are moved in a reproducible way. This study explores the possibility of using such a phantom-based setup to evaluate motion correction strategies in PET/MR of the human head. METHOD: An MR-compatible robotic system was used to generate rigid movements of a head-like phantom. Different tools, either from the manufacturer or open-source software, were used to estimate and correct for motion based on the PET data itself (SIRF with SPM and NiftyReg) and MR data acquired simultaneously (e.g. MCLFIRT, BrainCompass). Different motion estimates were compared using data acquired during robot-induced motion. The effectiveness of motion correction of PET data was evaluated by determining the segmented volume of an activity-filled flask inside the phantom. In addition, the segmented volume was used to determine the centre-of-mass and the change in maximum activity concentration. RESULTS: The results showed a volume increase between 2.7 and 36.3% could be induced by the experimental setup depending on the motion pattern. Both, BrainCompass and MCFLIRT, produced corrected PET images, by reducing the volume increase to 0.7-4.7% (BrainCompass) and to -2.8-0.4% (MCFLIRT). The same was observed for example for the centre-of-mass, where the results show that MCFLIRT (0.2-0.6 mm after motion correction) had a smaller deviation from the reference position than BrainCompass (0.5-1.8 mm) for all displacements. CONCLUSIONS: The experimental setup is suitable for the reproducible generation of movement patterns. Using open-source software for motion correction is a viable alternative to the vendor-provided motion-correction software.

MRI-guided lumbar spinal injections with body-mounted robotic system: cadaver studies.

INTRODUCTION: This paper reports the system integration and cadaveric assessment of a body-mounted robotic system for MRI-guided lumbar spine injections. The system is developed to enable MR-guided interventions in closed bore magnet and avoid problems due to patient movement during cannula guidance. MATERIAL AND METHODS: The robot is comprised by a lightweight and compact structure so that it can be mounted directly onto the lower back of a patient using straps. Therefore, it can minimize the influence of patient movement by moving with the patient. The MR-Conditional robot is integrated with an image-guided surgical planning workstation. A dedicated clinical workflow is created for the robot-assisted procedure to improve the conventional freehand MRI-guided procedure. RESULTS: Cadaver studies were performed with both freehand and robot-assisted approaches to validate the feasibility of the clinical workflow and to assess the positioning accuracy of the robotic system. The experiment results demonstrate that the root mean square (RMS) error of the target position to be 2.57 ± 1.09 mm and of the insertion angle to be 2.17 ± 0.89°. CONCLUSION: The robot-assisted approach is able to provide more accurate and reproducible cannula placements than the freehand procedure, as well as to reduce the number of insertion attempts.

A Novel Matrix-Array-Based MR-Conditional Ultrasound System for Local Hyperthermia of Small Animals.

OBJECTIVE: The goal of this work was to develop a novel modular focused ultrasound hyperthermia (FUS-HT) system for preclinical applications with the following characteristics: MR-compatible, compact probe for integration into a PET/MR small animal scanner, 3D-beam steering capabilities, high resolution focusing for generation of spatially confined FUS-HT effects. METHODS: For 3D-beam steering capabilities, a matrix array approach with 11 × 11 elements was chosen. For reaching the required level of integration, the array was mounted with a conductive backing directly on the interconnection PCB. The array is driven by a modified version of our 128 channel ultrasound research platform DiPhAS. The system was characterized using sound field measurements and validated using tissue-mimicking phantoms. Preliminary MR-compatibility tests were performed using a 7T Bruker MRI scanner. RESULTS: Four 11 × 11 arrays between 0.5 and 2 MHz were developed and characterized with respect to sound field properties and HT generation. Focus sizes between 1 and 4 mm were reached depending on depth and frequency. We showed heating by 4 °C within 60 s in phantoms. The integration concept allows a probe thickness of less than 12 mm. CONCLUSION: We demonstrated FUS-HT capabilities of our modular system based on matrix arrays and a 128 channel electronics system within a 3D-steering range of up to ±30°. The suitability for integration into a small animal MR could be demonstrated in basic MR-compatibility tests. SIGNIFICANCE: The developed system presents a new generation of FUS-HT for preclinical and translational work providing safe, reversible, localized, and controlled HT.

Robot-Assisted Image-Guided Interventions.

Image guidance is a common methodology of minimally invasive procedures. Depending on the type of intervention, various imaging modalities are available. Common imaging modalities are computed tomography, magnetic resonance tomography, and ultrasound. Robotic systems have been developed to enable and improve the procedures using these imaging techniques. Spatial and technological constraints limit the development of versatile robotic systems. This paper offers a brief overview of the developments of robotic systems for image-guided interventions since 2015 and includes samples of our current research in this field.

Image-Guided High-Intensity Focused Ultrasound, A Novel Application for Interventional Nuclear Medicine?

Image-guided high-intensity focused ultrasound (HIFU) has been increasingly used in medicine over the past few decades, and several systems for such have become commercially available. HIFU has passed regulatory approval around the world for the ablation of various solid tumors, the treatment of neurologic diseases, and the palliative management of bone metastases. The mechanical and thermal effects of focused ultrasound provide a possibility for histotripsy, supportive radiation therapy, and targeted drug delivery. The integration of imaging modalities into HIFU systems allows for precise temperature monitoring and accurate treatment planning, increasing the safety and efficiency of treatment. Preclinical and clinical results have demonstrated the potential of image-guided HIFU to reduce adverse effects and increase the quality of life postoperatively. Interventional nuclear image-guided HIFU is an attractive noninvasive option for the future.

Body-Mounted Robotic System for MRI-Guided Shoulder Arthrography: Cadaver and Clinical Workflow Studies.

This paper presents an intraoperative MRI-guided, patient-mounted robotic system for shoulder arthrography procedures in pediatric patients. The robot is designed to be compact and lightweight and is constructed with nonmagnetic materials for MRI safety. Our goal is to transform the current two-step arthrography procedure (CT/x-ray-guided needle insertion followed by diagnostic MRI) into a streamlined single-step ionizing radiation-free procedure under MRI guidance. The MR-conditional robot was evaluated in a Thiel embalmed cadaver study and healthy volunteer studies. The robot was attached to the shoulder using straps and ten locations in the shoulder joint space were selected as targets. For the first target, contrast agent (saline) was injected to complete the clinical workflow. After each targeting attempt, a confirmation scan was acquired to analyze the needle placement accuracy. During the volunteer studies, a more comfortable and ergonomic shoulder brace was used, and the complete clinical workflow was followed to measure the total procedure time. In the cadaver study, the needle was successfully placed in the shoulder joint space in all the targeting attempts with translational and rotational accuracy of 2.07 ± 1.22 mm and 1.46 ± 1.06 degrees, respectively. The total time for the entire procedure was 94 min and the average time for each targeting attempt was 20 min in the cadaver study, while the average time for the entire workflow for the volunteer studies was 36 min. No image quality degradation due to the presence of the robot was detected. This Thiel-embalmed cadaver study along with the clinical workflow studies on human volunteers demonstrated the feasibility of using an MR-conditional, patient-mounted robotic system for MRI-guided shoulder arthrography procedure. Future work will be focused on moving the technology to clinical practice.