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Title: ENHANCED DEGRADATION AND PEPTIDE SPECIFICITY OF MMP-SENSITIVE SCAFFOLDS FOR NEOVASCULARIZATION OF ENGINEERED TISSUES
Creator: Sokic, Sonja
Date: 2013, 2013-07
Description: Biomaterial strategies for engineering tissues of clinically relevant size require the formation of rapid and stable neovascularization. The...
Show moreBiomaterial strategies for engineering tissues of clinically relevant size require the formation of rapid and stable neovascularization. The ability of an engineered scaffold to induce vascularization is highly dependent on its rate of degradation. During the process of material degradation, the scaffold should degrade in a manner allowing for cellular infiltration, lumen formation, and extracellular matrix (ECM) synthesis. Matrix metalloproteinases (MMPs) play a key role in mediating cell-induced proteolytic matrix degradation, remodeling, and controlled neovascularization. Poly (ethylene glycol) PEG hydrogels have been extensively investigated as scaffolds for tissue engineering applications due to their ease of chemical modification allowing for the recapitulation of key aspects of the neovascularization process. The goal of the work described in this thesis was to develop strategies to enhance and control the degradation of MMP-sensitive PEG diacrylate (PEGDA) hydrogels without inducing changes to the bulk physical and mechanical properties of the material and to further study the effect of the cleavage site concentration and MMP-sensitive peptide substrate specificity on the rate of neovascularization and tissue remodeling in vitro and in vivo. In the first part of this study, a detailed investigation was completed to investigate the effects of the mechanical and physical properties of the scaffolds as well as the role of proteolytically mediated hydrogel degradation on 3D fibroblast invasion within MMPsensitive PEGDA hydrogels. Initial studies focused on the use of a modified version of a previously published multistep conjugation method to generate degradable PEGDA macromer conjugates containing variations in the number of MMP-sensitive domains. Theoretical and experimental characterization of this multistep conjugation demonstrated xi that this method leads to the formation of multiple species that directly affect the compressive modulus and degradation rate of the scaffold making it difficult to control degradation independent of alterations in the bulk physical and mechanical hydrogel properties. After manipulation of multiple polymerization conditions, hydrogels with similar compressive moduli but different hydrogel degradation rates were synthesized. These initial studies showed that an increase in the incorporation of proteolytically sensitive domains in PEGDA hydrogels of similar modulus lead to enhanced degradation and 3D fibroblast invasion. In this study, the role of soluble FGF-1 on fibroblast invasion within these scaffolds was investigated and it was demonstrated that the inclusion of FGF-1 in the scaffolds results in further enhancement of fibroblast invasion in a dosedependent fashion. Further studies were necessary to develop a more controllable and robust approach in tuning scaffold degradation independent of alterations in the bulk physical and mechanical properties. In order to address this, a novel approach was developed to engineer protease-sensitive peptides with multiple proteolytic cleavage sites that could be covalently crosslinked into hydrogels without compromising the physical and mechanical biomaterial properties. This approach avoided the need for utilizing a multistep conjugation process as peptides could be incorporated into the backbone of PEG using a single step conjugation. Using this approach, hydrogels formed with the engineered peptides led to significantly enhanced degradation and neovascularization in vitro as compared to scaffolds with a single protease sensitive peptide between crosslinks. In addition, hydrogels with enhanced susceptibility to degradation promoted vascularization over a wider range of matrix properties. This approach allowed for controlled xii concentration of the proteolytic cleavage sites within the matrix and thus tuning of hydrogel degradation for tissue engineering applications. In the final study, MMP-sensitive peptide substrates specific to degradation by MMPs known to be expressed during neovascularization were screened for degradation and their role in neovascularization. MMP-sensitive PEGDA hydrogels (SSite and TriSite) were synthesized with peptide substrates sensitive to cleavage by MMP-2, MMP- 9, MMP-14, a mixed sequence of MMP-2, 9 and 14, and compared to the peptide substrate used in the previous studies, which is degraded by collagenase enzymes. The hydrogels were evaluated for their sensitivity and specificity to degradation by MMPs, in terms of cleavage site concentration, and for their role in neovascularization and tissue remodeling in vitro and in vivo. The presented approach allows for the incorporation of varying cleavage site concentration and MMP-sensitive peptide substrates into PEG hydrogels without alterations in the mechanical and physical properties of the hydrogels. Results showed that without the incorporation of growth factors in this scaffold, vascularization and tissue invasion was supported in all MMP-sensitive hydrogel groups regardless of the MMP-sensitive peptide substrate embedded in the matrix. In addition, the cleavage site concentration had a profound impact in enhancing vascularization in vitro and tissue invasion in vivo. These techniques can be used to tune the properties of polymer scaffolds for neovascularization and tissue remodeling. In addition, these studies provide insight into the effect of the physical, mechanical, and degradative properties of these systems and on the role of cleavage site concentration, and MMP substrate specificity on xiii neovascularization and tissue invasion within proteolytically degradable PEG hydrogel constructs.
PH.D in Biomedical Engineering, July 2013
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Title: DISRUPTION OF EPILEPTIC SEIZURES USING TARGETED MULTI-SITE ELECTRICAL STIMULATION
Creator: Sobayo, Tiwalade
Date: 2015, 2015-12
Description: Neuronal populations in the brain achieve levels of synchronous electrophysiological activity during both normal brain function and...
Show moreNeuronal populations in the brain achieve levels of synchronous electrophysiological activity during both normal brain function and pathological states such as epileptic seizures. Understanding how the dynamics of neuronal oscillators in the brain evolve from normal to diseased states is a critical component towards decoding such complex behaviors. In my studies, I assessed multi-site dynamics underlying seizure evolution in limbic epilepsy by analyzing oscillators in recordings of local field potentials from three brain structures (bilateral hippocampi and anteromedial thalamus) in a rat model of temporal lobe epilepsy extracted using the empirical mode decomposition (EMD) technique. The analysis revealed patterns of multi-site phase coherence during initiation and termination phases of seizures. The multi-site synchrony events as seizures naturally terminated were used to model electrical deep brain stimulation (DBS) protocols aimed at stopping ongoing epileptic seizures. The location and frequency of the natural termination synchrony varied between subjects but was stable in time within each animal. My studies reveal that DBS protocols were significantly more effective at rapidly stopping seizures when the frequency and location of multi-site stimulation reflected the endogenous synchrony dynamics observed in each subject. These results strongly suggest that tailoring DBS protocols to individual endogenous rhythms that may represent how brains naturally resolve epileptic seizures could play a critical role in vastly improving the overall efficacy of this important therapy.
Ph.D. in Biomedical Engineering, December 2015
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Title: CELL-MATRIX INTERACTIONS IN ADIPOSE TISSUE FUNCTION
Creator: Vaicik, Marcella K.
Date: 2015, 2015-07
Description: The overall goal of this work is to apply in vivo and in vitro models to study the basement membrane protein laminin α4 (lama4) in adipocyte...
Show moreThe overall goal of this work is to apply in vivo and in vitro models to study the basement membrane protein laminin α4 (lama4) in adipocyte function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the lama4 gene (Lama4−/−) and compared to wild-type animals (Lama4+/+). The Lama4−/−mice phenotype was investigated to evaluate if the differences were due specifically to the adipose tissue function. Physical activity and food intake does not differ between Lama4+/+ and Lama4−/− mice. However, Lama4−/− mice have a significantly increased metabolic rate at 25°C and 16°C compared to Lama4+/+ mice. In contrast, in thermoneutral conditions at 30°C both Lama4+/+ and Lama4−/− mice exhibit equivalent metabolic rates. Interestingly, when room temperature housed mice fat pads were evaluated with immunohistochemistry, Lama4−/− mice exhibit significantly increased UCP-1 expression in subcutaneous adipose. These results suggest that beiging, white to brown adipocytes, in subcutaneous adipose tissue in Lama4−/− mice may lead to decreased adipose tissue accumulation and improved metabolic function. While animal models indicate the absence of lama4 results in more beiging in subcutaneous adipose tissue, an in vitro tissue engineered model was developed to study the adipocyte function in a controlled microenvironment. Primary cell spheroids developed from Lama4+/+ and Lama4−/− were incorporated into synthetic poly(ethylene glycol) (PEG) hydrogels within a range of stiffnesses. When the cells were given the same chemical cues their functions differed depending upon microenvironment stiffness. Beige function in adipocyte cells in 3D can be influenced by matrix stiffness. In conclusion, the laminin alpha 4 basement membrane protein absence in adipose tissue results in adipocyte functional changes in vivo. The Lama4−/− mice have resistance to diet induced weight gain and increased metabolic rate at room temperature and when cold challenged. The Lama4−/− mice had increased beiging in the subcutaneous depot. Additionally, a tissue engineered model was developed to further study cell-ECM interactions first identified in an animal model. These in vivo findings and the engineered model of adipose tissue have great potential for studying obesity and other adipose related diseases. Future work will require continued interdisciplinary collaboration towards the successful identification and screening of novel therapeutics using engineered tissue models.
Ph.D. in Biomedical Engineering, July 2015
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Title: THE EFFECT OF FLOW ON MICROPARTICLE TRANSPORT AND THE ROLE OF MICROPARTICLES IN THROMBOSIS
Creator: Lee, Ying-hui
Date: 2012-11-27, 2012-12
Description: Elevated monocyte/macrophage-derived microparticles (MPs) have been found to correlate with thrombotic complications. These MPs carry tissue...
Show moreElevated monocyte/macrophage-derived microparticles (MPs) have been found to correlate with thrombotic complications. These MPs carry tissue factor (TF), the principal coagulation pathway initiator, as their parental cells and expose anionic phospholipid phosphatidylserine (PS), which can promote thrombin generation and fibrin formation. During thrombus development, MPs may be delivered to the injured/dysfunctional vascular endothelium or biomaterial surfaces and influence the process of thrombosis. MPs are submicron membrane vesicles that may have increased transport and/or binding capabilities compared to platelets or other cell types due to their decreased size and their higher Brownian diffusion. MPs and their surface molecules can be delivered to surfaces, either biological or prosthetic, and alter the local environment. Little is known of the mechanisms by which MPs are transported to and impart their biological activity on surfaces, especially in blood. Such a transfer of activity will depend on the ability of MPs to be transported to the surface, the strength of adhesion of the MPs on the surface and the nature of the activity/host interaction. In the present study, physical and biological properties of MPs generated from macrophage-like cell lines by endotoxin stimulation were characterized, the transport of MPs to surface by flow was investigated, and the import biological activity on surfaces was elucidated. We observed that the deposition of MPs suspended in buffer on glass surfaces was strongly shear-dependent using a well-defined parallel plate flow chamber. The diffusivity coefficients of MPs at shear rate ranges ranging from 100 to 3200 s-1 were determined from the classical mass transport equation proposed by Leveque and the values were found to be of the same order of magnitude as predicted by Brownian xi diffusion. MPs non-specific attachment to glass was dominated by electrostatic interactions; this was verified by changing the surrounding ionic strength of the suspending solution. In addition to shear rate, red blood cells (RBCs) also influenced MP adhesion due to the complex movement of RBCs. Such movement has been shown to enhance the adhesion of platelets (1-2 micron size cells) to surfaces in flowing blood. MP lateral transport was enhanced at low concentrations of RBCs and reduced at higher concentration of RBCs. The reduction of MP deposition was due to the competition for surface binding sites between the two populations of MPs. The two types of MPs studied here, those produced by macrophages after endotoxin stimulation and those produced by RBCs during experimental preparation (repeated centrifugal washing) have the capability of nonspecific binding to artificial surfaces in a competitive manner. Finally, we demonstrated that the amount of adherent MPs on surfaces influenced fibrin formation via both a TF-dependent and a negatively charged phospholipid pathway. These findings suggest that procoagulant MPs may modulate thrombotic events under certain conditions, especially in MP-associated diseases. The knowledge of the effects of flow on MP transport and the influence of increased MPs on thrombosis may provide novel insights for the transfer of biological activity to relatively passive surfaces.
PH.D in in Biomedical Engineering, December 2012
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Title: NEOVASCULARIZAnON WITHIN POROUS PEG HYDROGELS
Creator: Chiu, Yu-chieh
Date: 2011-11, 2011-12
Description: Development of engineered tissues of clinically relevant size requires the ability to control vascularization within biomaterial scaffolds....
Show moreDevelopment of engineered tissues of clinically relevant size requires the ability to control vascularization within biomaterial scaffolds. Poly(ethylene glycol) (PEG) hydrogels have been extensively investigated for use as synthetic scaffolds to support engineered tissue formation. The goal of this work described was to develop techniques that can be used to enhance vascularized tissue formation in PEG-based hydrogels. In the first part of the study a technique was developed to generate porous PEG hydrogels using a salt leaching technique. This technique was then used to examine the role of pore size on vascularization and tissue remodeling in porous PEG hydrogel in vitro and in vitro. Both in vitro and in vivo studies showed that vessel invasion was pore size dependent. In addition, a thin layer of inflammatory tissue was observed between PEG hydrogel and blood vessels that formed within the gels. This layer suggested that inflammatory cells, not vascular cells, interacted with the surface of the material. This suggests that peptides covalently incorporated within PEG may not directly interact with endothelial cells (ECs) following implantation. The porous PEG hydrogels were very stable in vitro and in vivo and did not exhibit any signs of degradation. Hydrogels used in tissue engineering need to exhibit controlled degradation. In order to address the stability of PEG hydrogels, porous hydrogels were rendered using degradable PEG-co-(L-Lactic acid) diacrylate PEG-PLLA-DA. This polymer is degraded via hydrolysis of the PLLA chains. The porous PEG-PLLA-DA hydrogels were generated by solvent casting, photopolymerization, and particulate leaching. The influence of polymer conditions on the architecture, degradation, and mechanical properties of the hydrogels were investigated in vitro. The hydrogels were found to exhibit autofluorescence that allowed for the unique ability to nondestructively image hydrogel structure under fully swelled conditions using confocal microscopy. Initial pore size was a function of particulate size and independent of polymer concentration. Interestingly, pore size remained stable though out the study, and was not a function of degradation. In addition, degradation time of porous PEG-LLA-DA hydrogels was influenced by polymer concentration. Compressive modulus was a function of polymer concentration and pore size and decreased during hydrogel degradation. The incorporation of cell adhesion sequences into the hydrogel showed that they can support cell adhesion with morphology varying with pore size. This technique could be used to tailor porous biodegradable scaffolds for tissue engineering applications. In the final portion of this thesis a poly-lysine (PLL) molecule was synthesized in order to allow clustering of adhesion sequences in PEG hydrogels. Clusters of peptide sequences have been shown to enhance cell interactions with substrate surfaces. The sequence was synthesized and purified by high performance liquid chromatography (HPLC) and characterized by mass spectrometry. The side chains of the PLL molecule was used to attach peptide sequences. Cysteine contained within the PLL allowed incorporation into the PEG hydrogel by mixed mode polymerization. Cells were observed to adhere to hydrogels containing the RGD clusters and not to the control gels. The results presented here describe various techniques that can be used to optimize the design of polymer scaffolds for tissue engineering. In addition, the data provide insight into the process of vascularization in porous hydrogels and the influence of synthesis conditions and degradation on properties of porous hydrogels. Future studies should investigate the optimization of these material techniques for control of neovascularization within PEG hydrogels for tissue engineering applications.
Ph.D. in Biomedical Engineering, December 2011
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Title: QUANTITATIVE ANALYSIS OF THE EFFECTS OF BIOFUNCTIONAL AND PHYSICAL GRADIENTS ON CELL BEHAVIOR IN POLY (ETHYLENE GLYCOL) DIACRYLATE HYDROGELS
Creator: Turturro, Michael
Date: 2012-10-29, 2012-12
Description: The continued enhancement of tissue engineered scaffolds relies on their ability to stimulate the formation of a stable microvascular network...
Show moreThe continued enhancement of tissue engineered scaffolds relies on their ability to stimulate the formation of a stable microvascular network within the biomaterial. In vivo, the spatial presentation of immobilized extracellular matrix cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The overall goals of this thesis are to develop a technique for the generation of gradients of physical properties and incorporated biofunctionality within poly(ethylene glycol) diacrylate (PEGDA) scaffolds and to investigate the effects of these gradients on 3D cell invasion and neovascularization. To this end, a novel photopolymerization technique for generating spatial variations in matrix properties and incorporated biofunctionality within synthetic PEGDA hydrogels, perfusion-based frontal polymerization (PBFP), was developed. This technique relies on the controlled perfusion of a photoinitiator to a reaction chamber containing a precursor solution and results in the propagation of a polymer reaction front that travels through the monomer solution creating a gradient in hydrogel crosslinking. Manipulation of the magnitude of the gradient can be achieved through alterations in the polymerization conditions. Scaffolds with embedded gradients were designed and optimized based on a range of properties shown to support 2D cell adhesion, proliferation, and 3D vascular cell invasion in bulk photopolymerized hydrogels with homogeneous properties. An in vitro model of neovascularization was used to evaluate the effect of these gradients on vascular sprout formation. Sprout invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, sprout xvi length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked matrix metalloproteinase (MMP)-sensitive peptide presentation, and immobilized YRGDS concentration. In vivo tissue invasion was shown to be directly related to gradient properties and orientation. Alterations in the magnitude of the gradient in elastic modulus enhanced the directionality of invading vascular sprouts while restricting in vivo tissue invasion.
PH.D in Biomedical Engineering, December 2012
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Title: MULTIMODAL NEUROIMAGING IN BLAST INDUCED TRAUMATIC BRAIN INJURY
Creator: Stout, Jeffrey
Date: 2015, 2015-12
Description: Recent military conflicts in Iraq and Afghanistan have resulted in an increase in the number of blast related traumatic brain injury (TBI)...
Show moreRecent military conflicts in Iraq and Afghanistan have resulted in an increase in the number of blast related traumatic brain injury (TBI) cases, currently estimated in excess of 300,000. Current neuroimaging methods, including MRI and CT, are generally not sensitive enough to diagnose blast TBL This research represents several advancements in the understanding of long-term TBI related changes as well as imaging comorbid neurocognitive deficits and psychopathologies. The multi modal approach was taken to leverage the differing sensitivities of each imagmg modality to better identify neuroimaging changes associated with blast TBL T l-weighted MRI was utilized to assess cortical thickness reduction in the TBI subjects, resulting in right temporal lobe decreases that were associated with posttraumatic stress disorder (PTSD) and neurobehavioral symptom indices. Utilizing positron emission tomography (PET), several areas of metabolic change were associated with blast TBI, PTSD, repetitive head injury, and TBI severity. Functional MRI was used to assess working memory deficit, demonstrating relatively normal function in the mild TBI subject, except for at higher cognitive loads; whereas the moderate TBI subjects demonstrated a trend of dysfunction at most levels of cognitive load. Fractional anisotropy (FA) changes were assessed using diffusion tensor imaging, however there was no resulting statistical significance due to differences in the locations of single subject FA changes that could not be realized at the group level using standard analyses. Investigation into multimodal searchlight to integrate the sensitivities of each imaging modality into a single statistical measure, provided enhanced sensitivity to TBI-induced changes in neuroimaging versus single modal searchlight and identified several clusters of change most notably in the cerebellum, temporal lobes, brainstem, and internal capsule. Through a multimodal approach we have shown several areas of damage and dysfunction associated with blast TBI in subjects greater than one year post injury. This research is important due to the large numbers of subjects currently experiencing long-term post concussive symptoms. Our findings show that both TBI and PTSD playa large role in the changes identified on neuroimaging. This research can provide information to assist in the understanding , diagnosis , and treatment of blast TBI.
Ph.D. in Biomedical Engineering, December 2015
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Title: EXPLORING THE SHEAR-AND-TIME DEPENDENT DEGRADATION OF VON WILLEBRAND FACTOR UNDER VENTRICULAR ASSIST DEVICE-RELATED FLOW CONDITIONS
Creator: Yang, Shuo
Date: 2015, 2015-12
Description: Abnormalities in VWF can cause impaired blood coagulation which results in higher bleeding tendency in patients with this disorder. Alteration...
Show moreAbnormalities in VWF can cause impaired blood coagulation which results in higher bleeding tendency in patients with this disorder. Alteration in VWF is characteristic in ventricular assist devices (VADs) implanted subjects with failing hearts. The nature of the abnormalities produced and the conditions which produce such abnormalities are not fully understood. The studies in this thesis investigate quantitatively the effects of VADs and VAD-related flow conditions on VWF degradation. This thesis consists of three studies: 1) an in vitro VAD loop study in which was investigated the degradation effects of three VADs either under preclinical development (VAD I) or being commercially available (VAD II & III); 2) a viscometer shear study in which was investigated a variety of factors under the controlled condition of a modified Couette viscometer, namely, shear stress, exposure time, pulsatile frequency and protease function, with respect to VWF degradation 3) a tubular shear study in which was investigated the relative degradation effects of shear stress versus exposure time under more VAD-related shear stresses (10 - 100 times higher than physiological levels) and exposure times of miliseconds. In the VAD flow loop, significant VWF degradation induced by VADs wee observed with an approximately 95% loss of high molecular weight VWF by 60 minutes. In the viscometer and the tubular studies, the factors studied enhanced VWF degradation in the following manner: increased shear stress above physiological levels, prolonged exposure time and higher pulsatile shear frequency were associated with greater degradation; shear stress was a more dominant factor than exposure time with respect to the degradation; and a various shear stress regions demonstrated maximal degradation effects. In addition, calcium-dependent protease function was a necessity for VWF degradation at all shear stress levels investigated. The studies also revealed that the unfolding of VWF to expose the cleavage sites appeared to take more time under shear than the refolding to re-cover those sites under static conditions. Critical shear regions may be important for unfolding and degrading VWF multimers of various sizes.
Ph.D. in Biomedical Engineering, December 2015
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Title: MEASUREMENT OF INTRARETINAL NITRIC OXIDE IN EARLY DIABETIC RETINOPATHY
Creator: Guthrie, Micah
Date: 2014, 2014-12
Description: Diabetic retinopathy (DR) is the most frequent cause of new cases of blindness among adults aged 20-74 years. Nearly all patients with Type 1...
Show moreDiabetic retinopathy (DR) is the most frequent cause of new cases of blindness among adults aged 20-74 years. Nearly all patients with Type 1 diabetes and greater than 60% of patients with Type 2 diabetes will develop retinopathy within the rst two decades of the disease. Nitric oxide (NO) has been shown to play a role in the progression of DR, contributing to neuronal dysfunction and the breakdown of the blood-retina barrier early stages of the disease. The objective of the current study was to investigate the changes in intraretinal NO levels in early DR. To accomplish this, a dual NO/electroretinogram (ERG) electrode was developed to make the rst direct measurements of NO concentration throughout the in vivo retina. These electrodes were validated in an in vivo animal model by comparing control recordings to those taken after injection of the broad spectrum nitric oxide synthase (NOS) inhibitor L-NG-Nitroarginine methyl ester (L-NAME). Control NO pro les showed high levels of NO in the photoreceptor layer with localized areas of increased NO in the amacrine/ganglion cell layer. L-NAME NO pro les showed substantially reduced NO in the retina, indicating that the electrodes were measuring actual NO. The electrodes were then used to record NO pro les from the retinas of rats made diabetic with streptozotocin (STZ). The recordings were obtained three weeks after injection of STZ. Blood glucose levels were also monitored in order to correlate the blood glucose level with intraretinal NO concentration. It was found that mild diabetic rats (blood glucose 250-400 mg/dL) had higherthan- control levels of NO throughout their retinas. Severe diabetics (500-600 mg/dL) had lower-than-control levels, while moderate diabetics (400-500 mg/dL) did not have signi cantly di erent NO levels than controls. The NO pro les from the severe diabetics were very similar to L-NAME pro les, indicating that NOS production may be abnormal in severe diabetics. It was also found that intraretinal NO concentration was inversely correlated with the blood glucose of diabetic rats. To determine if the changes in NO seen in diabetic rats were due to direct tissue exposure to high glucose, NO pro les were also recorded from rats acutely injected with glucose solution to achieve similar levels of hyperglycemia. No changes in NO levels were seen in the retinas of these acute hyperglycemic rats, indicating that there are other factors besides high glucose contributing to the NO changes in DR. The results show that there is not a simple increase in NO as severity of diabetes increases and highlight the importance of being able to make measurements of bioavailable NO in retinal tissue. The electrodes were able to detect clear di erences in experimental DR, indicating their utility in investigating NO changes in the early stages of the disease. Future work with the electrodes needs to be performed to investigate the mechanisms of NO changes in DR in order to develop potential treatments which could mitigate the damage at an early stage before vision loss occurs.
M.S. in Biomedical Engineering, December 2014
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Title: NEUROPATHOLOGIC CORRELATES OF BRAIN MACROSTRUCTURE
Creator: Kotrotsou, Aikaterini
Date: 2014, 2014-07
Description: Alzheimer’s disease, the most common form of dementia, is a degenerative disorder of the brain that leads to memory loss. Clinical diagnostic...
Show moreAlzheimer’s disease, the most common form of dementia, is a degenerative disorder of the brain that leads to memory loss. Clinical diagnostic techniques in use today rely on mental and behavioral tests and physical examinations and only provide diagnoses of possible or probable Alzheimer’s disease. However, lately it has become clear that clinical-pathological correspondence is not always consistent. A definitive diagnosis of Alzheimer’s disease is only possible via histology, when the density of neurofibrillary tangles and amyloid plaques is measured. Therefore, the development of a reliable neuroimaging technique that allows detection of Alzheimer’s pathology during life is needed. This method would be noninvasive, and could allow the detection of Alzheimer’s disease in the early stages, and could be also used to monitor the progression of the disease through time. The purpose of this work was to investigate the use of magnetic resonance imaging (MRI) as diagnostic tool for Alzheimer’s pathology and other age-related neurodegenerative pathologies that are common in older persons. To uncover the anatomical origins and determine the macrostructural signatures of age-related neuropathologies, it is necessary to link MRI findings with pathologic information on the same individuals. In this work, we focused on imaging cerebral hemispheres ex-vivo, when a complete pathology report was available from a board-certified neuropathologist. The main difference between this work and any other study is the abundance of postmortem imaging data paired with neuropathology data in a relatively large pool of subjects. First, we developed and validated a protocol to perform ex-vivo MR volumetry. By using this protocol we observed the longitudinal behavior of the volume of different brain regions. Furthermore, we tested the hypothesis that volumetric measurements performed ex-vivo are associated with in-vivo measurements. It was shown that: (a) regional brain volumes measured with this approach for ex-vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem, and (b) a linear correspondence was detected between in-vivo and ex-vivo measurements, suggesting that this approach captures information linked to antemortem macrostructural brain characteristics. Using the approach for ex-vivo MR volumetry, we combined ex-vivo MR volumetry with pathology on the same adults. AD pathology was significantly negatively correlated with volumes of cortical gray matter regions, mainly in the temporal, frontal, parietal and cingulate cortices, subcortical gray matter, and whole-hemisphere white matter. A significant negative correlation was shown between hippocampal sclerosis and volumes of the hippocampus, as well as other temporal and frontal gray matter regions. Finally, we performed a morphometric MRI study to investigate associations of brain volumes with pathology using voxel-based analysis. This technique allows the assessment of gray and white matter volumes in subjects with different pathologies compared with controls in an automated fashion, across the whole brain. AD pathology was negatively associated with regions of gray matter and white matter located in temporal and frontal lobes, and orbitofrontal cortex. This work examined the associations of brain volumes with Alzheimer’s pathology and other typed of age-related neurodegenerative pathologies. Combining histological result with MR images requires that the time elapsed between imaging and histology is minimal. Ex-vivo MRI provides images at essentially the same time-point as histological examination of the tissue, and this study is unique in that it involves a large number of cadaveric brain hemispheres. The findings of this ex-vivo study could allow for future standardization of MRI as a biomarker of neurodegenerative diseases, and also allow in identification and classification of subjects in groups for tests of new drugs.
Ph.D. in Biomedical Engineering, July 2014
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Title: POSTMORTEM MRI OF THE ELDERLY HUMAN BRAIN: METHODS AND APPLICATIONS TO HISTOPATHOLOGICALLY VERIFIED ALZHEIMER’S DISEASE AND OTHER NEUROPATHOLOGIES OF AGING
Creator: Dawe, Robert J.
Date: 2011-04-08, 2011-05
Description: Currently, a definitive diagnosis of Alzheimer’s disease is only possible postmortem, when the distribution and type of pathology in the brain...
Show moreCurrently, a definitive diagnosis of Alzheimer’s disease is only possible postmortem, when the distribution and type of pathology in the brain can be directly verified via histology. Clinical diagnostic techniques in use today rely on behavioral and neuropsychological criteria and only provide diagnoses of possible or probable Alzheimer’s disease, both of which indicate that significant irreversible neuronal damage has already occurred. Therefore, a neuroimaging technique for detection of Alzheimer’s pathology during life is highly sought after. Such a technique would be noninvasive, could provide a quantitative evaluation of potential therapies in patients, and could eventually be used for early detection of Alzheimer’s disease. The purpose of this work was to investigate the use of magnetic resonance imaging (MRI) as diagnostic tool for Alzheimer’s and other types of pathology that are common in the elderly human brain. In order to correlate imaging data with a diagnosis of neuropathology that was guaranteed to be accurate, we focused on imaging cerebral hemispheres postmortem (ex vivo), when a complete pathology report was available from a board-certified neuropathologist. The main difference between this work and any other study is the abundance of postmortem imaging data paired with neuropathology data in a relatively large pool of subjects. First, we examined the relation between postmortem hippocampal volume, measured from MR images, and pathological diagnosis of Alzheimer’s and other common types of pathology. It was shown that Alzheimer’s, along with hippocampal sclerosis, are associated with a dramatic reduction in hippocampal volume. Furthermore, the pattern of hippocampal atrophy differs between these two types of neuropathology, which may provide a means of distinguishing one from the other in vivo using MR images. Next, the transverse relation time constant, T2, was examined over time in five postmortem hemispheres that were undergoing chemical fixation via immersion in formaldehyde solution. This investigation yielded two important pieces of information: (a) for the purposes of obtaining stable measurements of T2, the ideal time to conduct postmortem MRI of the human brain is at least one month postmortem, and (b) correction of T2 measurements for the postmortem interval to imaging is both possible and necessary for analysis of T2 alterations associated with pathology. Using the information gleaned from the study of changes in transverse relaxation over time, we next examined the dependence of T2 on the presence of Alzheimer’s pathology. Significant prolongation of T2 was demonstrated in various white matter regions in cases of Alzheimer’s, suggesting degeneration of that tissue. Significant shortening of T2 was detected in the basal ganglia, suggesting that accumulation of iron in that region is associated with the progression of Alzheimer’s disease. Finally, a method of conducting high quality diffusion tensor MRI of postmortem cerebral hemispheres was developed. Compared to in vivo diffusion tensor MRI, the postmortem variant of the technique is much more challenging, since the signal to noise ratio is affected very negatively by a combination of faster transverse relaxation, reduced water diffusivity, and the resulting need for longer diffusion-sensitizing gradients. To a large extent, these problems have been solved, and we have now implemented a protocol for routine diffusion tensor MRI of recently deceased human brains which takes less than one hour of scan time. This work examined three MRI techniques that hold great promise in their ability to detect Alzheimer’s and other types of neuropathology: hippocampal volumetry, mapping of the transverse relaxation time constant T2, and diffusion tensor imaging. The fact that all three techniques were carried out postmortem is an important contribution, since it allows for imaging results to be correlated with a complete and accurate pathological diagnosis of disease. Findings from postmortem studies could one day be translated to the in vivo case, where they can potentially be used for antemortem diagnosis of Alzheimer’s disease.
Ph.D. in Biomedical Engineering, May 2011
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Title: PREDICTING CORTICAL RESPONSE DURING TRANSCRANIAL MAGNETIC STIMULATION IN HUMANS
Creator: Krieg, Todd
Date: 2014, 2014-07
Description: Transcranial magnetic stimulation (TMS) is capable of noninvasively activating neurons in the brain. TMS can induce persistent effects and is...
Show moreTranscranial magnetic stimulation (TMS) is capable of noninvasively activating neurons in the brain. TMS can induce persistent effects and is being increasingly used in both clinical and research applications. Despite this growing interest, the relationship between TMS-generated electric fields (E-fields) and specific cortical electrophysiological responses is not well understood. Most analytical approaches focus on applied magnetic field strength in the target region as the primary factor, placing activation on the gyral crowns. However, imaging studies show cortical targets are typically located in the sulcal banks. To study this causal relationship, we combined subject-specific detailed finite element modeling (FEM) to calculate induced E-field information and employed concurrent TMS-PET data as a measure of cortical response. The research presented in this work is divided into three main parts, each one building on the results of the previous: (1) We determined that neocortical surface orientation was a critical determinant of regional activation by studying the locations of activation during TMS on the cortical surface. Results indicated that brain activations were primarily sulcal for both the TMS and task activations. This study provided further evidence that a major factor in cortical activation during TMS is the orientation of the cortical surface with respect to the induced E-fields. This was demonstrated by the fact that the sulcal bank of the primary motor cortex had larger cerebral blood flow (CBF) responses during TMS despite the gyral crown of the cortex being subjected to a larger magnetic field magnitude. (2) We sought to determine the E-field characteristics that lead to cortical activation. We found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and non-active. Specifically, active regions had significantly higher E-field components in the normal orthodromic direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high spatial gradient. In contrast, nonactive regions had higher E-field vectors in the antidromic normal direction. This provides important new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality. (3) Finally, two different but related algorithms were formulated using different optimization approaches that provide a means for predicting topographical maps of cortical activation in humans. This is the first study to produce an algorithm for predicting the electrophysiological responses of neurons in the cortex based on both gross and microscopic brain anatomy correlated to relevant experimental recordings. This new innovation could provide an invaluable tool for predicting regions of cortical activation that may permit, among other benefits, improved prescriptive TMS protocols to optimize therapeutic response to TMS treatment.
Ph.D. in Biomedical Engineering, July 2014
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Title: DEVELOPMENT OF A DIGITAL HUMAN BRAIN ATLAS
Creator: Zhang, Shengwei
Date: 2013, 2013-05
Description: A digital human brain atlas plays a crucial role in brain mapping for the neuroimaging community. Traditionally, a digital brain atlas...
Show moreA digital human brain atlas plays a crucial role in brain mapping for the neuroimaging community. Traditionally, a digital brain atlas contains anatomical information, while structural properties are not presented. Recent development of diffusion tensor imaging (DTI) allows for unique acquisition of information regarding the microstructure of brain tissue. The accuracy of the spatial normalization and subsequent comparisons is contingent upon the use of a DTI template representative of the micro-architecture of the human brain. The previously developed “IIT DTI brain template” was produced in ICBM-152 space. However, low-dimensional registration was used, leading to a mismatch of DTI information across subjects and a mismatch of the anatomy in the IIT and ICBM-152 templates. In this thesis, a significantly improved DTI brain template in ICBM-152 space was developed. The accuracy of spatial normalization in DTI data depends on the quality of data, the effectiveness of the registration technique, and the characteristics of the DTI brain template. Both study-specific and standardized human brain DTI templates exist. The role of both types of templates in spatial normalization warrants further investigation. In this thesis, the effect of standardized and study-specific human brain DTI templates on the accuracy of spatial normalization was investigated. Conventional atlas-based white matter (WM) segmentation is widely used for automated selection of ROI on DTI investigations. However, it suffers from misregistration and inaccurate spatial transformation across subjects. Skeletonized atlasbased segmentation was recently adopted in several DTI studies. However, the use of xiii skeletonized atlas-based segmentation in studies of WM ROIs has not yet been evaluated. In this thesis, the effects of conventional and skeletonized atlas-based segmentation on DTI investigations of WM ROIs were compared. An accurate digital human brain atlas containing different types of high quality MRI data and anatomical labels for both WM and gray matter (GM) in standardized space is desirable for a variety of brain imaging studies. The IIT2 DTI template was developed recently in ICBM-152 space. In this thesis, the quality of the IIT2 template was further enhanced. Furthermore, this publicly available resource was extended into a comprehensive GM atlas of the human brain.
PH.D in Biomedical Engineering, May 2013
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Title: Investigation of Retinal Hemodynamics in a Diabetic Animal Model and VEGF Induced Animal Model
Creator: Turturro, Sanja
Date: 2011-05-11, 2011-05
Description: Diabetic retinopathy (DR) is a complication of diabetes that can ultimately lead to vision loss. Early changes of DR include leukocyte...
Show moreDiabetic retinopathy (DR) is a complication of diabetes that can ultimately lead to vision loss. Early changes of DR include leukocyte adhesion, pericyte loss, and alterations in retinal blood flow. These changes typically occur prior to clinical diagnosis and can develop into more severe problems such as neovascularization and angiogenesis. The objective of the current study was to investigate retinal hemodynamics in early stages of DR in a diabetic animal model and to evaluate the effect of insulin therapy on retinal hemodynamics in diabetic rats in order to demonstrate how controlled blood glucose levels may regulate changes in vasculature. Lastly, the role of vascular endothelial growth factor (VEGF) on retinal hemodynamics of a normal animal were studied to determine the effects of elevated levels of VEGF on retinal vasculature. Volumetric blood flow (VBF) was quantified using average blood velocity and average diameter measured by using the scanning laser ophthalmoscope (SLO) and the particle tracking method. Pericyte coverage was also quantified with a whole-mount retina technique. In diabetic rats, it was shown that arterial and venous VBF decreased beginning at two weeks post onset of diabetes and continued to decrease throughout the eight week time period. There was no significant loss of pericytes at the eight week time point, however, structural abnormalities were observed at the capillary level. Following insulin therapy, the VBF values of treated diabetic animals were comparable to normal animal VBF values and insulin therapy seemed to normalize VBF of diabetic animals. Exogenous levels of VEGF in normal animals showed significant changes in retinal hemodynamics and vasculature. Future experiments should include investigation of factors that may alter retinal blood flow and quantification of VEGF levels in diabetic animals.
Ph.D. in Biomedical Engineering, May 2011
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Title: CONTROLLED AND EXTENDED RELEASE OF ANTIANGIOGENIC AGENTS FOR THE ENHANCED TREATMENT OF CHOROIDAL NEOVASCULARIZATION
Creator: Osswald, Christian R.
Date: 2015, 2015-07
Description: Current U.S. Food and Drug Administration (FDA)-approved drug therapies for choroidal neovascularization (CNV) secondary to age-related...
Show moreCurrent U.S. Food and Drug Administration (FDA)-approved drug therapies for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), also known as wet AMD, require monthly or bimonthly intravitreal (IVT) injections of bolus antiangiogenic agents such as anti-vascular endothelial growth factors (anti-VEGFs) [1]. Less-frequent administration of anti-VEGFs via controlled and extended release is needed to lower the socio-economic impact and lessen the potential side-effects associated with frequent IVT injections. While a controlled delivery system is beneficial, the challenges of initial burst (IB), maintenance of drug bioactivity, and understanding the drug distribution in the diseased eye must be addressed to design an optimal system to address this need. The main goal of this study was to develop a drug delivery system (DDS) capable of delivering anti-VEGF for six months. Additionally, we propose that controlled and extended release of anti-VEGF will yield a greater reduction in CNV growth compared to bolus administration of the same drug. Thus, the current monthly/bimonthly treatment regimen could be replaced by, say, a semi-annual treatment. To accomplish this goal, three specific aims were performed: 1) Development of an injectable microsphere-hydrogel DDS with minimal IB and prolonged release of bioactive anti-VEGF; 2) Verification and validation of the efficacy of said DDS in vivo; and 3) A proof-of-concept finite element analysis comparing the drug distribution throughout a diseased eye to that of a healthy eye.
Ph.D. in Biomedical Engineering, July 2015
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Title: ENGINEERING OF CLINICAL-SCALE, IN VITRO VASCULARIZED BONE TISSUE FOR IMPLANTATION
Creator: Gandhi, Jarel K.
Date: 2016, 2016-05
Description: Tissue engineering has been a rapidly expanding field dedicated to regeneration of tissue. The field has focused on application through...
Show moreTissue engineering has been a rapidly expanding field dedicated to regeneration of tissue. The field has focused on application through combinations of 3 key components: cells, signals, and scaffolds. One ambitious combination of all three is the desire to engineer functional tissues in vitro to meet the clinical-demand of organ replacement. While major advances have been made, a critical obstacle that has yet to be overcome is the need to grow large volumes of complex 3D tissue. In this proposal, this issue is addresed in two ways: the use of a perfusion bioreactor system to culture 3D scaffolds to enhance mass transport, and engineering of a vascular network withing the scaffold for rapid perfusion once implanted in vivo. This thesis aims to address both aspects for bone tissue engineering by engineering pre-vascularized, mineralizing scaffolds that can be scaled up to clinically-relevant volumes by using a tubular perfusion bioreactor system (TPS). To address this, 3 aims were addressed. First, 3D culture of endothelial colony forming cells (ECFCs), a clinically-relevant cell population, was demonstrated utilizing fibrin gels within the TPS. The TPS allowed for viable culture of ECFCs within fibrin bead scaffold up to 1 week without a reduction in cell amount or genomic quality of the cells. Second, a co-culture model of angiogenesis utilizing ECFCs and mesenchymal stem cells (MSCs) was demonstrated to reproducibly form pre-formed vessel networks within a mineralizing fibrin scaffold. Data shows that MSC suspension concentration and fibrinogen concentration modulate the angiogenic response. Mineralization is demonstrated without the use of osteogenic media utilizing shear stress within the TPS. Finally, functionality of the pre-formed vessels is demonstrated following implantation to a SCID mouse model. Engineered human vessels showed anastasmosis to the host vasculature, with evidence of interconnected host and human vessel networks as well as formation of hybrid vessels. Additionally, evidence of mineralization within the scaffolds is maintained in TPS-cultured samples. In demonstrating these aims, future work should focus on fortifying the scaffold material to enable addressing implantation and persistence of clinically-relevant tissue volumes. In conclusion, pre-vascularization within bioreactor-cultured scaffolds represents a promising solution for future tissue engineering application.
Ph.D. in Biomedical Engineering, May 2016
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Title: BIOMATERIAL SYSTEMS WITH PERSISTENT GROWTH FACTOR GRADIENTS IN VIVO FOR TISSUE ENGINEERING APPLICATIONS
Creator: Akar, Banu
Date: 2016, 2016-12
Description: Tissue engineering aims to develop strategies for the replacement of damaged, injured or missing tissues with biologically compatible...
Show moreTissue engineering aims to develop strategies for the replacement of damaged, injured or missing tissues with biologically compatible substitutes such as bioengineered tissues. However, generating tissues of su cient volume for clinical application requires the formation of stable and extensive vasculature within the tissue constructs. The overall goal of this work is to enhance vascularization using a gradient biomaterial system and apply this research to engineering vascularized bone of clinical size. First, a method was developed to create persistent growth factor gradients with an adjustable gradient magnitude in vivo. This method generated persistent gradients of platelet-derived growth factor (PDGF-BB) within brin/poly (ethylene glycol) (PEG) sca olds. The presence of a growth factor gradient within the system was veri ed in vivo using near-infrared imaging. Also, a computational model was developed to investigate gradient characteristics within the system. Gradient properties can be controlled by varying the degradation rate of the gradient layer components or dose of PDGF-BB delivered. The angiogenic potential of gradient sca olds was tested in rodents using a subcutaneous implantation model. The depth of tissue invasion and density of blood vessels formed in response to the biomaterial increased with dose of the growth factor. The gradient biomaterial system allows formation of persistent gradients that can be in uenced by biomaterial characteristics, and enhances vascularization. Therefore, this biomaterial system can be used for tissue engineering applications. Second, the brin/PEG-based sca olds were modi ed to be degradable via hydrolysis and to include bioactive ceramic particles (hydroxyapatite and -tri-calcium phosphate). Characteristics of the hydrogel ceramic composites were investigated in vitro and in vivo. The presence of ceramic particles extended degradation time of thehydrogels in vitro and in vivo. Hydrogel ceramic composites were tested in a rodent cranial defect model and enhanced bone tissue regeneration. Third, strategies developed from the previous studies were combined to prepare ceramic supplemented gradient sca olds for bone tissue engineering applications. A gradient layer was applied to the hydrogel-ceramic composites and bone tissue response was evaluated in a periosteum guided large animal model. Ceramic supplemented gradient sca olds augmented vascularization and bone regeneration in vivo. In conclusion, a biomaterial system with persistent growth factor gradients was developed and enhanced vascularization and bone regeneration in vivo. This system holds a great potential for tissue engineering applications.
Ph.D. in Biomedical Engineering, December 2016
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Title: FIBRILLIZED PEPTIDE HYDROGELS AND MICROGELS FOR 3D CELL CULTURE AND TISSUE ENGINEERING
Creator: Tian, Ye “field”
Date: 2013, 2013-12
Description: Self-assembling peptide-based nanofibers and hydrogels have been widely applied as cell delivery vehicles, vaccine adjuvants, and scaffolds...
Show moreSelf-assembling peptide-based nanofibers and hydrogels have been widely applied as cell delivery vehicles, vaccine adjuvants, and scaffolds for tissue engineering and 3D cell culture. Self-assembling peptides, owing to their specific sequences, self-associate into nanofibers when dissolved in aqueous buffers. Highly concentrated peptide solutions can form hydrogels, when triggered by increased ionic strength, pH adjustment, and/or change in temperature. The advantages of these peptide materials are that 1) they are chemically defined, which minimizes their batch-to-batch variances, 2) they are modular, which allows for ease in synthesis and the inclusion of multiple different functional ligand-conjugated peptides, 3) they are controllably immunogenic. Although the general feasibility of self-assembling peptide hydrogels for 3D cell encapsulation has been demonstrated by commercial products and several research groups including our own, these materials are not without their shortcomings. Their application as artificial matrices is hindered by 1) their relatively low mechanical strength and vulnerability to fracture, 2) their extreme thermodynamic stability and lack of mechanisms for degradation, and 3) their temporary cytotoxicity during the cell encapsulation processes. In this thesis, I have designed new peptide/depsipeptide sequences, as well as encapsulation processes, to address the above-mentioned limitations. Briefly, I have designed microgels for cell encapsulation as an alternative to bulk encapsulation, which partly solved the fracture-in-gel problem. I have designed ester bond-containing depsipeptides to impart highly controllable biodegradation properties to the materials. I have also designed peptides whose gelation can be triggered by minor pH adjustment, to achieve high degrees of cell survival in the early steps of cell xiii encapsulation.
PH.D in Biomedical Engineering, December 2013
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Title: PRE-CLINICAL IN VIVO AND IN VITRO ASSESSMENT OF HEMOSTATIC EFFECTS OF CONTINUOUS-FLOW VENTRICULAR ASSIST DEVICES
Creator: Crandall, Daniel
Date: 2011-07, 2011-07
Description: Heart failure results in significant morbidity and mortality for those afflicted. The current gold standard treatment is allogenic heart...
Show moreHeart failure results in significant morbidity and mortality for those afflicted. The current gold standard treatment is allogenic heart transplantation, however insufficient supply of donor organs limits the effectiveness of this treatment to ideal candidates. This has led to interest in mechanical circulatory support. The most recent generation of devices are smaller, continuous-flow devices with increased durability compared to their predecessors. However, these new devices exhibit increased rates of hemostatic events – both thromboembolic and hemorrhagic. This thesis details an in vivo evaluation of hemostatic parameters in a bovine animal model to evaluate the effect of the ventricular assist device (VAD), and compares these results to what has been seen clinically. Most importantly this thesis has found that bovines do not experience pathophysiologic degradation of high molecular weight Von Willebrand Factor (VWF) as a result of VAD placement, whereas this complication is well documented in humans. This is due to a decreased sensitivity to shear stress induced cleavage of VWF in bovines when compared to humans, as demonstrated in this thesis. Due to the inability to replicate clinical conditions with the bovine animal model, this thesis develops an alternative methodology using an in vitro flow loop using the same human donor blood on all pumps tested. This methodology eliminates the need for interspecies extrapolation; allows for more direct comparisons by eliminating donor variation; and is both cheaper and faster than animal models. This methodology could provide an invaluable option for evaluating hemostatic effects of various pump design parameters.
Ph.D. in Biomedical Engineering, July 2011
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Title: THE IMPACT OF THE JOINT POSTURE ON FINGER NEUROMECHANICS
Creator: Qiu, Dan
Date: 2014, 2014-05
Description: This dissertation presents a series of studies investigating the neuromechanical properties of the index finger with special emphasis on how...
Show moreThis dissertation presents a series of studies investigating the neuromechanical properties of the index finger with special emphasis on how these properties varied with finger posture. A cadaver study was performed to measure the mapping relationship between tendon force and the resulting fingertip force. A strong linear relationship between magnitude of the tendon force and magnitude of the produced fingertip force was confirmed, up to the force levels examined. The finger posture, however, strongly influenced both fingertip force direction and magnitude. Two fundamental hypotheses of finger biomechanical modeling were then tested in further cadaveric studies. The preliminary results supported the assumption of linear superposition of the contributions of individual tendon forces to the overall fingertip force, at least for two muscles up to the force levels tested. It is also confirmed that the index finger force was almost exclusively produced by the muscles of the index finger, with relatively minor contributions from the other compartments of flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), or extensor digitorum communis (EDC). An in-vivo human subject study was performed to examine muscle activation patterns during isometric fingertip force production across task directions and finger postures. It was shown that significant changes in muscle excitation patterns occurred, especially with variations in interphalangeal (IP) posture. These changes involved fundamental variation in the underlying pattern rather than just scaling of a given activation pattern. An anatomically correct force-based computer model of the index finger was built to study the roles of different structures and characteristics in finger task performance. The model was validated with the cadaver study result to display its reliability in predicting fingertip xiii force and dynamic movement for given tendon forces. The model was then employed to estimate some hard-to-measure variables including joint contact force and joint passive torque components. The simulation of tendon injuries with the model, including Boutonniere deformation and mallet finger, was able to predict the abnormal finger joint movements under these patho-mechanical conditions. The model simulation also suggested that fingertip force capacity was largely maintained after selected tendon pulley excision surgeries.
PH.D in Biomedical Engineering, May 2014
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