Many biological systems, such as cell cultures in vitro, are complex, non-linear, and time varying, resulting in challenges for the development of effective control methods. Therefore, it is beneficial to develop simulation environments to understand dynamics of these biological systems and, for example, compare different control strategies. In this paper, we created a mathematical model to simulate temperature-dependency of beating human cardiomyocyte cultures. The developed system can be used for comparing different closed-loop control strategies and for studying how sensitive the beating of cardiomyocytes is for temperature variations. We employed the system for comparing the performance of fuzzy logic-based and traditional Proportional-Integral controllers and presented, how their performances varied in different cell culture cases. Our results indicate clearly, how the fuzzy logic-based controller can outperform the traditional Proportional-Integral controller when they are implemented to control the beating of cardiomyocyte cultures. Note to Practitioners—This paper was motivated by the challenge of creating controllable engineered living materials. For this reason, we created a simulation environment to help the development of these materials, thus to reduce the discovery time. As a demonstration, we showed in this paper how the developed simulation environment can be used to design and compare different controller strategies, such as the traditional Proportional-Integral-Derivate controller and controllers based on fuzzy-logic. In the paper, we implemented different controllers and cardiomyocyte environments to study how beating of cardiomyocyte cultures could be controlled in an optimal way in vitro. We show, how fuzzy-logic controllers outperform the traditional PI-controller when applied to a highly non-linear and time-varying biological system.

The aim was to study if odors evaporated by an olfactory display prototype can be used to affect participants' cognitive and emotionrelated responses to audio-visual stimuli, and whether the display can benefit from objective measurement of the odors. The results showed that odors and videos had significant effects on participants' responses. For instance, odors increased pleasantness ratings especially when the odor was authentic and the video was congurent with odors. The objective measurement of the odors was shown to be useful. The measurement data was classified with 100% accuracy removing the need to speculate whether the odor presentation apparatus is working properly.

Microfluidic devices are promising tools with which to create an environment that mimics a cell's natural microenvironment more closely than traditional macroscopic cell culture approaches. In these devices, temperature is one of the most important environmental factors to monitor and control. However, direct temperature measurement at the cell area can disturb cell growth and potentially prevent optical monitoring, and is typically difficult to implement. On the other hand, indirect measurement could overcome these challenges. Therefore, using the system identification method, we have developed models to estimate the cell area temperature from external measurements without interfering cells. In order to validate the proposed models, we performed large sets of experiments. The results show that the models are able to catch the dynamics of temperature in a desired area with a high level of accuracy, which means that indirect temperature measurement using the model can be implemented in the future cell culture studies. The usefulness of the model is also demonstrated by simulations that use estimated temperature as a feedback signal in a closed-loop system. We also present tuning of a model-based controller and a noise study, which shows that the tuned controller is robust for typical ambient room temperature variations.

This paper introduces a novel micro-force sensing approach utilizing an electroplated nickel microspring and a precision linear slider (PLS) for micro-tensile testing applications. After investigating the effects of friction forces in a PLS, an electroplated nickel microspring is designed, fabricated and integrated into the PLS, and the proposed micro-force sensor concept is validated through experimental results. The microspring fabricated in this paper is limited to forces up to 6 mN with the average sensitivity of 36.63 µN/µm. It is shown that the friction forces introduce uncertainties only to the forces less than 500 µN. The proposed approach allows the fabrication of micro-force sensors for the force ranges of up to tens of Millinewtons for different applications.

This paper presents a novel method for automated manipulation of individual paper fiber bonds using a microrobotic platform, a computer vision algorithm and a robotic software framework. This is a challenging task due to the three-dimensional, heterogeneous and complex morphology of the fiber bonds. The goal is to automatically grasp the fiber bond, and break it by pulling apart the fibers it consists of. We present the components of the microrobotic platform, and the different rules utilized in detecting suitable grasp points from a 3D reconstruction of the bond generated from an image pair. We demonstrate the functionality of the approach with bond breaking experiments of seven fiber bonds. The time required for grasping and breaking of a bond is 10 - 15 seconds making the approach much faster than the current state-of-the-art testing, which is based on manual manipulation. The success rate of the tests is as high as 80 %.

BACKGROUND: Orientation and the degree of isotropy are important in many biological systems such as the sarcomeres of cardiomyocytes and other fibrillar structures of the cytoskeleton. Image based analysis of such structures is often limited to qualitative evaluation by human experts, hampering the throughput, repeatability and reliability of the analyses. Software tools are not readily available for this purpose and the existing methods typically rely at least partly on manual operation. RESULTS: We developed CytoSpectre, an automated tool based on spectral analysis, allowing the quantification of orientation and also size distributions of structures in microscopy images. CytoSpectre utilizes the Fourier transform to estimate the power spectrum of an image and based on the spectrum, computes parameter values describing, among others, the mean orientation, isotropy and size of target structures. The analysis can be further tuned to focus on targets of particular size at cellular or subcellular scales. The software can be operated via a graphical user interface without any programming expertise. We analyzed the performance of CytoSpectre by extensive simulations using artificial images, by benchmarking against FibrilTool and by comparisons with manual measurements performed for real images by a panel of human experts. The software was found to be tolerant against noise and blurring and superior to FibrilTool when analyzing realistic targets with degraded image quality. The analysis of real images indicated general good agreement between computational and manual results while also revealing notable expert-to-expert variation. Moreover, the experiment showed that CytoSpectre can handle images obtained of different cell types using different microscopy techniques. Finally, we studied the effect of mechanical stretching on cardiomyocytes to demonstrate the software in an actual experiment and observed changes in cellular orientation in response to stretching. CONCLUSIONS: CytoSpectre, a versatile, easy-to-use software tool for spectral analysis of microscopy images was developed. The tool is compatible with most 2D images and can be used to analyze targets at different scales. We expect the tool to be useful in diverse applications dealing with structures whose orientation and size distributions are of interest. While designed for the biological field, the software could also be useful in non-biological applications.

An automatic computer vision algorithm that detects individual paper fibres from an image, assesses the possibility of grasping the detected fibres with microgrippers and detects the suitable grasping points is presented. The goal of the algorithm is to enable automatic fibre manipulation for mechanical characterisation, which has traditionally been slow manual work. The algorithm classifies the objects in images based on their morphology, and detects the proper grasp points from the individual fibres by applying given geometrical constraints. The authors test the ability of the algorithm to detect the individual fibres with 35 images containing more than 500 fibres in total, and also compare the graspability analysis and the calculated grasp points with the results of an experienced human operator with 15 images that contain a total of almost 200 fibres. The detection results are outstanding, with fewer than 1% of fibres missed. The graspability analysis gives sensitivity of 0.83 and specificity of 0.92, and the average distance between the grasp points of the human and the algorithm is 220 µm. Also, the choices made by the algorithm are much more consistent than the human choices.

This paper discusses design and implementation of an illumination system for microrobotic manipulation of natural fibrous materials, such as paper fibers. Three different illumination types potentially suitable for this imaging task are discussed and prototypes are built for further testing. The final illumination system is implemented based on the test results. It uses polarized light and it is integrated to the sample holder of a microrobotic platform. The final system provides an excellent contrast between the fibers and the background.

The integration of biomaterials into micro/nano-sensors or micro/nano-systems is expected to improve the properties of such systems or even lead to the development of novel innovative systems. A key problem to be solved beforehand is the development and realization of proper preparation, handling and manipulation methods with respect to an industrial usage. To enable such a usage, the methods have to be automatable, robust to environmental changes as well as feasible in a scanning electron microscope (SEM). According to these points, the target of the presented efforts is to develop these methods for a future design of nanoelectronic parts and to solve packaging problems at the nanoscale. As a consequence, the paper presents a novel concept for the usage of biomaterials, such as DNA and wood fibers/fibrils, for the packaging at the nanoscale. Novel methods for the DNA-handling with an atomic force microscope (AFM) at dry conditions, which can also be used in the vacuum chamber of a SEM will be presented as well as wood fibers/fibrils manipulation methods in the SEM.

This paper introduces a microrobotic platform to manipulate and characterize individual paper fibers. Mechanical characterization of individual paper fibers determines the key parameters which affect the quality of paper sheets. Current laboratory tests are based on bulk paper fiber measurements. This paper presents a microrobotic platform which is able to characterize the flexibility of individual paper fibers directly, not in bulk amount and using indirect estimations. The flexibility of three different pulp samples is measured and the experimental results are reported.

This paper introduces the latest technology developments in the field of adherent cell culturing. This highly multidisciplinary field is first matched with its numerous applications, such as the production of therapeutics, drug development, and toxicology. Further, the paper focuses on perfusion cell culturing systems intended for difficult-to-culture cells (such as primary and stem cells) and high-content screening (HCS) purposes. Parts of such advanced adherent cell culturing systems are presented including the open questions related to them. The system constituents are addressed in terms of cells and tissue models, cell culturing media, culturing vessels, actuation instrumentation, measurement instrumentation, and control. Finally, the paper outlines future directions for laboratory automation with regard to cultivation of primary and stem cells. Note to Practitioners-This paper discusses the latest technology developments and open automation challenges in the field of adherent cell culturing. Adherent cells are cells that need a surface to attach in order to grow. Most of the human cells are adherent cells. With the legislation push supported by the cost reductions, researchers are avoiding testing of various new compounds (e.g., drug candidates, environmental toxins) on animals. Instead, human cells are grown outside of the body (i.e., in vitro) for testing purposes. Growing cells in vitro is a challenge. The cells need to be maintained at a correct temperature, pH, oxygen, and humidity levels, and they need to be fed with a proper mixture of nutrients and growth factors. In other words, the cell cultivation system, which keeps the cells alive, must mimic the human body conditions as close as possible. Instruments have been developed to perform the needed functions, and a few robot-based automation systems are available to transfer the cells from an instrument to another with high throughput. Cells traditionally cultured are immortalized cell lines of cancer origin and of one cell type. These are easier to cultivate but are not as good models of human tissues as researchers would wish. Therefore, biologists are developing new models which contain many types of cells taken directly from a patient. These various kinds of primary cell cultures are more demanding to cultivate and need sophisticated, preferably integrated instruments and control algorithms to ensure homogenous stable environment for all of the cells. This paper provides an insight in the applications and current research trends of adherent cell cultivation. It also discusses the various subsystems needed and the automation engineering challenges posed by the new tissue models being developed by the biologists.

This paper introduces a feedforward charge control method, which controls the displacement by the amount of current fed to the actuator. The method includes estimation and compensation of the power losses occurring in the actuator. Power losses are estimated with an experimentally created dynamic model, that does not include the load and self heating effects. Even though the method is based on feedforward control, the amount of current is controlled in closed loop, using a precise current measurement and a PID controller. Experiments with a piezo bender show promising results; the hysteresis was nearly reduced to one part in twenty and drift to one part in ten, in comparison to open-loop voltage control. The proposed method can predict the power losses quite accurately and can therefore be utilized not only for the control but also for power estimation in applications where power consumption is critical.

Piezoelectric actuators have such disadvantageous properties as hysteresis nonlinearity and drift. This paper discusses a hybrid model to describe those properties. The model consists of a dynamic linear part and a static nonlinear part. The dynamic part uses two poles to describe the dynamic response and the drift property. The static nonlinear part modifies the parameters of the linear dynamic model to adapt the model to hysteresis nonlinearity and gain nonlinearity. The model is generated for a piezohydraulic actuator based on a multi-stage step signal. Simulation and experimental results show that the model is able to predict the drift and the nonlinear properties of the actuator.

The paper presents a new parallel micromanipulator that is composed of three piezohydraulic actuation systems. The basic elements of the actuation system are a piezoelectric actuator, a bellows and hydraulic oil. The use of the flexible bellows results in a new type of parallel structure, where the joints are integrated into actuator links. The joint-free tripod-like micromanipulator is controlled using a real-time control software that is based on a multi-level architecture. Control is organised in four levels for nonlinearity compensation, position feedback control, supervision and tackling of automatic operations. The micromanipulator presented provides an exceptional combination of submicrometer resolution, large work space, miniature size and advanced control.

This paper focuses on the open-loop and closed-loop position control of a tripod-like joint-free parallel micromanipulator that is composed of three piezohydraulic actuation systems. The micromanipulator is controlled in open-loop using a general inverse kinematics model. Open-loop control is sufficient in many applications but when high accuracy and high speed are required, closed-loop control must be applied. The closed-loop control of the micromanipulator is organized in multiple levels. The first level compensates nonlinearities of the actuation systems and the second level controls the position of the end-effector. Level three is a supervisory level and level four tackles automatic operations. Level two, i.e. the position feedback controller, consists essentially of two single input/single output (SISO) proportional-integral (PI) controllers and an incremental form of the inverse kinematics model. The experimental results show that the position feedback control efficiently eliminates drift and vibration of the end-effector.

This paper describes a new miniaturized actuation system designed especially for parallel link micromanipulators; the system is mechanically designed to form a very compact structure when used in parallel configuration. It consists of a monolithic unimorph type of piezoelectric actuator, an electro-deposited bellows, a tank and hydraulic fluid. The displacement of the piezoelectric element is hydraulically magnified and converted to the displacement of the bellows. The piezohydraulic actuator provides movement from a micrometer level up to a maximum displacement of 500 /spl mu/m.