A haptic training environment for the heart myoblast cell injection procedure

The heart muscle of a cardiac arrest victim continues to accumulate damage throughout its lifetime. This reduces the heart's ability to pump sufficient oxygen and nutrient blood to meet the body's needs. Medical researchers have shown that direct injection of pre-harvested skeletal myoblast cells into the heart can restore some muscle function [1]. This operative procedure usually necessitates the surgeon to open a patient's chest. The open chest procedure is usually a lengthy process and often extends the recovery time of the patient. Alternatively, a high accuracy surgical aid robotic system can be used to assist the thoracoscopic surgery [2][3]. While the robotic surgical method aids faster patient recovery, a less experienced surgeon can potentially cause damage to surrounding tissue.

This paper presents a study into the development of a virtual haptically-enabled heart myoblast injection simulation environment, which can be used to train new surgeons to get hands on experience with the process. The paper also discusses the development of a generic constraint motion technique for needle insertion. Experiments on human performance measures and efficacy, while interacting with haptic feedback training models, are also presented. The experiment involved 10 operators, with each person repeating the needle insertion and injection 10 times. A notable improvement in the task execution time with the number of repetitions was observed. Operators improved their time by up to 300% compared to their first training attempt for a static heart scenario. Under a dynamic heart motion, operator's performance was slightly lower, with the successful rate of completing the experiment reduced from 84% to 75%.

3D particle-based cell modelling for haptic microrobotic cell injection

Introducing haptic interface to conduct microrobotic intracellular injection has many beneficial implications. In particular, the haptic device provides force feedback to the bio-operator's hand. This paper introduces a 3D particle-based model to simulate the deformation of the cell membrane and corresponding cellular forces during microrobotic cell injection. The model is based on the kinematic and dynamic of spring – damper multi particle joints considering visco-elastic fluidic properties. It simulates the indentation force feedback as well as cell visual deformation during the microinjection. The model is verified using experimental data of zebrafish embryo microinjection. The results demonstrate that the developed cell model is capable of estimating zebrafish embryo deformation and force feedback accurately.

Haptic microrobotic cell injection system

Microrobotic cell injection is the subject of increasing research interest. At present, an operator relies completely on visual information and can be subject to low success rates, poor repeatability, and extended training times. This paper focuses on increasing operator performance during cell injection in two ways. First, our completed haptic cell injection system aims to increase the operator's performance during real-time cell injection. Haptic bilateralism is investigated and a mapping framework provides an intuitive method for manoeuvring the micropipette in a manner similar to handheld needle insertion. Volumetric virtual fixtures are then introduced to haptically assist the operator to penetrate the cell at the desired location. The performance of the volumetric virtual fixtures is also discussed. Second, the haptically enabled cell injection system is replicated as a virtual environment facilitating virtual offline operator training. Virtual operator training utilizes the same mapping framework and haptic virtual fixtures as the physical system allowing the operator to train offline and then directly transfer their skills to real-time cell injection.

Haptic virtual reality training environment for micro-robotic cell injection

Micro-robotic cell injection is typically performed manually by a trainedbio-operator, and success rates are often low. To enhance bio-operator performance during real-time cell injection, our earlier work introduced a haptically-enabled micro-robotic cell injection system. The system employed haptic virtual fixtures to provide haptic guidance according to articular performance metrics. This paper extends the work by replicating the system within a virtual reality (VR) environment for bio-operator training. Using the virtual environment, the bio-operator is able to control the virtual injection process in the same way they would with the physical haptic micro-robotic cell injection system, while benefiting from the enhanced visualisation capabilities offered by the 3D VR environment. The system is achieved using cost-effective components offering training at much lower cost than using the physical system.

Keyboard control method for virtual reality micro-robotic cell injection training

The rapid development of virtual reality offers significant potential for skills training applications. Our ongoing work proposes virtual reality operator training for the micro-robotic cell injection procedure. The interface between the operator and the system can be achieved in many different ways. The computer keyboard is ubiquitous in its use for everyday computing applications and also commonly utilized in virtual reality systems. Based on the premise that most people have experience in using a computer keyboard, as opposed to more sophisticated input devices, this paper considers the feasibility of using a keyboard to control the micro-robot for cell injection. In this study, thirteen participants underwent the experimental evaluation. The participants were asked to perform three simulated trial sessions in a virtual micro-robotic cell injection environment. Each session consisted of ten cell injection trials and relevant data for each trial were recorded and analyzed. Results showed participants' performance improvement after the three sessions. It was also observed that participants intuitively controlled multiple axes of the micro-robot simultaneously despite the absence of instruction on how to do so. This continued throughout the experiments and suggests skills transfer from other keyboard based interactions. Based on the results provided, it is suggested that keyboard control is a feasible, simple and low-cost control method for the virtual micro-robot.

Haptic technology for micro-robotic cell injection training systems — a review

Currently, the micro-robotic cell injection procedure is performed manually by expert human bio-operators. In order to be proficient at the task, lengthy and expensive dedicated training is required. As such, effective specialized training systems for this procedure can prove highly beneficial. This paper presents a comprehensive review of haptic technology relevant to cell injection training and discusses the feasibility of developing such training systems, providing researchers with an inclusive resource enabling the application of the presented approaches, or extension and advancement of the work. A brief explanation of cell injection and the challenges associated with the procedure are first presented. Important skills, such as accuracy, trajectory, speed and applied force, which need to be mastered by the bio-operator in order to achieve successful injection, are then discussed. Then an overview of various types of haptic feedback, devices and approaches is presented. This is followed by discussion on the approaches to cell modeling. Discussion of the application of haptics to skills training across various fields and haptically-enabled virtual training systems evaluation are then presented. Finally, given the findings of the review, this paper concludes that a haptically-enabled virtual cell injection training system is feasible and recommendations are made to developers of such systems.

Design of a virtual reality training system for micro-robotic cell injection

This paper discusses the design of a virtual reality (VR) training system for micro-robotic cell injection. A brief explanation of cell injection and the challenges associated with the procedure are first presented. This is followed by discussion of the skills required by the bio-operator to achieve successful injection, such as accuracy, trajectory and applied force. The design of the VR system which includes the visual display, input controllers, mapping strategies, haptic guidance and output data is then discussed. Initial evaluation of the VR system is presented including analysis and discussion based on conducted user evaluations. Finally, given the findings of the initial evaluation, this paper concludes that an effective haptically-enabled virtual cell injection training system is feasible, and recommendations for improvement and future work are given.

Virtual reality training for micro-robotic cell injection

This research was carried out to fill the gap within existing knowledge on the approaches to supplement the training for micro-robotic cell injection procedure by utilising virtual reality and haptic technologies.

Towards haptic microrobotic intracellular injection

This paper proposes a system providing the operator with an intuitive method for controlling a micromanipulator during intracellular injection. A low-cost haptic device is utilised and 3D position-to-position kinematic mapping allows the operator to control the micropipette using a similar method to handheld needle insertion. The workspaces of the haptic device and micromanipulator are analysed and the importance of appropriate scaling to positioning resolution and tracking performance is investigated. The control issues integral to achieving adequate control of the micromanipulator using the Phantom Omni haptic device are addressed. Aside from offering an intuitive method for controlling the micropipette, this work lays the foundation for real-time haptic assistance in the cell injection task.

Haptic guidance for microrobotic intracellular injection

The ability for a bio-operator to utilise a haptic device to manipulate a microrobot for intracellular injection offers immense benefits. One significant benefit is for the bio-operator to receive haptic guidance while performing the injection process. In order to address this, this paper investigates the use of haptic virtual fixtures for cell injection and proposes a novel force field virtual fixture. The guidance force felt by the bio-operator is determined by force field analysis within the virtual fixture. The proposed force field virtual fixture assists the bio-operator when performing intracellular injection by limiting the micropipette tip's motion to a conical volume as well as recommending the desired path for optimal injection. A virtual fixture plane is also introduced to prevent the bio-operator from moving the micropipette tip beyond the deposition target inside the cell. Simulation results demonstrate the operation of the guidance system.

Haptic microrobotic intracellular injection assistance using virtual fixtures

In manual cell injection the operator relies completely on visual information for task feedback and is subject to extended training times as well as poor success rates and repeatability. From this perspective, enhancing human-in-the-loop intracellular injection through haptic interaction offers significant benefits. This paper outlines two haptic virtual fixtures aiming to assist the human operator while performing cell injection. The first haptic virtual fixture is a parabolic force field designed to assist the operator in guiding the micropipette's tip to a desired penetration point on the cell's surface. The second is a planar virtual fixture which attempts to assist the operator from moving the micropipette's tip beyond the deposition target location inside the cell. Preliminary results demonstrate the operation of the haptically assisted microrobotic cell injection system.

Virtual haptic cell model for operator training

Microrobotic cell injection is an area of growing research interest. Typically, operators rely on visual feedback to perceive the microscale environment and are subject to lengthy training times and low success rates. Haptic interaction offers the ability to utilise the operator’s haptic modality and to enhance operator performance. Our earlier work presented a haptically enabled system for assisting the operator with certain aspects of the cell injection task. The system aimed to enhance the operator’s controllability of the micropipette through a logical mapping between the haptic device and microrobot, as well as introducing virtual fixtures for haptic guidance. The system was also designed in such a way that given the availability of appropriate force sensors, haptic display of the cell penetration force is straightforward. This work presents our progress towards a virtual replication of the system, aimed at facilitating offline operator training. It is suggested that operators can use the virtual system to train offline and later transfer their skills to the physical system. In order to achieve the necessary representation of the cell within the virtual system, methods based on a particle-based cell model are utilised. In addition to providing the necessary visual representation, the cell model provides the ability to estimate cell penetration forces and haptically display them to the operator. Two different approaches to achieving the virtual system are discussed.

Formulation and simulation of a 3D mechanical model of embryos for microinjection

The understanding of cell manipulation, for example in microinjection, requires an accurate model of the cells. Motivated by this important requirement, a 3D particlebased mechanical model is derived for simulating the deformation of the fish egg membrane and the corresponding cellular forces during microrobotic cell injection. The model is formulated based on the kinematic and dynamic of spring- damper configuration with multi-particle joints considering the visco-elastic fluidic properties. It simulates the indentation force feedback as well as cell visual deformation during microinjection. A preliminary simulation study is conducted with different parameter configurations. The results indicate that the proposed particle-based model is able to provide similar deformation profiles as observed from a real microinjection experiment of the zebrafish embryo published in the literature. As a generic modelling approach is adopted, the proposed model also has the potential in applications with different types of manipulation such as micropipette cell aspiration.

Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression.

A role for α4 and β7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. However, the individual contributions of their respective ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-cadherin expressed on the blood-brain barrier has not been determined. In the present paper, it is shown that an antibody directed against MAdCAM-1, the preferential ligand for α4β7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(_35-55)) autoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte function-associated antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 monotherapy, nor combinational antibody blockade was preventative when administered late in the course of disease progression. In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS. Critically, antivascular addressin therapy must be given eaA role for alpha4 and beta7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. However, the individual contributions of their respective ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-cadherin expressed on the blood-brain barrier has not been determined. In the present paper, it is shown that an antibody directed against MAdCAM-1, the preferential ligand for alpha4beta7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) autoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte function-associated antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 monotherapy, nor combinational antibody blockade was preventative when administered late in the course of disease progression. In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS. Critically, antivascular addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a single treatment modality.

Zebrafish granulocyte colony-stimulatingZebrafish granulocyte colony-stimulating factor receptor signaling promotes myelopoiesis and myeloid cell migration

Granulocyte colony-stimulating factor receptor (GCSFR) signaling participates in the production of neutrophilic granulocytes during normal hematopoietic development, with a particularly important role during emergency hematopoiesis. This study describes the characterization of the zebrafish gcsf and gcsfr genes, which showed broad conservation and similar regulation to their mammalian counterparts. Morpholino-mediated knockdown of gcsfr and overexpression of gcsf revealed the presence of an anterior population of myeloid cells during primitive hematopoiesis that was dependent on GCSF/GCSFR for development and migration. This contrasted with a posterior domain that was largely independent of this pathway. Definitive myelopoiesis was also partially dependent on a functional GCSF/GCSFR pathway. Injection of bacterial lipopolysaccharide elicited significant induction of gcsf expression and emergency production of myeloid cells, which was abrogated by gcsfr knockdown. Collectively, these data demonstrate GCSF/GCSFR to be a conserved signaling system for facilitating the production of multiple myeloid cell lineages in both homeostatic and emergency conditions, as well as for early myeloid cell migration, establishing a useful experimental platform for further dissection of this pathway.