Temporal and local fluctuations in O2 in tumors require adaptive mechanisms to support cancer cell survival and proliferation. The transcriptome associated with cycling hypoxia (CycHyp) could thus represent a prognostic biomarker of cancer progression.
Genetic variation within plant species is determined by a number of factors such as reproductive mode, breeding system, life history traits and climatic events. In alpine regions, plants experience heterogenic abiotic conditions that influence the population's genetic structure. The aim of this study was to investigate the genetic structure and phylogeographic history of the subalpine shrub Rhododendron ferrugineum across the Pyrenees and the links between the populations in the Pyrenees, the Alps and Jura Mountains. We used 27 microsatellite markers to genotype 645 samples from 29 Pyrenean populations, three from the Alps and one from the Jura Mountains. These data were used to estimate population genetics statistics such as allelic richness, observed heterozygosity, expected heterozygosity, fixation index, inbreeding coefficient and number of migrants. Genetic diversity was found to be higher in the Alps than in the Pyrenees suggesting colonization waves from the Alps to the Pyrenees. Two separate genetic lineages were found in both the Alps and Pyrenees, with a substructure of five genetic clusters in the Pyrenees where a loss of genetic diversity was noted. The strong differentiation among clusters is maintained by low gene flow across populations. Moreover, some populations showed higher genetic diversity than others and presented rare alleles that may indicate the presence of alpine refugia. Two lineages of R. ferrugineum have colonized the Pyrenees from the Alps. Then, during glaciation events R. ferrugineum survived in the Pyrenees in different refugia such as lowland refugia at the eastern part of the chain and nunataks at high elevations leading to a clustered genetic pattern.
A novel robotic sensor is proposed to measure both the contact angle and the force acting between the tip of a surgical robot and soft tissue. The sensor is manufactured using a planar lithography process that generates microchannels that are subsequently filled with a conductive liquid. The planar geometry is then molded onto a hemispherical plastic scaffolding in a geometric configuration enabling estimation of the contact angle (angle between robot tip tangent and tissue surface normal) by the rotation of the sensor around its roll axis. Contact force can also be estimated by monitoring the changes in resistance in each microchannel. Bench top experimental results indicate that, on average, the sensor can estimate the angle of contact to within ±2° and the contact force to within ±5.3 g.
Object Endoscopy plays an increasingly important role in minimally invasive neurosurgery. Visual feedback from the endoscope tip helps the surgeon prevent unwanted tissue contact. However, critical feedback regarding tissue deformation and trauma from proximal endoscope components is currently unavailable. A system for force feedback along the endoscope length could provide significant clinical benefit by warning of impending damage. The authors manufactured and tested a novel pressure-sensing polymer skin for use in pressure feedback during intracranial endoscopy. Methods A photolithography process on a silicon wafer was used to produce a pattern of 80-?m-tall extrusions to serve as a positive mold for the sensor array. A thin layer of polydimethylsiloxane polymer was molded onto these features. Demolding the polymer from the wafer and sealing with another polymer layer resulted in microchannels. These microchannels were filled with a conductive liquid metal and connected to recording hardware. Spiral channel patterns were designed to create a 3 × 3 array of pressure-sensor pads, which were wrapped around a standard neuroendoscope operating sheath. Pressure readings from the compressed sensor array were translated into a color-coded graphic user interface. Calibration experiments were conducted, and the sensor was evaluated through cortical compression tests on explanted ovine brain. Results The sensing endoscope operating sheath was successfully calibrated to detect and display pressures within a range consistent with normal and tissue-threatening compressions. Conclusions Force-feedback mechanisms for the neuroendoscopist are critically lacking with contemporary endoscopes. The authors designed a pressure-sensing skin technology for improved pressure feedback during endoscopy as a means for minimizing collateral tissue damage during endoscopy.
Beating-heart image-guided intracardiac interventions have been evolving rapidly. To extend the domain of catheter-based and transcardiac interventions into reconstructive surgery, a new robotic tool delivery platform and a tissue approximation device have been developed. Initial results using these tools to perform patent foramen ovale closure are described.
The expression by tumor cells of proteins with aberrant structure, expression or distribution accounts for the development of a humoral immune response. Autoantibodies (aAb) directed against tumor-associated antigens (TAA) may thus be particularly relevant for early detection of cancer. Serological proteome analysis (SERPA) aims to identify such circulating aAb through the immunoblotting of 2D-separated tumor cell proteins with cancer patient serum and the consecutive MS identification of proteins in reactive spots. This method has the advantage to use post-translationally modified proteins as a source of potential TAA. Here, we applied this strategy by using colorectal tumor cells pre-exposed to hypoxia in order to promote the expression of a pattern of TAA more likely to represent in vivo conditions. We used two human HCT116 and HT29 colorectal cancer cell lines exposed for 48 hours to 1% O2. Spots positive after immunoblotting of 2D-separated lysates of hypoxic cells with the sera of tumor-bearing mice, were collected and analysed by MS for protein identification. Among the hypoxia-specific immunogenic proteins, we identified a phosphorylated form of eukaryotic translation elongation factor 2 (phospho-Thr56 eEF2). We confirmed the increased phosphorylation of this protein in hypoxic colorectal tumor cells as well as in mouse tumors. Using a specific immunoassay, we could detect the presence of corresponding anti-phospho-Thr56 eEF2 aAb in the serum of tumor-bearing mice (vs healthy mice). We further documented that the detection of these aAb preceded the detection of a palpable tumor mass in mice and validated the presence of anti-phospho-Thr56 eEF2 aAb in the serum of patients with adenomatous polyps and colorectal carcinoma. In conclusion, this study validates a phosphorylated form of eEF2 as a new TAA and more generally, provides evidence that integrating hypoxia upstream of SERPA offers a more relevant repertoire of TAA able to unmask the presence of circulating aAb.
Three-dimensional ultrasound can be an effective imaging modality for image-guided interventions since it enables visualization of both the instruments and the tissue. For robotic applications, its realtime frame rates create the potential for image-based instrument tracking and servoing. These capabilities can enable improved instrument visualization, compensation for tissue motion as well as surgical task automation. Continuum robots, whose shape comprises a smooth curve along their length, are well suited for minimally invasive procedures. Existing techniques for ultrasound tracking, however, are limited to straight, laparoscopic-type instruments and thus are not applicable to continuum robot tracking. Toward the goal of developing tracking algorithms for continuum robots, this paper presents a method for detecting a robot comprised of a single constant curvature in a 3D ultrasound volume. Computational efficiency is achieved by decomposing the six-dimensional circle estimation problem into two sequential three-dimensional estimation problems. Simulation and experiment are used to evaluate the proposed method.
Achieving superior outcomes through the use of robots in medical applications requires an integrated approach to the design of the robot, tooling and the procedure itself. In this paper, this approach is applied to develop a robotic technique for closing abnormal communication between the atria of the heart. The goal is to achieve the efficacy of surgical closure as performed on a stopped, open heart with the reduced risk and trauma of a beating-heart catheter-based procedure. In the proposed approach, a concentric tube robot is used to percutaneously access the right atrium and deploy a tissue approximation device. The device is constructed using a metal MEMS fabrication process and is designed to both fit the manipulation capabilities of the robot as well as to reproduce the beneficial features of surgical closure by suture. Experimental results demonstrate device efficacy through manual in-vivo deployment and bench-top robotic deployment.
Concentric tube robots are a novel continuum robot technology that is well suited to minimally invasive surgeries inside small body cavities such as the heart. These robots are constructed of concentrically combined pre-curved elastic tubes to form 3D curves. Each telescopic section of the robot is either of fixed or variable curvature. One advantage of this approach is that the component tube curvatures, lengths and stiffnesses can easily be fabricated to be procedure- and patient-specific. This paper proposes an optimization framework for solving the robot design problem. Given a 3D description of the constraining anatomy, the number of fixed and variable curvature robot sections and a tip workspace description, the algorithm solves for the robot design that possesses the desired workspace, remains inside the anatomical constraints and minimizes the curvature and length of all sections. The approach is illustrated in the context of beating-heart closure of atrial septal defects.
A family of passive echogenic markers is presented by which the position and orientation of a surgical instrument can be determined in a 3-D ultrasound volume, using simple image processing. Markers are attached near the distal end of the instrument so that they appear in the ultrasound volume along with the instrument tip. They are detected and measured within the ultrasound image, thus requiring no external tracking device. This approach facilitates imaging instruments and tissue simultaneously in ultrasound-guided interventions. Marker-based estimates of instrument pose can be used in augmented reality displays or for image-based servoing. Design principles for marker shapes are presented that ensure imaging system and measurement uniqueness constraints are met. An error analysis is included that can be used to guide marker design and which also establishes a lower bound on measurement uncertainty. Finally, examples of marker measurement and tracking algorithms are presented along with experimental validation of the concepts.
Three-dimensional ultrasound has been an effective imaging modality for diagnostics and is now an emerging modality for image-guided minimally-invasive interventions since it enables visualization of both instruments and tissue. Challenges to ultrasound-guided interventions arise, however, due to the low signal-to-noise ratio and the imaging artifacts created by the interventional instruments. Metallic instruments, in particular, are strong scatters and so produce a variety of artifacts. For many interventions, the manual or robotic instrument is comprised of a long curved tubular structure with specialized tooling at its tip. Toward the goal of developing a surgical navigation system, this paper proposes an image processing algorithm for enhancing the tubular structure of imaged instruments while also reducing imaging artifacts. Experiments are presented to evaluate the effectiveness of the approach in the context of robotic instruments whose shape comprises a smooth curve along their length.
Replacing open-heart surgical procedures with beating-heart interventions substantially decreases the trauma and risk of a procedure. One of the most challenging procedures to perform on the beating heart is valve repair. To address this need, this paper proposes a tool for replacing mitral valve chordae to correct regurgitation. The chordae is secured to the papillary muscle and leaflet using NiTi tissue anchors that also incorporate an internal adjustment mechanism to enable initial adjustment as well as subsequent readjustment of chordae length. Efficacy of the proposed tool for chordae replacement and reduction of regurgitation was demonstrated in an ex-vivo heart simulator.
We propose a novel systematic approach to optimizing the design of concentric tube robots for neurosurgical procedures. These procedures require that the robot approach specified target sites while navigating and operating within an anatomically constrained work space. The availability of preoperative imaging makes our approach particularly suited for neurosurgery, and we illustrate the method with the example of endoscopic choroid plexus ablation. A novel parameterization of the robot characteristics is used in conjunction with a global pattern search optimization method. The formulation returns the design of the least-complex robot capable of reaching single or multiple target points in a confined space with constrained optimization metrics. A particular advantage of this approach is that it identifies the need for either fixed-curvature versus variable-curvature sections. We demonstrate the performance of the method in four clinically relevant examples.
Concentric tube robots are a novel class of continuum robots that are constructed by combining pre-curved elastic tubes such that the overall shape of the robot is a function of the relative rotations and translations of the constituent tubes. Frictionless kinematic and quasistatic force models for this class of robots have been developed that incorporate bending and twisting of the tubes. Experimental evaluation of these models has revealed, however, a directional dependence of tube rotation on robot shape that is not predicted by these models. To explain this behavior, this paper models the contributions of friction arising from two sources: the distributed forces of contact between the tubes along their length and the concentrated bending moments generated at discontinuities in curvature and at the boundaries. It is shown that while friction due to distributed forces is insufficient to explain the experimentally observed tube twisting, a simple model of frictional torque arising from concentrated moments provides a good match with the experimental data.
This paper presents a novel actuation technology for robotically assisted MRI-guided interventional procedures. Compact and wireless, the actuators are both powered and controlled by the MRI scanner. The design concept and performance limits are described and derived analytically. Simulation and experiments in a clinical MR scanner are used to validate the analysis and to demonstrate the capability of the approach for needle biopsies. The concepts of actuator locking mechanisms and multi-axis control are also introduced.
Computational phylogenetic analysis coupled to promoter sequence alignment was used to understand mechanisms of transcriptional regulation and to identify potentially coregulated genes. Our strategy was validated on the human ANT4 gene which encodes the fourth isoform of the mitochondrial adenine nucleotide translocator specifically expressed during spermatogenesis. The movement of sperm flagella is driven mainly by ATP generated by glycolytic pathways, and the specific induction of the mitochondrial ANT4 protein presented an interesting puzzle. We analysed the sequences of the promoters, introns and exons of 30 mammalian ANT4 genes and constructed regulatory models. The whole human genome and promoter database were screened for genes that were potentially regulated by the generated models. 80% of the identified co-regulated genes encoded proteins with specific roles in spermatogenesis and with functions linked to male reproduction. Our in silico study enabled us to precise the specific role of the ANT4 isoform in spermatozoid bioenergetics.
This paper introduces the first stiffness controller for continuum robots. The control law is based on an accurate approximation of a continuum robots coupled kinematic and static force model. To implement a desired tip stiffness, the controller drives the actuators to positions corresponding to a deflected robot configuration that produces the required tip force for the measured tip position. This approach provides several important advantages. First, it enables the use of robot deflection sensing as a means to both sense and control tip forces. Second, it enables stiffness control to be implemented by modification of existing continuum robot position controllers. The proposed controller is demonstrated experimentally in the context of a concentric tube robot. Results show that the stiffness controller achieves the desired stiffness in steady state, provides good dynamic performance, and exhibits stability during contact transitions.
A novel approach toward construction of robots is based on a concentric combination of precurved elastic tubes. By rotation and extension of the tubes with respect to each other, their curvatures interact elastically to position and orient the robots tip, as well as to control the robots shape along its length. In this approach, the flexible tubes comprise both the links and the joints of the robot. Since the actuators attach to the tubes at their proximal ends, the robot itself forms a slender curve that is well suited for minimally invasive medical procedures. This paper demonstrates the potential of this technology. Design principles are presented and a general kinematic model incorporating tube bending and torsion is derived. Experimental demonstration of real-time position control using this model is also described.
Concentric tube robots are a subset of continuum robots constructed by combining pre-curved elastic tubes. As the tubes are rotated and translated with respect to each other, their curvatures interact elastically, enabling control of the robots tip configuration as well as the curvature along its length. This technology is projected to be useful in many types of minimally invasive medical procedures. Because these robots are flexible by design, they deflect considerably when applying forces to the external environment. Thus, in contrast to rigid-link robots, their kinematic and static force models are coupled. This paper derives a multi-tube quasistatic model that relates tube rotations and translations together with externally applied loads to robot shape and tip configuration. The model can be applied in robot design, procedure planning as well as control. For validation, the multi-tube model is compared experimentally to a computationally-efficient single-tube approximate model.
A novel approach to constructing robots is based on concentrically combining pre-curved elastic tubes. By rotating and extending the tubes with respect to each other, their curvatures interact elastically to position and orient the robots tip, as well as to control the robots shape along its length. Since these robots form slender curves, they are well suited for minimally invasive medical procedures. A substantial challenge to their practical use is the real-time solution of their kinematics that are described by differential equations with split boundary equations. This paper proposes a numerically efficient approach to real-time position control. It is shown that the forward kinematics are smooth functions that can be pre-computed and accurately approximated using Fourier series. The inverse kinematics can be solved in real time using root finding applied to the functional approximation. Experimental demonstration of real-time position control using this approach is also described.
Subgraph extraction is a powerful technique to predict pathways from biological networks and a set of query items (e.g. genes, proteins, compounds, etc.). It can be applied to a variety of different data types, such as gene expression, protein levels, operons or phylogenetic profiles. In this article, we investigate different approaches to extract relevant pathways from metabolic networks. Although these approaches have been adapted to metabolic networks, they are generic enough to be adjusted to other biological networks as well.
Molecular docking was used in order to prioritize organic syntheses or experimental evaluations. Different GSK-3beta protein models were generated in silico from a known X-ray structure. A set of 42 known inhibitors were then flexibly docked into each rigid model and re-scored with various functions, which led to different rankings. The biological activities of the chemicals were then compared to each set of results and one of the rigid models emerged in combination with two scoring functions as giving the best correlation. This methodology constitutes an easy and accurate way to generate reliable models for virtual database screening.
Stiffness control of a continuum robot can prevent excessive contact forces during robot navigation inside delicate, uncertain and confined environments. Furthermore, it enables the selection of tip stiffnesses that match varying task requirements. This paper introduces a computationally-efficient approach to continuum-robot stiffness control that is based on writing the forward kinematic model as the product of two transformations. The first transformation calculates the non-contact kinematics of the robot and can be formulated based on the specific type of continuum robot under consideration. The second transformation calculates the tip deflection due to applied forces and is efficiently computed using the special Cosserat rod model. To implement a desired tip stiffness, the two transformations are used to solve for the actuator positions that deform the manipulator so as to generate the required tip force at the measured tip position. The efficacy of the proposed controller is demonstrated experimentally on a concentric-tube continuum robot.
Biomarker discovery is an important topic in biomedical applications of computational biology, including applications such as gene and SNP selection from high-dimensional data. Surprisingly, the stability with respect to sampling variation or robustness of such selection processes has received attention only recently. However, robustness of biomarkers is an important issue, as it may greatly influence subsequent biological validations. In addition, a more robust set of markers may strengthen the confidence of an expert in the results of a selection method.
During needle-based procedures, transitions between tissue layers often lead to rupture events that involve large forces and tissue deformations and produce uncontrollable crack extensions. In this paper, the mechanics of these rupture events is described, and the effect of insertion velocity on needle force, tissue deformation, and needle work is analyzed. Using the J integral method from fracture mechanics, rupture events are modeled as sudden crack extensions that occur when the release rate J of strain energy concentrated at the tip of the crack exceeds the fracture toughness of the material. It is shown that increasing the velocity of needle insertion will reduce the force of the rupture event when it increases the energy release rate. A nonlinear viscoelastic Kelvin model is then used to predict the relationship between the deformation of tissue and the rupture force at different velocities. The model predicts that rupture deformation and work asymptotically approach minimum values as needle velocity increases. Consequently, most of the benefit of using a higher needle velocity can be achieved using a finite velocity that is inversely proportional to the relaxation time of the tissue. Experiments confirm the analytical predictions with multilayered porcine cardiac tissue.
During needle-based procedures, transitions between tissue layers often involve puncture events that produce substantial deformation and tend to drive the needle off course. In this paper, we analyze the mechanics of these rupture events corresponding to unstable crack propagation during the insertion of a sharp needle in an inhomogeneous tissue. The force-deflection curve of the needle prior to a rupture event is modeled by a nonlinear viscoelastic Kelvin model and a stress analysis is used to predict the relationship between rupture force and needle velocity. The model predicts that the force-deflection response of the needle is steeper and the tissue absorbs less energy when the needle moves faster. The force of rupture also decreases for faster insertion under certain conditions. The observed properties are sufficient to show that maximizing needle velocity minimizes tissue deformation and damage, and consequently, results in less needle insertion position error. The model predicts that tissue deformation and absorbed energy asymptotically approach lower bounds as velocity increases. Experiments with porcine cardiac tissue confirm the analytical predictions.
A recent approach to steerable needle design is based on combining pre-curved tubes concentrically. By rotating and extending the tubes with respect to each other, the position and orientation of the needle tip, as well as the shape of the inserted length, can be controlled. Prior models neglected torsional twisting in the curved portions of the tubes. This paper presents a mechanics model that includes torsion, applies to any number of tubes and allows curvature and stiffness to vary with arc length. While the general model is comprised of differential equations, an analytic solution is given for two tubes of constant curvature. This solution enables analytic prediction of "snap through" instability based on a single dimensionless parameter. Simulation and experiments are used to illustrate the results.
A new Tetratrichomonas species was identified by molecular and phylogenetic approaches in the pleural fluid from a patient with encysted empyema leading to dyspnea. This observation raised the questions of the real prevalence of pulmonary trichomonosis in humans, the zoonotic potential of trichomonads, and the existence of human-host-adapted strains.
Achieving superior outcomes through the use of robots in medical applications requires an integrated approach to the design of the robot, tooling and the procedure itself. In this paper, this approach is applied to develop a robotic technique for closing abnormal communication between the atria of the heart. The goal is to achieve the efficacy of surgical closure as performed on a stopped, open heart with the reduced risk and trauma of a beating-heart catheter-based procedure. In the proposed approach, a concentric tube robot is used to percutaneously access the right atrium and deploy a tissue approximation device. The device is constructed using a metal microelectromechanical system (MEMS) fabrication process and is designed to both fit the manipulation capabilities of the robot as well as to reproduce the beneficial features of surgical closure by suture. The effectiveness of the approach is demonstrated through ex vivo and in vivo experiments.
The excellent imaging capabilities of MRI technology are standardizing this modality for a variety of interventional procedures. To assist radiologists, MRI compatible robots relying on traditional actuation technologies are being developed. Recently, a robot that is not only MRI compatible but also MRI powered was introduced. This surgical robot is imaged and actuated through interleaved MRI pulses, and can be controlled to perform automated needle insertion. Using the electromagnetic field generated by the MRI scanner, the robot can exercise adequate forces to puncture tissue. Towards the goal of automation, this paper reports results on tracking and control of an MRI-powered robot tagged with a fiducial marker. Tracking is achieved using non-selective RF pulses and balanced gradient readouts. To suppress the signal received from the tissue, spoiler gradients and background suppression are introduced. Their effects on tracking are quantified and are used to optimize the algorithm. Subsequently, a Kalman filter is employed for robustness. The developed algorithm is used to demonstrate position controlled needle insertion ex vivo.
The analysis of gene promoters is essential to understand the mechanisms of transcriptional regulation required under the effects of physiological processes, nutritional intake or pathologies. In higher eukaryotes, transcriptional regulation implies the recruitment of a set of regulatory proteins that bind on combinations of nucleotide motifs. We developed a computational analysis of promoter nucleotide sequences, to identify co-regulated genes by combining several programs that allowed us to build regulatory models and perform a crossed analysis on several databases. This strategy was tested on a set of four human genes encoding isoforms 1 to 4 of the mitochondrial ADP/ATP carrier ANT. Each isoform has a specific tissue expression profile linked to its role in cellular bioenergetics.
The initial success seen in adult cardiac surgery with the application of available robotic systems has not been realized as broadly in pediatric cardiac surgery. The main obstacles include extended set-up time and complexity of the procedures, as well as the large size of the instruments with respect to the size of the child. Moreover, while the main advantage of robotic systems is the ability to minimize incision size, for intracardiac repairs, cardiopulmonary bypass is still required. Catheter-based interventions, on the other hand, have expanded rapidly in both application as well as the complexity of procedures and lesions being treated. However, despite the development of sophisticated devices, robotic systems to aid catheter procedures have not been commonly applied in children. In this article, we describe new catheter-like robotic delivery platforms, which facilitate safe navigation and enable complex repairs, such as tissue approximation and fixation, and tissue removal, inside the beating heart. Additional features including the tracking of rapidly moving tissue targets and novel imaging approaches are described, along with a discussion of future prospects for steerable robotic systems.
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