Nonlinear Adaptive Optimal Controller Design for Anti-Angiogenic Tumor Treatment.

Angiogenesis is an important process in tumor growth as it represents the regime when the tumor recruits blood vessels from the surrounding tissue to support further tumor growth. Anti-angiogenic treatments aim to shrink the tumor by interrupting the vascularization of the tumor; however, the anti-angiogenic agents are costly and the tumor response to these agents is nonlinear. Simple dosing schemes, e.g., a constant dose, may yield higher cost or lower efficacy than an approach that considers the tumor system dynamics. Hence, in this study, the administration of anti-angiogenic treatment is considered as a nonlinear control problem. The main aim of the controller design is to optimize the anti-angiogenic tumor therapy, specifically, to minimize the tumor volume and drug dose. Toward this aim, two nonlinear optimal controllers are presented. The first controller ensures exponential tracking of a desired, optimal tumor volume profile under the assumption that all parameters in the system model are known. The second controller, on the other hand, assumes all the parameters are unknown and provides asymptotic tracking. Both controllers take pharmacokinetics and pharmacodynamics into account, as well as the carrying capacity of the vascular network. Lyapunov based arguments are used to design the controllers, using stability arguments, and numerical simulation results are presented to demonstrate the effectiveness of the proposed method.

Learning to perceive haptic distance-to-break in the presence of friction.

Two experiments employed attunement and calibration training to investigate whether observers are able to identify material break points in compliant materials through haptic force application. The task required participants to attune to a recently identified haptic invariant, distance-to-break (DTB), rather than haptic stimulation not related to the invariant, including friction. In the first experiment participants probed simulated force-displacement relationships (materials) under 3 levels of friction with the aim of pushing as far as possible into the materials without breaking them. In a second experiment a different set of participants pulled on the materials. Results revealed that participants are sensitive to DTB for both pushing and pulling, even in the presence of varying levels of friction, and this sensitivity can be improved through training. The results suggest that the simultaneous presence of friction may assist participants in perceiving DTB. Potential applications include the development of haptic training programs for minimally invasive (laparoscopic) surgery to reduce accidental tissue damage. (PsycINFO Database Record

Simulator-based assessment of haptic surgical skill: a comparative study.

The aim of this study was to examine if the forces applied by users of a haptic simulator could be used to distinguish expert surgeons from novices. Seven surgeons with significant operating room expertise and 9 novices with no surgical experience participated in this study. The experimental task comprised exploring 4 virtual materials with the haptic device and learning the precise forces required to compress the materials to various depths. The virtual materials differed in their stiffness and force-displacement profiles. The results revealed that for nonlinear virtual materials, surgeons applied significantly greater magnitudes of force than novices. Furthermore, for the softer nonlinear and linear materials, surgeons were significantly more accurate in reproducing forces than novices. The results of this study suggest that the magnitudes of force measured using haptic simulators may be used to objectively differentiate experts' haptic skill from that of novices. This knowledge can inform the design of virtual reality surgical simulators and lead to the future incorporation of haptic skills training in medical school curricula.

Endovascular seldinger needle placement: a simulator for examining haptic skills.

In this work, we develop an affordable haptic simulator for examining haptic skills required for endovascular Seldinger needle placement.

A CMI (cell metabolic indicator)-based controller for achieving high growth rate Escherichia coli cultures.

A large fraction of biopharmaceuticals are produced in Escherichia coli, where each new product and strain currently requires a high degree of growth characterization in benchtop and industrial bioreactors to achieve economical production protocols. The capability to use a standard set of sensors to characterize a system quickly without the need to conduct numerous experiments to determine stable growth rate for the strain would significantly decrease development time. This paper presents a cell metabolic indicator (CMI) which provides better insight into the E. coli metabolism than a growth rate value. The CMI is the ratio of the oxygen uptake rate (OUR) of the culture and the base addition rate (BAR) required to keep pH at a desired setpoint. The OUR and BAR are measured using a off-gas sensor and pH probe, respectively, and thus the CMI can be computed online. Experimental results demonstrate the relationship between CMI and the different cell metabolic states. A previously published model is augmented with acid production dynamics, allowing for comparison of the CMI-based controller with an open-loop controller in simulation. The CMI-based controller required little a priori knowledge about the E. coli strain in order to achieve a high growth rate. Since many different types of cells exhibit similar behaviors, the CMI concept can be extended to mammalian and stem cells.

A real-time adaptive oxygen transfer rate estimator for metabolism tracking in Escherichia coli cultures.

Oxygen transfer rate (OTR) is the most significant signal for aerobic bioprocess control, since most microbic metabolic activity relies on oxygen consumption. However, accurate estimation of OTR is challenging due to the difficulty of determining uncertain oxygen transfer parameters and system dynamics. This paper presents an adaptive estimator, which incorporates exhaust gas, stir speed and dissolved oxygen measurements, to predict the real-time OTR. The design of this estimator takes into account the headspace dilution effect, off-gas sensor dynamics and uncertain oxygen transfer parameters. Through simulation the estimated real-time OTR is shown to accurately track quick changes of oxygen demand in the culture. Thus, it can be applied to a variety of controls and estimation purposes, such as determining when the culture is in oxidative or overflow metabolism.

A haptic simulator to increase laparoscopic force application sensitivity.

Laparoscopic surgery demands perceptual-motor skills that are fundamentally different from open surgery, and laparoscopists must be adept at perceiving tissue interaction at the surgical site and then applying precise amounts of forces through instruments without damaging tissues. A haptic simulator that emulates multiple salient laparoscopic tasks and renders differing degrees of forces was created. Two of the haptic skills tasks were evaluated in two studies to determine their ability to distinguish and then train laparoscopic force application sensitivity. Results suggested that the simulator has the capability of rendering salient force feedback information to which novices become increasingly more perceptually sensitive.

Salient haptic skills trainer: initial validation of a novel simulator for training force-based laparoscopic surgical skills.

BACKGROUND: There is an increasing need for efficient training simulators to teach advanced laparoscopic skills beyond those imparted by a box trainer. In particular, force-based or haptic skills must be addressed in simulators, especially because a large percentage of surgical errors are caused by the over-application of force. In this work, the efficacy of a novel, salient haptic skills simulator is tested as a training tool for force-based laparoscopic skills. METHODS: Thirty novices with no previous laparoscopic experience trained on the simulator using a pre-test-feedback-post-test experiment model. Ten participants were randomly assigned to each of the three salient haptic skills-grasping, probing, and sweeping-on the simulator. Performance was assessed by comparing force performance metrics before and after training on the simulator. RESULTS: Data analysis indicated that absolute error decreased significantly for all three salient skills after training. Participants also generally decreased applied forces after training, especially at lower force levels. Overall, standard deviations also decreased after training, suggesting that participants improved their variability of applied forces. CONCLUSIONS: The novel, salient haptic skills simulator improved the precision and accuracy of participants when applying forces with the simulator. These results suggest that the simulator may be a viable tool for laparoscopic force skill training. However, further work must be undertaken to establish full validity. Nevertheless, this work presents important results toward addressing simulator-based force-skills training specifically and surgical skills training in general.

Objective differentiation of force-based laparoscopic skills using a novel haptic simulator.

BACKGROUND: There is a growing need for effective surgical simulators to train the novice resident with a core skill set that can be later used in advanced operating room training. The most common simulator-based laparoscopic skills curriculum, the Fundamentals of Laparoscopic Skills (FLS), has been demonstrated to effectively teach basic surgical skills; however, a key deficiency in current surgical simulators is lack of validated training for force-based or haptic skills. In this study, a novel haptic simulator was examined for construct validity by determining its ability to differentiate between the force skills of surgeons and novices. METHODS: A total of 34 participants enrolled in the study and were divided into two groups: novices, with no previous surgical experience and surgeons, with some level of surgical experience (including upper level residents and attendings). All participants performed a force-based task using grasping, probing, or sweeping motions with laparoscopic tools on the simulator. In the first session, participants were given 3 trials to learn specific forces associated with locations on a graphic; after this, they were asked to reproduce forces at each of the locations in random order. A force-based metric (score) was used to record performance. RESULTS: On probing and grasping tasks, novices applied significantly greater overall forces than surgeons. When analyzed by force levels, novices applied greater forces on the probing task at lower and mid-range forces, for grasping at low-range forces ranges and, for sweeping at high-range forces. CONCLUSIONS: The haptic simulator successfully differentiated between novice and surgeon force skill level at specific ranges for all 3 salient haptic tasks, establishing initial construct validity of the haptic simulator. Based on these results, force-based simulator metrics may be used to objectively measure haptic skill level and potentially train residents. Haptic simulator development should focus on the 3 salient haptic skills (grasping, probing, and sweeping) where precise force application is necessary for successful task outcomes.

Assessing surgeon and novice force skill on a haptic stiffness simulator for laparoscopic surgery.

Though several simulators and training methods are available for basic laparoscopic skills, few have addressed force-based skills. In this work, we discuss a haptic simulator that renders virtual materials of different stiffness profiles to be used for haptic skills differentiation. A force-based task was designed on the simulator and the performance of surgeons and novices was analyzed. Results indicate that surgeons and novices differ in their ability to use the haptic device to reproduce target stiffness levels. This work provides an important step towards quantifying haptic skill metrics for the design of surgical skills training simulators.

Haptic tasks for physical laparoscopic ("Box") trainers to differentiate surgeon skill.

In this work, we present four tasks, primarily testing haptic laparoscopic skill that can be simulated in a conventional box trainer. Results from examining expert surgeon and novice performance is presented as evidence that these tasks can be used for training haptic skills for laparoscopy in a box trainer.

Characterizing the effects of cell settling on bioprinter output.

The time variation in bioprinter output, i.e. the number of cells per printed drop, was studied over the length of a typical printing experiment. This variation impacts the cell population size of bioprinted samples, which should ideally be consistent. The variation in output was specifically studied in the context of cell settling. The bioprinter studied is based on the thermal inkjet HP26A cartridge; however, the results are relevant to other cell delivery systems that draw fluid from a reservoir. A simple mathematical model suggests that the cell concentration in the bottom of the reservoir should increase linearly over time, up to some maximum, and that the cell output should be proportional to this concentration. Two studies were performed in which D1 murine stem cells and similarly sized polystyrene latex beads were printed. The bead output profiles were consistent with the model. The cell output profiles initially followed the increasing trend predicted by the settling model, but after several minutes the cell output peaked and then decreased. The decrease in cell output was found to be associated with the number of use cycles the cartridge had experienced. The differing results for beads and cells suggest that a biological process, such as adhesion, causes the decrease in cell output. Further work will be required to identify the exact process.

Role of haptic feedback in a basic laparoscopic task requiring hand-eye coordination.

This work discusses the role and importance of haptic feedback and simulator training for simple laparoscopic tasks akin to the FLS peg-transfer task. Results from a study designed to examine haptics for this purpose are discussed.

Perceptual metrics: towards better methods for assessing realism in laparoscopic simulators.

This work proposes a novel class of metrics for assessing haptic realism in laparoscopic surgical simulators. Results from a proposed perceptual metric are presented and discussed.

Comparative study of haptic training versus visual training for kinesthetic navigation tasks.

Kinesthetic motion appears in tasks ranging from minimally invasive surgical procedures to patient rehabilitation. In this work, a comparative study is performed using two training paradigms for kinesthetic tasks. Subjects are trained to learn a complex 3D path through either the haptic method or the visual method. After the training period, subjects trace the learned 3D path without any feedback. Performance is evaluated primarily based on path deviation and time. Results indicate that haptically trained users have significantly higher performance than visually trained users. Other relevant results are also presented that can have a significant effect in the design of haptics-based interaction systems.