Soft tissue viscoelastic properties: measurements, models and interpretation

The quantification of mechanical properties of soft tissues has been of great interest for more than two decades because they have the potential of being used as biomarkers for disease diagnosis. Indentation techniques, the most recognized techniques for characterizing mechanical properties, are widely used for basic science investigations in research labs. The use of elastography techniques coupled with imaging technologies has been growing rapidly in recent years, which is promising for clinical applications. Each technique produces different mechanical behaviors due to the interaction of the stimuli and the structure of the tissue. An appropriate model will parameterize these behaviors to reflect the corresponding tissue microscopic features with high fidelity. The objective of this thesis is to identify combinations of techniques and models that will yield mechanical parameters with diagnostic interpretations about tissue microenvironment. Three techniques for characterizing tissue viscoelastic properties were developed and validated, each offers strengths in a large variety of applications. Indentation based techniques measure low-frequency force-displacement curves under different loading profiles. Ultrasound-based techniques and optical based techniques measure the dispersion behaviors of the propagating wave velocities at mid-to-high frequency ranges. When a material is linear, isotropic, and contains only elastic components, the “intrinsic” elastic modulus of the material can be obtained independently of the technique used when corrections are properly made to eliminate the bias from boundary effects. If the material includes time-dependent components, models must be included in the analysis to provide parametric estimates. Classical models for viscoelastic solids such as the Kelvin-Voigt model do not fully represent mechanical measurements in tissues because they are not material continua. Tissue properties are determined in part by fluid movement in the open- and closed-cell compartments found within a viscoelastic collagen matrix that is actively maintained by the embedded cells to meet programmed needs. These biphasic (solid/fluid) media exhibit multifaceted deformation responses that are particularly difficult to model using a concise feature set. The Kelvin-Voigt fractional derivative (KVFD) model introduced in this study represents the measurement data of a broad range in both time and frequency domain with a small number of parameters, and it yields stable estimates for many types of phantoms and tissues. It is superior to the integer derivative models for the materials and techniques we used in this study. Moreover, the KVFD model provides a three-dimensional feature space of mechanical properties that properly characterizes the composition and structure of a material. This was validated through measurements on gelatin-cream emulsion samples exhibiting viscoelastic behavior, as well as ex vivo liver tissue samples. For the elastic property, KVFD parameter E_0 mainly represents the elasticity of the solid matrix and is approximately equal to the shear modulus no matter which technique is used. For the viscous property, when combined with different measurement techniques, KVFD model parameter α and τ represent different tissue components. The combination of these techniques and the KVFD model have the potential to be able to distinguish between healthy and pathological tissues described by the histological features

Robust Displacement Estimation for Ultrasound Elastography and Thermal Imaging

Ultrasound imaging is becoming the modality of choice for many diagnostic and surgical procedures. Besides being inexpensive and safe, ultrasonography is emerging as a quantitative tool able to image tissue properties. In this dissertation we focus on elastography and thermal imaging, which both rely on the measurement of real or apparent motion in ultrasound image sequences. In ultrasound elastography, signal decorrelation is widely viewed as the major limiting factor for adoption of into clinical practice. In this dissertation we focus on improving the robustness of a displacement estimation method based on dynamic programming, addressing multiple weak points. We propose a set of tools which can improve its ability to overcome displacement discontinuities and regions of poorly correlated RF data. The method is further extended to three dimensional data. Phantom, animal and human studies are presented for experimental validation. The addition of robust tools results in an improved ability to achieve repeatable, artifact-free strain maps, without compromising computational speed. In thermal imaging, we focus on the estimation of real and apparent motion while the tissue temperature is increased in an ablation procedure. Estimating heat-induced echo shifts is a very difficult problem because of their very small amplitude, on the order of tens of microns. They can easily be masked by other sources of deformation/movement from the environment such as patient motion or hand tremor. In this dissertation, we build upon the robust displacement estimation method for elastography, with the additional deployment of an iterative motion compensation algorithm. The validation experiments are performed on laboratory induced ablation lesions, where the ultrasound probe is either held by the operator's hand or supported by a robotic arm. We demonstrate the ability to detect and remove non-heat induced tissue motion at every step of the ablation procedure. Our results exceed the state of the art in both the accuracy of temperature estimation as well as the length of time over which temperature estimation can be performed. Previous research in the area of motion compensation resulted in good results for experiments lasting less than 10 seconds. Our experiments lasted close to 20 minutes

Novel applications, model, and methods in magnetic resonance elastography

Magnetic Resonance Elastography (MRE) is a non-invasive imaging technique that maps and quantifies the mechanical properties of soft tissue related to the propagation and attenuation of shear waves. There is considerable interest in whether MRE can bring new insight into pathologies. Brain in particular has been of utmost interest in the recent years. Brain tumors, Alzheimer's disease, and Multiple Sclerosis have all been subjects of MRE studies. This thesis addresses four aspects of MRE, ranging from novel applications in brain MRE, to physiological interpretation of measured mechanical properties, to improvements in MRE technology. First, we present longitudinal measurements of the mechanical properties of glioblastoma tumorigenesis and progression in a mouse model. Second, we present a new finding from our group regarding a localized change in mechanical properties of neural tissue when functionally stimulated. Third, we address contradictory results in the literature regarding the effects of vascular pressure on shear wave speed in soft tissues. To reconcile these observations, a mathematical model based on poro-hyperelasticity is used. Finally, we consider a part of MRE that requires inferring mechanical properties from MR measurements of vibration patterns in tissue. We present improvements to MRE reconstruction methods by developing and using an advanced variational formulation of the forward problem for shear wave propagation

Microdevices and Microsystems for Cell Manipulation

Microfabricated devices and systems capable of micromanipulation are well-suited for the manipulation of cells. These technologies are capable of a variety of functions, including cell trapping, cell sorting, cell culturing, and cell surgery, often at single-cell or sub-cellular resolution. These functionalities are achieved through a variety of mechanisms, including mechanical, electrical, magnetic, optical, and thermal forces. The operations that these microdevices and microsystems enable are relevant to many areas of biomedical research, including tissue engineering, cellular therapeutics, drug discovery, and diagnostics. This Special Issue will highlight recent advances in the field of cellular manipulation. Technologies capable of parallel single-cell manipulation are of special interest

Numerical modelling of additive manufacturing process for stainless steel tension testing samples

Nowadays additive manufacturing (AM) technologies including 3D printing grow rapidly and they are expected to replace conventional subtractive manufacturing technologies to some extents. During a selective laser melting (SLM) process as one of popular AM technologies for metals, large amount of heats is required to melt metal powders, and this leads to distortions and/or shrinkages of additively manufactured parts. It is useful to predict the 3D printed parts to control unwanted distortions and shrinkages before their 3D printing. This study develops a two-phase numerical modelling and simulation process of AM process for 17-4PH stainless steel and it considers the importance of post-processing and the need for calibration to achieve a high-quality printing at the end. By using this proposed AM modelling and simulation process, optimal process parameters, material properties, and topology can be obtained to ensure a part 3D printed successfully

Surface Modification of Ti Implant for Enhancing Biotribology and Cells Attachment

Implant success strongly depends on the proper integration of bone to biomaterial surface. By the selected retrieval cases, inadequate integration of bone screws was a dominated factor caused failure. The surface modification technology that improve osteointegration by inducing TiO2 nanotubes (NT) on Ti-based implants has a potential applications in orthopaedic implants. NT generated by anodization method provide a vertically aligned nanotube structure that enhances the integration between bone tissue and implant surface by improving osteoblasts attachment. Although cells to NT is positive, the mechanical weakness of NT has also been well-documented and is an obstacle to its applications. The thesis comprise a detailed method to improve NT mechanical stability, by introducing an interfacial bonding layer at NT bottom and Ti substrate, and retaining vertically aligned nanotubes. The physicochemical properties of this structure optimized TiO2 nanotubes (SO-NT) was systematically characterized, the SO-NT has been demonstrated with improved biotribological and biocorrosive performance. The uniform hyperfine interfacial bonding layer with nano-sized grains exhibited a strong bonding to NT layer and Ti substrate. It was observed, the layer not only effectively dissipates external impacts and shear stress but also acts as a good corrosion resistance barrier to prevent the Ti substrate from corrosion. The SO-NT modified bone screw has also demonstrated with enhanced fretting corrosion resistance than NT and pristine Ti6Al4V on screws. Since the elongated osteoblasts were observed on NT and SO-NT compared with Ti surface, the nanotubes structure has been shown with promoting of osteoblasts attachment. However, the mechanism of cell nanotubes interactions are largely in controversial. In order to reveal the cell-nanomaterial interactions, nanotopographies including Nanoconvex, Nanoconcave and Nanoflat were generated and characterized to evaluate the cell initial attachment behaviour. Human osteoblasts were observed with spindle shape on Nanoconcave, cells on Nanoflat were well-spreading but in sphere shape, while the osteoblasts on Nanoconvex were with the minimum spreading areas. Cell-materials interface is mediated and influenced by the adsorption of ECM on nanomaterials. Thus, a novel fibronectin adsorption model was proposed by calculating Coulomb's force to illustrate the interact mechanism between protein and material that influence cell behaviours. The achievements of thesis are; 1. Retrieval analyzed two cases of implants failure and pointed out one of dominated failure factor, the lack of osteointegration. 2. Introduce the interfacial bonding layer that significantly improve the biotribological and biocorrosive performance of NT, and generated SO-NT. 3. Systematically evaluated the biotribological performance of Ti, NT and SO-NT, and propose a novel methodology to quantify the fretting degradation on bone screws. 4. Propose a novel model to estimate the fibronectin adsorption on Nanoflat, Nanoconvex and Nanoconcave by the Coulomb's force calculation

Implantable Microsystem Technologies For Nanoliter-Resolution Inner Ear Drug Delivery

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. The present work demonstrates a novel biocompatible, implantable, and scalable microsystem consisted of a thermal phase-change peristaltic micropump with wireless control and a refillable reservoir. The micropump is fabricated around a catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Direct-write micro-scale printing technology was used to build the mechanical components of the pump around the microtubing directly on the back of a printed circuit board assembly. In vitro characterization results indicated nanoliter resolution control over the desired flow rates of 10–100 nL/min by changing the actuation frequency, with negligible deviations in presence of up to 10× greater than physiological backpressures and ±3°C ambient temperature variation. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. A stand-alone, refillable, in-plane, scalable, and fully implantable microreservoir platform was designed and fabricated to be integrated with the micropump. The microreservoir consists two main components: a cavity for storing the drug and a septum for refilling. The cavity membrane is fabricated with thin Parylene-C layers, using a polyethylene glycol (PEG) sacrificial layer. The septum thickness is minimized by pre-compression down to 1 mm. The results of in vitro characterization indicated negligible restoring force for the optimized cavity membrane and thousands of punctures through the septum without leakage. The micropump and microreservoir were integrated into microsystems which were implanted in mice. The microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The results match with syringe pump gold standard. For the first time a miniature and yet scalable microsystem for inner ear drug delivery was developed, enabling drug discovery opportunities and translation to human

Development and Application of New Methods for Magnetic Resonance Elastography of the Brain

Accurate mechanical properties of the intact, living brain are essential for modeling traumatic brain injury (TBI). However, the properties of brain tissue in vivo have traditionally been measured in ex vivo samples. Magnetic resonance elastography (MRE) can be used to measure motion and estimate material properties of soft tissues in vivo, but MRE typically assumes tissue isotropy and homogeneity. The objective of this thesis is to improve MRE of soft tissue, like the brain, by developing and evaluating methods for in vivo estimation of heterogeneous, anisotropic properties. This was achieved through pursuit of the following aims: (1) quantifying the differences between in vivo and ex vivo brain tissue, thereby clarifying the need for in vivo measurements; (2) introducing and applying a new approach to anisotropic MRE, using data obtained during external actuation of the porcine brain in vivo, which highlighted the need for new actuation methods; and (3) developing and evaluating a method for anisotropic property estimation using MRE with actuation by harmonic focused ultrasound (FUS). This research has led to new methods for anisotropic MRE, and improved material property estimates of the brain and other soft tissues

Medical Ultrasound Imaging and Interventional Component (MUSiiC) Framework for Advanced Ultrasound Image-guided Therapy

Medical ultrasound (US) imaging is a popular and convenient medical imaging modality thanks to its mobility, non-ionizing radiation, ease-of-use, and real-time data acquisition. Conventional US brightness mode (B-Mode) is one type of diagnostic medical imaging modality that represents tissue morphology by collecting and displaying the intensity information of a reflected acoustic wave. Moreover, US B-Mode imaging is frequently integrated with tracking systems and robotic systems in image-guided therapy (IGT) systems. Recently, these systems have also begun to incorporate advanced US imaging such as US elasticity imaging, photoacoustic imaging, and thermal imaging. Several software frameworks and toolkits have been developed for US imaging research and the integration of US data acquisition, processing and display with existing IGT systems. However, there is no software framework or toolkit that supports advanced US imaging research and advanced US IGT systems by providing low-level US data (channel data or radio-frequency (RF) data) essential for advanced US imaging. In this dissertation, we propose a new medical US imaging and interventional component framework for advanced US image-guided therapy based on networkdistributed modularity, real-time computation and communication, and open-interface design specifications. Consequently, the framework can provide a modular research environment by supporting communication interfaces between heterogeneous systems to allow for flexible interventional US imaging research, and easy reconfiguration of an entire interventional US imaging system by adding or removing devices or equipment specific to each therapy. In addition, our proposed framework offers real-time synchronization between data from multiple data acquisition devices for advanced iii interventional US imaging research and integration of the US imaging system with other IGT systems. Moreover, we can easily implement and test new advanced ultrasound imaging techniques inside the proposed framework in real-time because our software framework is designed and optimized for advanced ultrasound research. The system’s flexibility, real-time performance, and open-interface are demonstrated and evaluated through performing experimental tests for several applications