"This dissertation describes the development of a methodology for implementing robotic systems for interventional procedures under intraoperative Magnetic Resonance Imaging (MRI) guidance. MRI is an ideal imaging modality for surgical guidance of diagnostic and therapeutic procedures, thanks to its ability to perform high resolution, real-time, and high soft tissue contrast imaging without ionizing radiation. However, the strong magnetic field and sensitivity to radio frequency signals, as well as tightly confined scanner bore render great challenges to developing robotic systems within MRI environment. Discussed are potential solutions to address engineering topics related to development of MRI-compatible electro-mechanical systems and modeling of steerable needle interventions. A robotic framework is developed based on a modular design approach, supporting varying MRI-guided interventional procedures, with stereotactic neurosurgery and prostate cancer therapy as two driving exemplary applications. A piezoelectrically actuated electro-mechanical system is designed to provide precise needle placement in the bore of the scanner under interactive MRI-guidance, while overcoming the challenges inherent to MRI-guided procedures. This work presents the development of the robotic system in the aspects of requirements definition, clinical work flow development, mechanism optimization, control system design and experimental evaluation. A steerable needle is beneficial for interventional procedures with its capability to produce curved path, avoiding anatomical obstacles or compensating for needle placement errors. Two kinds of steerable needles are discussed, i.e. asymmetric-tip needle and concentric-tube cannula. A novel Gaussian-based ContinUous Rotation and Variable-curvature (CURV) model is proposed to steer asymmetric-tip needle, which enables variable curvature of the needle trajectory with independent control of needle rotation and insertion. While concentric-tube cannula is suitable for clinical applications where a curved trajectory is needed without relying on tissue interaction force. This dissertation addresses fundamental challenges in developing and deploying MRI-compatible robotic systems, and enables the technologies for MRI-guided needle-based interventions. This study applied and evaluated these techniques to a system for prostate biopsy that is currently in clinical trials, developed a neurosurgery robot prototype for interstitial thermal therapy of brain cancer under MRI guidance, and demonstrated needle steering using both asymmetric tip and pre-bent concentric-tube cannula approaches on a testbed."

Near-infrared dyes can be used as theranostic agents in cancer management based on their optical imaging and localized hyperthermia capabilities. However, their clinical translatability is limited by issues such as photobleaching, short circulation times, and non-specific biodistribution. We studied the applications of IR820 in optical imaging and hyperthermia, and we prepared nanoconjugate formulations to overcome some of the aforementioned limitations. Free IR820 can be used for optical imaging, with a strong signal still present 24 hours after i.v. injection, an elimination plasma half-life in the order of hours, and primary biodistribution to liver, lung, and kidneys. After 808-mn laser exposure, IR820 can also raise in vitro temperatures to the 41-43°C range that can selectively inhibit cancer cell growth. We conjugated IR820 with PEG-diamine via ionic interactions to create nanoconjugates (IR820-PDNCs) with diameters of approximately 50-nm per SEM and a zeta potential of 2.0±0.9 mV. IR820-PDNCs enhanced cellular internalization compared to IR820 for imaging in SKOV-3, MES-SA, and Dx5 cancer cells. The nanoconjugates also significantly enhanced hyperthermia-mediated cytotoxicity in MES-SA and Dx5 compared to the free dye (p

No description available.

Image guided surgery (IGS), which has been developing fast recently, benefits significantly from the superior accuracy of robots and magnetic resonance imaging (MRI) which is a great soft tissue imaging modality. Teleoperation is especially desired in the MRI because of the highly constrained space inside the closed-bore MRI and the lack of haptic feedback with the fully autonomous robotic systems. It also very well maintains the human in the loop that significantly enhances safety. This dissertation describes the development of teleoperation approaches and implementation on an example system for MRI with details of different key components. The dissertation firstly describes the general teleoperation architecture with modular software and hardware components. The MRI-compatible robot controller, driving technology as well as the robot navigation and control software are introduced. As a crucial step to determine the robot location inside the MRI, two methods of registration and tracking are discussed. The first method utilizes the existing Z shaped fiducial frame design but with a newly developed multi-image registration method which has higher accuracy with a smaller fiducial frame. The second method is a new fiducial design with a cylindrical shaped frame which is especially suitable for registration and tracking for needles. Alongside, a single-image based algorithm is developed to not only reach higher accuracy but also run faster. In addition, performance enhanced fiducial frame is also studied by integrating self-resonant coils. A surgical master-slave teleoperation system for the application of percutaneous interventional procedures under continuous MRI guidance is presented. The slave robot is a piezoelectric-actuated needle insertion robot with fiber optic force sensor integrated. The master robot is a pneumatic-driven haptic device which not only controls the position of the slave robot, but also renders the force associated with needle placement interventions to the surgeon. Both of master and slave robots mechanical design, kinematics, force sensing and feedback technologies are discussed. Force and position tracking results of the master-slave robot are demonstrated to validate the tracking performance of the integrated system. MRI compatibility is evaluated extensively. Teleoperated needle steering is also demonstrated under live MR imaging. A control system of a clinical grade MRI-compatible parallel 4-DOF surgical manipulator for minimally invasive in-bore prostate percutaneous interventions through the patient’s perineum is discussed in the end. The proposed manipulator takes advantage of four sliders actuated by piezoelectric motors and incremental rotary encoders, which are compatible with the MRI environment. Two generations of optical limit switches are designed to provide better safety features for real clinical use. The performance of both generations of the limit switch is tested. MRI guided accuracy and MRI-compatibility of whole robotic system is also evaluated. Two clinical prostate biopsy cases have been conducted with this assistive robot.

Intra-operative imaging is sometimes available to assist in needle biopsy, but typical open- loop insertion does not account for unmodeled needle deflection or target shift. Robotic closed-loop compensation for deviation from an initial straight-line trajectory can reduce the targeting error, using image-guidance for rotational control of an asymmetric bevel tip. By pairing closed-loop trajectory compensation with a hands-on cooperatively controlled needle insertion, a physician's control of the procedure can be maintained while incorporating benefits of robotic accuracy. Additionally, if puncture of a membrane can be detected, an enhanced haptic response can assist the physician in perceived anatomical localization of the needle tip. Functionality was implemented on a needle placement robot suitable for use in the MR environment and capable of holding a typical clinically used biopsy gun. The robot is configured for cooperatively controlled needle insertion with continuous closed-loop image- guided needle rotation. The robot and custom controller were tested for their effect on the Signal-to-Noise ratio (SNR) of MR images, and the results showed an approximate drop of only 12% in signal when the robot was present, and no additional signal drop when the robot was powered on or moving. The hardware and software subsystems were developed for clinical translation, and after each was validated in the lab they were integrated into the clinical environment to mimic the workflow of MRI-guided targeted biopsy. The full system was evaluated in-bore at Brigham and Women’s Hospital in Boston, MA where experiments for real-time puncture detection and MR image-guided targeted needle insertions under cooperative control were performed. Results showed overall targeting accuracy was 3.42mm RMS, improving accuracy by approximately 50% as compared to clinical trials of prostate biopsy using manual needle insertion. A cooperatively controlled robotic biopsy is more likely to gain acceptance by physicians over teleoperation due to maintaining proximity to the surgical site, but regulatory hurdles regarding robotic needle insertion still exist. The current robotic system framework is suitable for clinical use as it was fully validated in-bore, but some modifications could be made to increase the likelihood of regulatory approval. With these modifications the system could be ready for cadaver and pre- clinical animal trials within one year, and ready for in-human clinical trials in the next two to three years.

<p>Based on the compressed sensing theorem, we present the integrated software and hardware platform for developing a total-variation based image restoration algorithm by applying prior image information and free-form deformation fields for image guided therapy. The core algorithm we developed solves the image restoration problem for handling missing structures in one image set with prior information, and it enhances the quality of the image and the anatomical information of the volume of the on-board computed tomographic (CT) with limited-angle projections. Through the use of the algorithm, prior anatomical CT scans were used to provide additional information to help reduce radiation doses associated with the improved quality of the image volume produced by on-board Cone-Beam CT, thus reducing the total radiation doses that patients receive and removing distortion artifacts in 3D Digital Tomosynthesis (DTS) and 4D-DTS. The proposed restoration algorithm enables the enhanced resolution of temporal image and provides more anatomical information than conventional reconstructed images.</p><p>The performance of the algorithm was determined and evaluated by two built-in parameters in the algorithm, i.e., B-spline resolution and the regularization factor. These parameters can be adjusted to meet different requirements in different imaging applications. Adjustments also can determine the flexibility and accuracy during the restoration of images. Preliminary results have been generated to evaluate the image similarity and deformation effect for phantoms and real patient's case using shifting deformation window. We incorporated a graphics processing unit (GPU) and visualization interface into the calculation platform, as the acceleration tools for medical image processing and analysis. By combining the imaging algorithm with a GPU implementation, we can make the restoration calculation within a reasonable time to enable real-time on-board visualization, and the platform potentially can be applied to solve complicated, clinical-imaging algorithms.</p> / Dissertation

The clinical efficacy of chemotherapy in solid tumours is limited by systemic toxicity and the inability to deliver a cytotoxic concentration of anticancer drugs to all tumour cells. Temperature sensitive drug carriers provide a mechanism for triggering the rapid release of chemotherapeutic agents in a targeted region. Thermally mediated drug release also leverages the ability of hyperthermia to increase tumour blood flow, vessel permeability, and drug cytotoxicity. Drug release from thermosensitive liposome drug carriers in the tumour vasculature serves as a continuous intravascular infusion of free drug originating at the tumour site. However, localized drug release requires precise heating to improve drug delivery and efficacy in tumours while minimizing drug exposure in normal tissue. Focused ultrasound can noninvasively heat millimeter-sized regions deep within the body, and can be combined with MR thermometry for precise temperature control. This thesis describes the development of strategies to achieve localized hyperthermia using MRI-controlled focused ultrasound, for the purpose of image-guided heat-triggered drug release from thermosensitive drug carriers. First, a preclinical MRI-controlled focused ultrasound system was developed as a platform for studies of controlled hyperthermia and drug delivery in rabbits. The feasibility of using ultrasound hyperthermia to achieve localized doxorubicin release from thermosensitive liposomes was demonstrated in normal rabbit muscle. Second, strategies were described for using MR thermometry to control ultrasound heating at a muscle-bone interface based on MR temperature measurements in adjacent soft tissue, demonstrating localized drug delivery in adjacent muscle and bone marrow. Third, fluorescence microscopy was employed to demonstrate that increased overall drug accumulation in rabbit VX2 tumours corresponds to high levels of bioavailable drug reaching their active site in the nuclei of tumour cells. The results of this thesis demonstrate that image-guided drug delivery using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia can be used to noninvasively achieve precisely localized drug deposition in soft tissue, at bone interfaces, and in solid tumours. Clinical application of this work could provide a noninvasive means of enhancing chemotherapy in a variety of solid tumours.

The clinical efficacy of chemotherapy in solid tumours is limited by systemic toxicity and the inability to deliver a cytotoxic concentration of anticancer drugs to all tumour cells. Temperature sensitive drug carriers provide a mechanism for triggering the rapid release of chemotherapeutic agents in a targeted region. Thermally mediated drug release also leverages the ability of hyperthermia to increase tumour blood flow, vessel permeability, and drug cytotoxicity. Drug release from thermosensitive liposome drug carriers in the tumour vasculature serves as a continuous intravascular infusion of free drug originating at the tumour site. However, localized drug release requires precise heating to improve drug delivery and efficacy in tumours while minimizing drug exposure in normal tissue. Focused ultrasound can noninvasively heat millimeter-sized regions deep within the body, and can be combined with MR thermometry for precise temperature control. This thesis describes the development of strategies to achieve localized hyperthermia using MRI-controlled focused ultrasound, for the purpose of image-guided heat-triggered drug release from thermosensitive drug carriers. First, a preclinical MRI-controlled focused ultrasound system was developed as a platform for studies of controlled hyperthermia and drug delivery in rabbits. The feasibility of using ultrasound hyperthermia to achieve localized doxorubicin release from thermosensitive liposomes was demonstrated in normal rabbit muscle. Second, strategies were described for using MR thermometry to control ultrasound heating at a muscle-bone interface based on MR temperature measurements in adjacent soft tissue, demonstrating localized drug delivery in adjacent muscle and bone marrow. Third, fluorescence microscopy was employed to demonstrate that increased overall drug accumulation in rabbit VX2 tumours corresponds to high levels of bioavailable drug reaching their active site in the nuclei of tumour cells. The results of this thesis demonstrate that image-guided drug delivery using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia can be used to noninvasively achieve precisely localized drug deposition in soft tissue, at bone interfaces, and in solid tumours. Clinical application of this work could provide a noninvasive means of enhancing chemotherapy in a variety of solid tumours.

Objetivo: O objetivo do estudo foi avaliar se o uso da terapia hemodinâmica pós-operatória guiada pelo índice cardíaco por método minimamente invasivo reduz o desfecho combinado de mortalidade em 30 dias e de complicações graves durante a internação hospitalar em pacientes com câncer submetidos à cirurgia de alto risco. Desenho: Estudo fase III, de superioridade, unicêntrico, randomizado e controlado realizado no Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Brasil. População: Pacientes adultos submetidos a cirurgia de alto risco para tratamento de câncer e que necessitaram de cuidados pós-operatórios em unidade de terapia intensiva. Intervenção: Um protocolo de terapia hemodinâmica pós-operatória guiada por metas (incluindo reposição volêmica, fármacos vasoativos e transfusão de hemácias para manter índice cardíaco maior ou igual a 2,5 L/min/m2) foi comparado a uma terapia padrão nas primeiras 8 horas de admissão dos pacientes na Unidade de Terapia Intensiva. Desfecho primário: Desfecho composto por mortalidade em 30 dias e complicações graves durante a internação hospitalar (infarto agudo do miocárdio, síndrome do baixo débito cardíaco, isquemia mesentérica, isquemia vascular periférica, embolia pulmonar, síndrome do desconforto respiratório agudo, acidente vascular cerebral, insuficiência renal aguda, infecção de ferida operatória profunda e reoperação). Resultados: Foram incluídos 128 pacientes, 64 no grupo terapia guiada por metas (TGM) e 64 no grupo terapia padrão (TP). Durante as 8 horas de intervenção, não houve diferença entre os grupos TGM e TP na quantidade de fluidos administrada (1295,1 mL ± 613,2 mL vs 1129 mL ± 557,5 mL, P=0,189), no número de pacientes que receberam norepinefrina (65,5% vs 51,6%, P= 0,211) e no número de pacientes expostos a transfusão de hemácias (3,1% vs 0, P=0,496). Um número maior de pacientes do grupo TGM recebeu dobutamina durante a intervenção quando comparado aos pacientes do grupo TP (54,7% vs 15,65%, P < 0,001. Não houve diferença entre os grupos em relação ao desfecho primário (53,1% no grupo TGM vs 43,8% no grupo TP, P= 0,289). Conclusão: A terapia hemodinâmica guiada pelo índice cardíaco aplicada nas primeiras 8h de pós-operatório não reduziu a mortalidade em 30 dias e as complicações graves durante a internação hospitalar quando comparada a estratégia padrão em pacientes com câncer submetidos a cirurgia de alto risco. A terapia hemodinâmica resultou em maior exposição dos pacientes à dobutamina, sem resultar em redução das complicações. Registro no Clinical Trials: NCT01946269 / Objectives: The aim of this study was to determine whether a postoperative hemodynamic therapy guided by the cardiac index based on minimally invasive cardiac output monitoring decreases the incidence of 30-day mortality and postoperative complications in oncologic patients undergoing high-risk non-cardiac surgery. Design: Phase III, single center, superiority, randomized and controlled trial performed at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Brazil. Population: Adult patients undergoing high-risk cancer surgery who required intensive care unit admission. Intervention: A hemodynamic goal directed therapy protocol (including fluids, vasoactive agents and red blood cells transfusion to reach a cardiac index equal or higher than 2.5 L/min/m2) was compared to usual care during the first 8 h of postoperative. Primary outcome: The primary outcome was a composite endpoint of 30-day mortality and severe complications during hospital stay (acute myocardial infarction, low cardiac output syndrome, mesenteric ischemia, peripheral vascular ischemia, pulmonary embolism, acute respiratory distress syndrome, stroke, acute kidney injury, deep wound infection and reoperation). Results: 128 patients were included in the study; 64 were allocated to the goal directed therapy group (GDT) and 64 to the usual care group (UC). During the 8-hour intervention, there were no differences between GDT and UC groups in the amount of administered fluid (1295.1 mL ± 613.2 mL) vs (1129 mL ± 557.5 mL), P=0.189), in the number of patients who received norepinephrine (65.5% vs. 51.6%, P= 0.211) and in the number of patients exposed to red blood cells transfusion (3.1% vs. 0, P= 0,496). However, more patients in GDT group needed dobutamine during intervention when compared to patients from the UC group (54.7% vs. 15.65%, P < 0.001). The primary outcome was reached by a similar proportion of patients in both groups (53.1% in GDT group vs. 43.8% in UC group, P=0.289). Conclusion: Postoperative hemodynamic therapy guided by cardiac index monitoring in the first 8-hour of postoperative does not reduce 30-day mortality and severe complications during hospital stay when compared to the usual care in cancer patients undergoing high-risk surgery. Also, hemodynamic therapy resulted in a higher needing of dobutamine without improving outcomes. Clinical Trials Register: NCT01946269.

La radiothérapie est souvent utilisée pour contrôler la progression d'un cancer. Cependant, la mauvaise spécificité de ciblage de la plupart des techniques de radiothérapie peut entraîner une réponse clinique ambiguë. Une stratégie alternative - et complémentaire - est d'utiliser des matériaux possédant un numéro atomique élevé et qui peuvent ainsi agir en synergie avec les rayonnements ionisants pour améliorer le ratio thérapeutique de la radiothérapie. Dans ce contexte, une nanoparticule (NP) théranostique à base de gadolinium (Gd) est particulièrement adaptée pour fournir simultanément une plus grande précision en Imagerie par Résonance Magnétique (IRM) et une meilleure efficacité en radiothérapie clinique. Au cours de cette thèse, nous avons étudié d'un point de vue préclinique la pharmacocinétique et le métabolisme de ces NP chez des rongeurs et des primates non humains afin d'élucider leurs voies d'élimination et de calculer la dose sans effet nocif observé (NOAEL). De plus, nous avons démontré la capacité d'imagerie et de thérapie de ces particules sur un modèle de souris porteuses de mélanome cérébral, ceci afin d'appuyer le potentiel des NP pour la radiothérapie guidée par IRM en clinique. Ces travaux de thèse - ainsi que des résultats précédents - ont contribué au début d'un essai clinique actuellement en cours / Combinations of chemotherapy and radiotherapy are often used to control cancer progression. However, the poor targeting specificity of most chemotherapies and radiotherapies can cause toxicity and ambiguous clinical response. In particular, dose escalation in radiotherapy inevitably increases radiation exposure for some surroundings normal tissues and organs, putting them at risk for debilitating damage. An alternative – and complementary – strategy is the use of materials with high atomic numbers (Z) that strongly interact with low energy photons to produce photoelectrons and Auger electrons In this context, a new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed by the team of Prof. Tillement for MRI-guided radiotherapy. AGuIX® is a 3-nm size nanoparticles of 9 kDa, consist of a polysiloxane network surrounded by Gd chelates. In this thesis, we investigated the elimination kinetics of AGuIX nanoparticle’s (NPs) from sub-cellular to whole organ scale using original and complementary techniques. This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated. We reported the preclinical pharmacokinetics and toxicology studies of intravenous AGuIX NPs administration in healthy and atherosclerosis non-human primates (NHP), the goal of which is to demonstrate the safety of AGuIX NPs, in particular, for pre-clinical evaluation. Subsequently, we performed experimental and theoretical studies to investigate the radiosensitization of AGuIX NPs, in particular with B16F10 mouse melanoma as a model for brain metastases. After, we implemented experimental and theoretical studies to precisely understand the mechanism of this radiosensitization, we suggest additional mechanism, potentially caused by chemical and biological effects induced by the combination of Gd and radiation (i.e. high yield of radicals formation and combination, and bystander effect)