D. McLean

Measurements and modelling of the compliance of human and porcine organs

Stress-strain data obtained from animal and human tissue have several applications including medical diagnosis, assisting in surgical instrument design and the production of realistic computer-based simulators for training in minimal access surgery. Such data may also be useful for corroborating mathematical models of tissue response. This paper presents data obtained from ex-vivo and in-vivo tissue indentation tests using a small indentor that is similar to instruments used in minimal access surgery. In addition, uniform stress tests provide basic material property data, via an exponential stress-strain law, to allow a finite element method to be used to predict the response for the non-uniform stresses produced by the small indentor. Data are obtained from harvested pig liver and spleen using a static compliance probe. Data for human liver are obtained from volunteer patients, undergoing minor open surgery, using a sterile hand-held compliance probe. All the results demonstrate highly non-linear stress-strain behaviour. Pig spleen is shown to be much more compliant than pig liver with mean elastic moduli of 0.11 and 4.0 MPa respectively. The right lobe of human liver had a mean elastic modulus of about 0.27 MPa. However, a single case of a diseased liver had a mean modulus of 0.74 MPa--nearly three times the stiffness. It was found that an exponential stress-strain law could accurately fit uniform stress test data and that subsequent finite element modelling for non-uniform stress around a small indentor matched measured force characteristics.

Image-based 3D modeling and validation of radiofrequency interstitial tumor ablation using a tissue-mimicking breast phantom

PurposeMinimally invasive treatment of solid cancers, especially in the breast and liver, remains clinically challenging, despite a variety of treatment modalities, including radiofrequency ablation (RFA), microwave ablation or high-intensity focused ultrasound. Each treatment modality has advantages and disadvantages, but all are limited by placement of a probe or US beam in the target tissue for tumor ablation and monitoring. The placement is difficult when the tumor is surrounded by large blood vessels or organs. Patient-specific image-based 3D modeling for thermal ablation simulation was developed to optimize treatment protocols that improve treatment efficacy.MethodsA tissue-mimicking breast gel phantom was used to develop an image-based 3D computer-aided design (CAD) model for the evaluation of a planned RF ablation. First, the tissue-mimicking gel was cast in a breast mold to create a 3D breast phantom, which contained a simulated solid tumor. Second, the phantom was imaged in a medical MRI scanner using a standard breast imaging MR sequence. Third, the MR images were converted into a 3D CAD model using commercial software (ScanIP, Simpleware), which was input into another commercial package (COMSOL Multiphysics) for RFA simulation and treatment planning using a finite element method (FEM). For validation of the model, the breast phantom was experimentally ablated using a commercial (RITA) RFA electrode and a bipolar needle with an electrosurgical generator (DRE ASG-300). The RFA results obtained by pre-treatment simulation were compared with actual experimental ablation.ResultsA 3D CAD model, created from MR images of the complex breast phantom, was successfully integrated with an RFA electrode to perform FEM ablation simulation. The ablation volumes achieved both in the FEM simulation and the experimental test were equivalent, indicating that patient-specific models can be implemented for pre-treatment planning of solid tumor ablation.ConclusionA tissue-mimicking breast gel phantom and its MR images were used to perform FEM 3D modeling and validation by experimental thermal ablation of the tumor. Similar patient-specific models can be created from preoperative images and used to perform finite element analysis to plan radiofrequency ablation. Clinically, the method can be implemented for pre-treatment planning to predict the effect of an individual’s tissue environment on the ablation process, and this may improve the therapeutic efficacy.

Optimized deployment of heat-activated surgical staples using thermography

We have developed a suture analogue, suitable for use in laparoscopic surgery, in the form of a staple constructed from NiTi shape memory alloy (SMA). Closure of the staple is effected by resistive heating via a (50–100 ms) pulse of electrical current (≈5 A). In order to optimize deployment protocols and minimize thermal collateral damage to tissue, the heat sink effect of the electrical contact rails, as well as the presence of contact hotspots must be considered. Here, we have employed high-resolution thermal imaging to observe the dynamic temperature distributions in SMA staples as a function of the pulse parameters. This has facilitated process optimization and also provided data from which to validate computational finite-element models of the heat transport phenomena.

Spatially controlled sonoporation of prostate cancer cells via ultrasound activated microbubble cavitation

Cells that are exposed to ultrasonic (US) energy, in the presence of ultrasound contrast agent microbubbles, may experience enhanced membrane permeability. If the effective dose of US exceeds some threshold, then cell lysis can result (lethal sonoporation), however for lower doses a transient enhancement of membrane permeability occurs (reversible or non lethal sonoporation). The merits of each mode are clear: lethal sonoporation constitutes a significant tumour therapy weapon, whilst its less intrusive counterpart, reversible sonoporation, represents an effective non-invasive targeted drug delivery technique. Until now, the mechanism of the dynamic interaction between microbubbles and cells has remained unknown. Moreover pores, which are the presumed mode of permeabilization have not been observed in a convincing fashion. We will demonstrate, for the first time, how an innovative hybridization of holographic optical trapping technology, together with the application of MHz pulsed US energy and subsequent high resolution observation using atomic force microscopy has been used to elucidate the fundamental mode for membrane permeabilization during sonoporation.

Intraluminal magnetisation of bowel by ferromagnetic particles for retraction and manipulation by magnetic probes.

Feasibility studies are needed to demonstrate that safe and effective manipulation of bowel during Minimal Access Surgery (MAS) can be obtained by use of magnetic force. This paper characterises two classes of magnetic particles: stainless steel microparticles (SS-μPs) and iron oxide nanoparticles (IO-nPs) in terms of their magnetisation, chemical composition, crystallinity, morphology and size distribution. Both magnetic particles were dispersed in a high viscosity biological liquid for intraluminal injection of bowel. Ex vivo porcine bowel segments were then retracted by permanent magnetic probes of 5.0 and 10mm diameter. Strong retraction forces reaching 6N maximum were obtained by magnetic fluid based on dispersion of SS-μPs. In contrast, the IO-nP-based magnetic liquid generated less attraction force, due to both lower magnetic and solution properties of the IO-nPs. The comparison of the two particles allowed the identification of the rules to engineer the next generation of particles. The results with SS-μPs provide proof on concept that intraluminal injection of magnetic fluid can generate sufficient force for efficient bowel retraction. Thereafter we shall carry out in vivo animal studies for efficacy and safety of both types of ferrofluids.

Mucoadhesive polymer films for tissue retraction in laparoscopic surgery: Ex-vivo study on their mechanical properties

Safe and effective manipulation of soft tissue during laparoscopic procedures can be achieved by the use of mucoadhesive polymer films. A series of novel adhesive polymer films were formulated in house based on either Carbopol or Chitosan modified systems. The mechanical properties of the polymers and their adherence to bowel were evaluated using ex-vivo pig bowel immersed in 37°C water bath and connected to an Instron tensiometer. Youngs modulus was 300 kPa for the Carbopol-polymer and 5 kPa for the Chitosan-polymer. The Chitosan-polymer exhibited much larger shear adhesion than its tensile adhesion: 3.4 N vs. 1.2. Both tensile and shear adhesions contributed to the large retraction force (2.6 N) obtained during l polymer-bowel retraction testing. Work of adhesion at the polymer/serosa interface, defined as the area under the force curve, was 64 mJ, which is appreciably larger than that reported with existing polymers. In conclusion, adhesive polymers can stick to the serosal side of the bowel with an adhesive force, which is sufficient to lift the bowel, providing a lower retraction stress than that caused by laparoscopic grasping which induces high localized pressures on the tissue.

Thermographic Investigation of The Heating Effect of High Intensity Focused Ultrasound

The purpose of this study was to use thermal imaging camera to investigate the localised heating effect of high intensity focused ultrasound (HIFU), to monitor temperature rise in real time and accurately. In order to visualise thermally induced protein coagulation, a phantom of polyacrylamide (PAA) gel containing fresh egg albumin was used as tissue mimicking material. A high resolution thermal camera was positioned directly over the samples to record thermal fluctuations. Two modes of ultrasound were investigated, i.e. continuous wave and pulsed wave. Through imaging processing and thermal analysis, the temperature profile of the phantoms during HIFU heating was obtained, and the optimised parameters for protein coagulation were identified. The experiments have shown that thermal imaging is an effective way to measure the bioheating effect of HIFU

Spatial redefinition of ultrasound pressure fields using polycarbonate lenses: Model and experimental validation

Exposure of cells and tissues to an ultrasound field is well known to elicit bioeffects when the pressures employed exceed some threshold value. Previous studies have shown that biological outcomes such as apoptosis, necrosis, as well as molecular uptake processes, can all be induced using particular pressure regimes. Moreover, the ready facility to focus ultrasound extracorporeally using curved tranducers has led to the realization that clinically relevant targets such as tumors: even those at deep seated anatomical locations; can be effectively treated via a non-invasive ultrasonic protocol. One can imagine that targets [notionally small tumours] could easily vary in size, and therefore that a single transducer would not necessarily be able to produce a focal region that covers the full target extent without resorting to some more elaborate protocol. One suggestion might be to move the transducer controllably in order to shift the focus in 3D and thus cover a larger area of the target with an appropriate exposure. Alternatively, different transducers could be employed for different target sizes, or one could choose the very flexible but expensive option of phased arrays, which allows automatic and programmable 3D spatio-temporal control of the pressure field. A further [relatively inexpensive] method is to make a single, focused transducer more versatile by incorporating ultrasonic lenses to modify pressure field distribution. For the purposes of the present work, we have investigated this latter route with a view to exploiting it as an alternative to high intensity focused ultrasound (HIFU) for treatment, and with a main aim of reducing collateral damage arising from iatrogenic heating.

Influence of Waveform on Cell Viability during Ultrasound Exposure

We examined the role of ultrasound standing waves, and their travelling wave counterparts, on cell viability in an in‐vitro insonation apparatus. Furthermore, the effect of distinct waveforms (sine and top‐hat) was also explored, together with the role of microbubble presence. Measurements of cell viability in standing wave scenarios demonstrated a relatively higher rate of lysis (63.13±10.89% remaining viable) compared with the travelling wave data, where 96.22±4.0% remained viable. Significant differences were also seen as a function of waveform, where insonations employing top‐hat wave shapes resulted in an average end stage viability of 30.31±5.71% compared with 61.94±14.28% in the sinusoidal counterparts.

Ultra high speed observations of cavitation derived microjetting phenomena

Ultrasound mediated molecular delivery (sonoporation) is a highly attractive route for cancer- and gene-therapy. This has been demonstrated, both in vitro and in animal trials, to achieve a number of critical bioeffects such as apoptosis, lysis and tumour regression. Moreover, it is now accepted that the clinical potential is enhanced when ultrasound contrast agent (UCA) microbubbles are present during insonation. However, the fundamental mechanism of interaction between cell and microbubble during US exposure remains elusive and this hampers attempts to optimise the approach. In addressing this deficiency in our understanding, we designed and constructed a unique apparatus that can optically guide an individual UCA microbubble to a predefined displacement relative to a planar substrate. In parallel with this, we undertook direct observations, via high speed imaging at MHz frame rates. We demonstrate how this approach has allowed us to observe a dynamic microscopic interaction during insonation, that may give rise to membrane permeabilization in biological cells.