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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (Ph.D.)--Case Western Reserve University, 2009 / Abstract Department of Biomedical Engineering Title from PDF (viewed on 20 April 2009) Available online via the OhioLINK ETD Center

Elastic and collagen fibers are the major load-bearing extracellular matrix (ECM) constituents of the vascular wall. Elastic fibers accommodate repeated cycles of extension and recoil that occur during pulsatile blood flow at lower levels of strain, whereas the recruitment of collagen fibers at higher levels of strain leads to nonlinear stiffening that protects blood vessels from overextension. Glycosaminoglycans (GAGs) provide a structural basis for multiple biological functions, such as the organization of ECM and the regulation of cell growth factors. There exists a complex interdependence of ECM compositional, structural, and mechanical properties. The overall goal of the research is to study the biomechanical and structural roles of different ECM constituents in vascular mechanics through coupled mechanical testing, advanced optical imaging, and microstructure-based constitutive modeling. Arteries function differently than veins in the circulatory system, however in several treatment options veins are subjected to sudden elevated arterial pressure. Our study improves the understanding of elastin and collagen fiber contribution to ECM mechanics of different vessel types. Our research demonstrates that ECM fiber distribution, recruitment, and content each play an important role in vascular function, and the important structural and functional differences between arteries and veins that should be taken into account when considering treatment options. While elastin and collagen have received extensive consideration, little is known about the biomechanical roles of GAGs in blood vessels. The mechanics of tissue with low GAG content can be indirectly affected by the interaction of GAGs with collagen fibers, which is one of the primary contributors to arterial mechanics. Our study suggests that that the interaction between GAGs and other ECM constituents plays an important role in the mechanics of the arterial wall, and GAGs should be considered in addition to elastic and collagen fibers when studying arterial function. A structure-based constitutive model was then developed to successfully predict arterial mechanics considering the contribution of GAGs to fiber recruitment. Building upon previous research, ongoing work is presented to study the fundamental yet clinically relevant structural-mechanical behavior of arterial ECM in diabetes using an integrated experimental and modeling approach.

abstract: The ultimate goal of human movement control research is to understand how natural movements performed in daily activities, are controlled. Natural movements require coordination of multiple degrees of freedom (DOF) of the arm. Here, patterns of arm joint control during daily functional tasks were examined, which are performed through rotation of the shoulder, elbow, and wrist with the use of seven DOF: shoulder flexion/extension, abduction/adduction, and internal/external rotation; elbow flexion/extension and pronation/supination; wrist flexion/extension and radial/ulnar deviation. Analyzed movements imitated two activities of daily living: combing the hair and turning the page in a book. Kinematic and kinetic analyses were conducted. The studied kinematic characteristics were displacements of the 7 DOF and contribution of each DOF to hand velocity. The kinetic analysis involved computation of 3-dimensional vectors of muscle torque (MT), interaction torque (IT), gravity torque (GT), and net torque (NT) at the shoulder, elbow, and wrist. Using a relationship NT = MT + GT + IT, the role of active control and the passive factors (gravitation and inter-segmental dynamics) in rotation of each joint was assessed by computing MT contribution (MTC) to NT. MTC was computed using the ratio of the signed MT projection on NT to NT magnitude. Despite the variety of joint movements required across the different tasks, 3 patterns of shoulder and elbow coordination prevailed in each movement: 1) active rotation of the shoulder and predominantly passive rotation of the elbow; 2) active rotation of the elbow and predominantly passive rotation of the shoulder; and 3) passive rotation of both joints. Analysis of wrist control suggested that MT mainly compensates for passive torque and provides adjustment of wrist motion according to requirements of both tasks. The 3 shoulder-elbow coordination patterns during which at least one joint moves largely passively represent joint control primitives underlying performance of well-learned arm movements, although these patterns may be less prevalent during non-habitual movements. The advantage of these control primitives is that they require minimal neural effort for joint coordination, and thus increase neural resources that can be used for cognitive tasks. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2018

Digital volume correlation (DVC) is a computational tool used to measure a 3D displacement field between a pair of 3D images (from, for example, magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, etc.). Studies in biomechanics have used DVC to quantify deformations in cells, tissues and organs, for the purpose of examining deformation and failure mechanisms, movement, and adaptation. The growing popularity of DVC has created increased demand for DVC algorithms that are computationally efficient, verified and validated. The goals of this project were to improve the efficiency of an existing DVC algorithm and to present a set of methods for robust verification and validation. This dissertation first introduces DVC through a series of 1D examples that illustrates the use of optimization to find the displacement field that produces the best match between the pair of images. Different methods of regularization are explored. The concept of downsampling of the images is introduced as a way to promote faster convergence and a better image match. In preparation for the move to 3D, the second part of the dissertation covers key concepts in 3D image acquisition and data preparation for the specific case of μCT imaging of human vertebrae. This section allows the reader to appreciate the use of DVC to enable study of failure mechanisms in the spine. The third section addresses the DVC method for 3D images. A custom process is introduced that uses rigid registration of the images to obtain an initial guess for the displacement field. The effect of the quality of the initial guess is then explored using test displacement fields. In the final section, new methods of verification and validation of DVC are presented. An “image-warping” code is presented that interpolates a given displacement field to every voxel of an image, producing a synthetic image. This code is used to warp one image of a pair that was analyzed by DVC, and the mismatch between the synthetic image and the second image of the pair is used to verify the success of the minimization. The image-warping code is also used to create synthetic images from artificial, “test” displacement fields of increasing complexity and realism as a tool for validating the accuracy of the DVC algorithm. Finally, an L-curve method is applied in order to fine tune selection of the regularization parameter. Though the improvements to DVC presented here were developed for the study of failure mechanisms of the spine, there is opportunity for broader application. The 1D examples can be mimicked to understand the foundations and limitations of similar DVC algorithms. Downsampling can also help these alternative algorithms to increase computational efficiency and improve image matching. Furthermore, the verification and validation methods presented here model an approach that others could use as they seek to improve their own algorithms.

During the progression of pulmonary arterial hypertension (PAH), the smooth muscle of the pulmonary artery changes phenotypically in several ways. Although many of these changes have been characterized, more remains to be understood about the mechanical properties of pulmonary arterial smooth muscle (PASM) cells and their role in PAH. To address this, PASM cells were studied using traction force microscopy to test their fluidization response to stretch, to determine if changes in contractility occur in the setting of PAH, and to screen a preliminary set of myosin inhibitors for those which relax the cell. As predicted, PASM cells produced a similar fluidization-resolidification response to transient stretch as shown in previous studies of other smooth muscle cell types. Although the statistical significance is not strong (p=0.082), PASM cells incubated in serum from PAH patients did show an increased average baseline contractility compared to cells treated with serum from normal volunteers. Of three myosin inhibitors tested, blebbistatin had a statistically significant (p=0.002) reduction in baseline contractility compared to untreated control cells. Taken together, these results support the hypothesis that stretch-induced fluidization is a feature of the normal PASM cell and suggest that factors in the PAH milieu may cause changes in the PASM cell, yielding a more contractile phenotype. A possible avenue for treating PAH may lie in using myosin inhibitor drugs such as blebbistatin to reduce contractility of the PASM cell.

Physiological tissue exists in a state of tension. Maintenance of this tension at a set level, a process termed tensional homeostasis, is imperative to the preservation of healthy cells and tissues, and multiple diseases such as cancer and atherosclerosis have been linked to the loss of the ability to maintain it. Despite this, very little is known about how this tension is established and maintained at the cellular level. Early reports on tensional homeostasis, which observed large cohorts of cells, hypothesized that constant tension levels exist at all length scales, including the cellular and subcellular length scales. Therefore, the main goal of this thesis was to begin to understand tensional homeostasis at the cellular level. In this thesis, we explore the impacts of both cell properties and environmental factors on the traction force dynamics of single cells and clusters of cells to try to understand how they establish and maintain tensional homeostasis. We observed that multicellularity is necessary for tensional homeostasis in endothelial cells, but that this phenomenon is cell type specific. Cell types like smooth muscle and fibroblasts maintain steady force at the single cell level. We explored the differences that might drive this difference and found that the cell adhesion protein cadherin is essential to tensional homeostasis and that inflammatory signaling can lead to its loss. We also work towards the creation of a tool that will allow us to better recapitulate in vivo conditions, which will allow us to study tensional homeostasis at the single cell level in the physiological context of cyclic stretch. This work suggests that tensional homeostasis is a complex process that is influenced by both internal and environmental factors. Some of these factors, like E-cadherin, which were previously known to affect mechanobiology may be more complex than previously realized. Finally, this thesis makes it clear that to fully understand how cells establish the homeostasis seen at the tissue level, we must look at traction dynamics rather than just a single snapshot in time. Studying tensional homeostasis in dynamic states may be essential to understanding processes such as wound healing, development, and disease progression.

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.

The inner hair cells in the mammalian cochlea transduce mechanical signals to electrical signals that provide input to the auditory nerve. The spatial-temporal displacement of the inner hair cell stereocilia (IHCsc) relative to basilar membrane (BM) displacement is central to characterizing the transduction process. This study specifically focuses on measuring displacement of the stereocilia hair bundles in the radial dimensions where they are most sensitive. To simplify the mechanical response of the cochlear partition, a mechanical probe was used to drive the BM. Optical imaging was used to measure radial displacement of the inner hair cell stereocilia local to the probe in ex vivo gerbil cochleae. The mechanical probe displaced the BM in the transverse direction using sinusoidal stimuli with frequencies ranging from 10 Hz to 42.5 kHz. IHCsc displacement measurements were made in the radial dimension as a function of their longitudinal location along the length of the BM. The results were used to quantify the frequency response, longitudinal space coupling, traveling wave velocity, and wavelength of the radial displacement of the stereocilia. The measurements were centered at two best frequency locations along the BM: Proximal to the round window (first turn), and in the second turn. At both locations, frequency tuning was seen that was consistent with published place maps. At both locations, traveling waves were observed simultaneously propagating basal and apical from the probe. The velocity of the traveling waves at the center frequency (CF) of the location was higher in the first turn than in the second. As the stimulus frequency increased and approached CF for a location, the traveling wavelength decreased. Differential motion of the BM and IHCsc was observed in the second turn as the stimulus frequency increased toward CF. The longitudinal coupling measured in this study was longer than observed in previous studies. In summary the results suggest that the shape of the wave patterns present on the BM are not sufficient to characterize the displacement of the IHCsc.