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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: IMAGING TISSUE SCAFFOLDS WITH X-RAY PHASE CONTRAST IMAGING
Creator: Doe, Frederick
Date: 2014, 2014-12
Description: A major challenge in tissue engineering is imaging within scaffolds. Biomaterials commonly used in tissue engineering have similar x-ray...
Show moreA major challenge in tissue engineering is imaging within scaffolds. Biomaterials commonly used in tissue engineering have similar x-ray absorption properties to native tissue, so they provide poor contrast in radiography. X-ray phase contrast imaging (XPCI) is an imaging modality that measures light/matter interactions other than absorption. By providing insight into these interactions, x-ray phase contrast imaging has the potential to allow imaging of materials used in biomedical applications. In this thesis, a technique for imaging explanted poly(ethylene glycol) (PEG) hydrogels is presented. PEG is a highly biocompatible polymer with widespread use in biomedical applications. Porous PEG hydrogels were synthesized with 100-150 μm pore size through a salt-leaching technique and loaded with fibrin, a natural protein known to stimulate vascularized tissue formation. The hydrogels were formed in the shape of disks and implanted subcutaneously in the backs of rodent animal models for 1, 2 and 3 weeks. The hydrogels and surrounding tissue were harvested at 1, 2, and 3 weeks. After explanation, the hydrogels were placed in formaldehyde and imaged at the National Light Source at Brookhaven National Laboratory using a multiple image radiography (MIR) technique. Five hundred angles were captured of each sample over 180°, and computed tomography was performed. The samples were compared to histological stains to identify specific tissue features that could be identified in the XPCI images. XPCI allowed imaging of hydrogels and identification of interfaces between native tissue and the PEG material. In addition, tissue invasion into the pores of the scaffold could be identified and could be used to quantify the depth of invasion. Muscle tissue could also be seen, and within muscle fibers were visible. With computed tomography, 3D volumes were constructed, enabling analysis throughout the samples.
M.S. in Biomedical Engineering, December 2014
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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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Title: CONTROLLED RELEASE OF VANCOMYCIN FROM A THERMORESPONSIVE HYDROGEL SYSTEM FOR THE PROPHYLACTIC TREATMENT OF POST-OPERATIVE ACUTE ENDOPHTHALMITIS
Creator: Dosmar, Emily
Date: 2017, 2017-05
Description: Current clinical treatment for preventing the post-operative endophthalmitis include a bolus injection of the antibiotic, vancoymin (VAN),...
Show moreCurrent clinical treatment for preventing the post-operative endophthalmitis include a bolus injection of the antibiotic, vancoymin (VAN), during surgery followed by a 1-2-week period of patient administered, topically applied antibiotics. Due to poor patient compliance, drug loss due to poor drug residence time for topically applied drops, and limitations of drug injection sites, there is a clinical need for a subconjunctival, sustained release drug delivery system. While a controlled drug delivery system is beneficial by eliminating patient drug administration and improving drug delivery, the challenges of initial burst (IB), drug release kinetics, and drug distribution must be addressed in order to design an optimal system to address this need. The primary goal of this study was to develop a drug delivery system (DDS) capable of delivering VAN for 10-14 days and replacing both the bolus VAN injection and the topical eye drops. We hypothesized that controlled and extended release of VAN will perform equally or better than bolus VAN administration and eye drops. To accomplish this goal, three specific aims were performed: 1) Development of an injectable drug delivery system to release bioactive VAN for at least 10 days; 2) Validation of the efficacy of the developed DDS; and 3) Development of a compartmental model analysis model used to predict the loading dose required to achieve therapeutic drug concentration in the vitreous.
Ph.D. in Biomedical Engineering, May 2017
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Title: MULTIVARIABLE ADAPTIVE IDENTIFICATION, FAULT DETECTION, DIAGNOSIS AND CONTROL OF ARTIFICIAL PANCREAS SYSTEMS
Creator: Turksoy, Kamuran
Date: 2015, 2015-05
Description: An artificial pancreas control system automates insulin pumps by using a closed-loop controller that receives information from sensors,...
Show moreAn artificial pancreas control system automates insulin pumps by using a closed-loop controller that receives information from sensors, computes the optimal insulin amount to be infused and manipulates the infusion rate of the pump for continuous blood glucose regulation in patients with type 1 diabetes. An integrated multivariable adaptive artificial pancreas control system is developed. Multivariable recursive time-series models are developed by using additional physiological measurements from a sport armband. The multivariable models are obtained with a proposed constrained weighted recursive identification algorithm to guarantee the stability conditions and satisfy the physiological properties of human body and glucose-insulin dynamics. Hypoglycemia early alarm system is developed based on the multivariable time-series models. By use of the physiological measurements, different thresholds are defined for different conditions such as meal, exercise and sleep for prevention of hypoglycemia. Generalized predictive control based adaptive control algorithm is proposed for blood glucose regulation in patients with type 1 diabetes. The control algorithm is completely adaptive and does not require any manual announcements. A meal detection algorithm is implemented into the control algorithm. Meals are detected based on the estimation of rate of appearance of glucose by use of Unscented Kalman filter. A novel framework is developed for meal bolus when a meal is detected. An artificial pancreas control system automates insulin pumps by using a closed-loop controller that receives information from sensors, computes the optimal insulin amount to be infused and manipulates the infusion rate of the pump for continuous blood glucose regulation in patients with type 1 diabetes. An integrated multivariable adaptive artificial pancreas control system is developed. Multivariable recursive time-series models are developed by using additional physiological measurements from a sport armband. The multivariable models are obtained with a proposed constrained weighted recursive identification algorithm to guarantee the stability conditions and satisfy the physiological properties of human body and glucose-insulin dynamics. Hypoglycemia early alarm system is developed based on the multivariable time-series models. By use of the physiological measurements, different thresholds are defined for different conditions such as meal, exercise and sleep for prevention of hypoglycemia. Generalized predictive control based adaptive control algorithm is proposed for blood glucose regulation in patients with type 1 diabetes. The control algorithm is completely adaptive and does not require any manual announcements. A meal detection algorithm is implemented into the control algorithm. Meals are detected based on the estimation of rate of appearance of glucose by use of Unscented Kalman filter. A novel framework is developed for meal bolus when a meal is detected. In addition to all, a fault detection and diagnosis algorithm is also developed. Multiway principal component analysis is used for detection of system failures. All proposed algorithms are tested with both simulation and clinical experiments. The result indicates that the proposed integrated artificial pancreas system provide significant improvements. The prosed system is able to deal with blood glucose regulation problem under various challenging conditions. Being fully automated and adaptive, it provides many advantages to patients with type 1 diabetes.
Ph.D. in Biomedical Engineering, May 2015
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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: GETTING RID OF THE WIRES: A TRANSCUTANEOUS POWER AND WIDEBAND TELEMETRY SYSTEM FOR MULTI-CHANNEL NEURAL RECORDING IMPLANTS
Creator: Rush, Alexander Daniel
Date: 2012-08-08, 2012-07
Description: This dissertation focuses on development of wireless power and data transmission hardware for use in a wireless neural recording system. This...
Show moreThis dissertation focuses on development of wireless power and data transmission hardware for use in a wireless neural recording system. This involves a comprehensive review of the applications requiring or strongly benefiting from wireless power and high data rate outward telemetry, multiparametric analysis of a system for wireless power and data transmission, and a detailed description of external and implanted hardware composing such a system. In this document “implanted” or “implantable” means that the hardware referred to by these terms is designed with the intention of being fully contained within the body with no physical connections crossing the skin.
Ph.D. in Biomedical Engineering, July 2012
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Title: MULTIFUNCTIONAL BIOMATERIAL SYSTEM FOR DRUG DELIVERY AND SCAFFOLDING TO PROMOTE NEOVASCULARIZATION IN TISSUE ENGINEERING
Creator: Jiang, Bin
Date: 2013, 2013-05
Description: The successful development of engineered tissues requires extensive vascular network formation. The overall goal of this work is to develop a...
Show moreThe successful development of engineered tissues requires extensive vascular network formation. The overall goal of this work is to develop a multifunctional biomaterial system for scaffolding and drug delivery to promote neovascularization in engineered tissue. Firstly, a drug delivery system was developed for molecules of different properties. Poly(lactic-co-glycolic acid) (PLGA) was prepared into microspheres using a double emulsion process for delivery of hydrophobic chlorhexidine (CHX) and hydrophilic platelet-derived growth factor-BB (PDGF-BB). Both drugs exhibited bioactivity after release and the efficacy of dual drug delivery was evaluated with an infected wound animal model. The simultaneous delivery of CHX and PDGF-BB improved wound healing and neovascularization while reducing bacteria levels. Therefore, the PLGA microspheres can be used for long-term active delivery of both hydrophobic and hydrophilic molecules in tissue engineering applications. Secondly, a 3D scaffold was developed for tissue engineering applications. Poly(ethylene glycol) (PEG) hydrogels with interconnected pores were generated with a salt leaching technique. Fibrin was filled in the pores by adding fibrinogen solution to hydrogel scaffolds pre-loaded with thrombin. The hydrogels were evaluated in a rodent subcutaneous implant model, showing that tissue invasion with a higher vascular density occurred when the hydrogels were loaded with fibrin. This composite hydrogel supports vascularized tissue ingrowth, and thus holds potential for tissue engineering applications. Thirdly, approaches from the previous studies were combined to develop a multifunctional biomaterial system for tissue engineering scaffolding and sequential xi growth factor delivery. PLGA microspheres were incorporated into a fibrin loaded porous hydrogel, in which the PEG based scaffold was modified to allow controlled degradation via hydrolysis. Different growth factors were encapsulated in fibrin and PLGA microspheres to provide temporal control of delivery. Growth factors released with the appropriate sequence promoted stable and functional blood vessel formation. In conclusion, a multifunctional biomaterials system was developed to provide structural and mechanical support for tissue regeneration, as well as delivery of signals that stimulate neovascularization. The system holds great potential for tissue engineering applications. Future work will require the extensive collaboration from interdisciplinary fields towards the successful development of engineered tissue substitutes.
PH.D in Biomedical Engineering, May 2013
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Title: DESIGN OF A DYNAMIC MUSCULOSKELETAL MODEL OF THE HUMAN HAND FOCUSED ON FUNCTIONAL TASKS
Creator: Barry, Alexander
Date: 2016, 2016-05
Description: This thesis explores the creation and validations of a simulated musculoskeletal model of the human hand with a focus on the aspects of...
Show moreThis thesis explores the creation and validations of a simulated musculoskeletal model of the human hand with a focus on the aspects of pinching. Specifically, the thumb, index finger, and wrist were represented in OpenSim 3.3, using anatomical definitions for increased accuracy. Specifically, the inclusion of physiological axes of rotation at all joints, anatomically accurate passive joint torques, and appropriate moment arms for each muscle. The model was subsequently validated against experimental results found in literature. First, the digit tip force directions produced by each of the 15 muscles were compared to those obtained by loading the corresponding tendons in cadaveric specimens and measuring three-dimensional force generation at the tip of the thumb or index finger. Second, isometric force generation by activation of multiple muscles were compared. Finally, dynamic simulations were run using electromyographic (EMG) recordings as inputs. The capabilities of the model were then explored by using it to predict activation patterns from imposed movement and to simulate extension deficits in a hand affected by stroke. The model generated isometric force in the correct directions for most individual muscles, with the extensor pollicis brevis (EPB) showing the largest directional differences between cadaveric and simulated results. With combined muscle activation patterns the model simulated force profiles accurately, showing only a 5.3% mean squared error (MSE) from the actual force profile. In terms of force magnitudes between the model and simulated results, the model produced significantly lower force magnitudes, especially in the thumb. This validation was also found to be reasonably accurate to the expected motions. With the model anatomically validated, two different simulations were run using the model. First, known kinematics were applied to the model and the muscle activations were simulated; the resultant joint angles were found to match the expected within 10% MSE. Second, a stroke affected hand was simulated, with activation deficits added to each of the muscles individually. It was found through this that, in the model, the intrinsic muscles played a larger role in force production and dynamic motion than the extrinsic muscles. In all, these validations and simulations produce a promising groundwork for the use of this model for further simulation.
M.S. in Biomedical Engineering, May 2016
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Title: CABLE ACTUATED FINGER EXOSKELETON DEVELOPMENT AND EXAMINATION OF INDEX FINGER AND THUMB COUPLING
Creator: Jones, Christopher L.
Date: 2014, 2014-05
Description: Finger-thumb coordination is crucial to interacting with our environment. This coordination remains incompletely understood, even in...
Show moreFinger-thumb coordination is crucial to interacting with our environment. This coordination remains incompletely understood, even in neurologically intact individuals, and is difficult to study with current interface devices. Knowledge of finger-thumb relationships during dynamic movement facilitate identification of key impairment mechanisms following stroke and thus, help to guide rehabilitation strategies. Accordingly, a high-bandwidth, biocompatible finger exoskeleton is developed and implemented in a pilot study to investigate coupling between the finger and thumb during pinching movements. Performance of the Cable Actuated Finger Exoskeleton (CAFE) is analyzed in the lab and during interaction with human subjects, both neurologically intact and survivors of stroke. The exoskeleton is found to perform exceedingly well, exceeding nearly all design requirements lending to the continued use of the CAFE a research platform for human motor control of the hand. During experimental trials, participants move through index finger and thumb palmar pinching movements while the CAFE delivers perturbations during the closing and opening phases of movement. Two experiments are conducted, delivering reflexinducing or joint-locking perturbations to the index finger. Muscle EMG and thumb tip trajectory are recorded during movement and variations in these parameters immediately following perturbation demonstrate the effect of coupling of the index finger and thumb. Reflexive coupling is evidenced in both healthy and post-stroke individuals by heteronymous reflexes in the unstretched muscles of the thumb. Similarly, kinematic changes are apparent in thumb movement following impedance perturbations of the index finger in both populations. Coupling is observed to vary with phase of movement in x xiii intact participants, but not following stroke, suggesting a loss of modulation following stroke. Most notably: in survivors of stroke impedance perturbations to the index finger during the opening phase of movement results in dramatically increased thumb opening.
PH.D in Biomedical Engineering, May 2014
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Title: DETERMINING CELL STIFFNESS USING MICROFLUIDICS
Creator: Penumarthy, Vineet Shyam
Date: 2019
Description: Sorting healthy cells from diseased cells is critical to detecting diseases and treating them before damage is done to a patient. These...
Show moreSorting healthy cells from diseased cells is critical to detecting diseases and treating them before damage is done to a patient. These diseases can be characterized based upon proteins, cytokines, DNA, pathology, blood tests, etc. However, another way of detecting them is using the mechanical properties of a cell, specifically the cell stiffness. In this study, a long microfluidic channel was designed, fabricated, and tested for flow using 6.7 µm polystyrene beads. Following this, Caco-2 cells and preadipocytes were flown through the channel and the travel time each cell took to flow through the channel was recorded, along with its cell diameter. The cells were then treated with blebbistatin, a myosin-II inhibitor, in order to soften the cell actin cytoskeleton and reduce the cell stiffness and were then flown through the channel again and the times taken to flow through were again recorded. We hypothesized that the stiffer a cell, the longer it would take to flow through the channel. From the results obtained using Caco-2 cells, we found that the blebbistatin treated cell times were much lower than the untreated cells, thus indicating that our hypothesis is true.
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Title: DEVELOPING NON-LINEAR AND ADAPTIVE NEURONAL SYNCHRONY AND CONNECTIVITY ANALYSIS TO PERSONALIZE CLOSED-LOOP DBS THERAPY FOR TREATING EPILEPSY
Creator: Farahmand, Sina
Date: 2019
Description: Epilepsy disease afflicts more than seventy million people worldwide. In approximately one third of the cases, antiepileptic medications fail...
Show moreEpilepsy disease afflicts more than seventy million people worldwide. In approximately one third of the cases, antiepileptic medications fail to control seizures. Over the last few decades, electrical stimulation of the brain has been evaluated as a potential alternative to treat surgically and medically refractory epilepsy patients. Despite some successes, most of the devices using this protocol operate based on pre-determined stimulation parameters (e.g. frequency and location of stimulation) that have little or no relationship to the individuals’ underlying brain dynamics, which we hypothesize may explain their low clinical efficacy in preventing or terminating seizures.In this study, a non-linear adaptive neuronal synchrony and connectivity analysis was developed in order to extract stimulation parameters from endogenous, multi-site brain dynamics of epilepsy patients. A non-linear analytical methodology was proposed to assess phase-synchrony dynamics in epilepsy patients as seizures evolve. This study revealed a desynchronization around seizure onset. However, the synchrony level started to increase gradually towards seizure end and reached its maximum at seizure termination. This results reveal that hyper-synchronization of the epileptic network may be a critical self-regulatory mechanism by which the brain terminates seizures. In the other phase of this study, a non-linear adaptive phase-connectivity analysis was developed in order to extract frequency and locations of stimulation that match the synchronized network dynamics at seizure termination. Matching these parameters to the endogenous brain dynamics of epilepsy patients as seizure naturally terminates may not only terminate seizures prior to their development, but it may also lead to a personalized deep brain stimulation (DBS) therapy with higher clinical efficacy.
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Title: EXPRESSION OF PPAR-γ AND PGC-1α TO INFLAMMATION IN HEPATOCYTES
Creator: HE, QIFAN
Date: 2019
Description: In this study, we examined that Proliferator-Activated Receptor γ (PPAR-γ) and Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α ...
Show moreIn this study, we examined that Proliferator-Activated Receptor γ (PPAR-γ) and Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α (PGC1α) protein expression in hepatocytes have different degrees of expression to Tumor Necrosis Factor α (TNFα) and rosiglitazone. To verify this objective, we employed lentivirus, instead of traditional plasmids, to transfect human hepatocytes (HepG2). Fluorescence-related protein of PPAR-γ and PGC-1α were delivered to hepatocytes, and inflammation was induced by adding TNFα and rosiglitazone to the medium. We successfully designed and created the lentivirus with high delivery efficiency, and determined that the test was true, indicating that PPAR-γ and PGC-1α proteins have different expression to inflammation in human hepatocytes.
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Title: Pre-implant Brain Activation Modeling to Drive Placement of Depth Leads in White Matter for Direct Neurostimulation Therapy in Epilepsy
Creator: Cendejas Zaragoza, Leopoldo
Date: 2019
Description: A critical step towards applying direct brain stimulation therapy in focal onset epilepsy is to effectively interface with epileptogenic...
Show moreA critical step towards applying direct brain stimulation therapy in focal onset epilepsy is to effectively interface with epileptogenic neural circuits using a limited set of active contacts. This takes special relevance when interacting with networks that exhibit two or more foci. A strategy to influence the maximum extent of the epileptogenic circuit is to stimulate white matter pathways to enhance propagation to distant epileptic tissue.A significant number of elements must be considered in the clinical response to stimulation delivered directly to neuronal populations. These variables include: stimulation parameter settings, number and interdependence of anatomical targets, electrode number, electrode location and orientation, geometry or shape of the electrode contacts, contact polarity, biophysical properties of stimulated medium, andtrajectory of axonal bundles adjacent to the stimulation site.This document addresses the development of a computational model which takes into consideration all the mentioned variables to predict activation of distant sites via white matter pathways. A method to calculate the extracellular potential field, induced by the application of time-dependent stimulation waveforms, is discussed. Such a method considers both the anisotropic conductivity nature of neural tissue and the electrochemical phenomena of the electrode-tissue interface. The response of white matter fibers is then evaluated by solving a compartmental cable model based in the Hodgkin and Huxley membrane description.The model was integrated into a pre-surgical workflow and was used prospectively to guide stereotactic implantation of depth leads to apply direct neurostimulation therapy in four patients with refractory focal onset epilepsy.
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Title: Inflammation induced changes in adipocytes
Creator: Kim, Kihwan
Date: 2019
Description: The significant features of Crohn’s Disease include creeping fat that covers more than 50% of both small and large intestine surfaces and high...
Show moreThe significant features of Crohn’s Disease include creeping fat that covers more than 50% of both small and large intestine surfaces and high level of inflammatory cytokines such as TNF-alpha and IL-6. However, the relationship between these two factors of Crohn’s Disease is still unknown. Therefore, verifying the relationship could contribute to understanding the cause of Crohn’s Disease. In this study, preadipocytes were used because they have a potential to grow as adipocytes which are developed as creeping fat. The objective of this study was to observe proliferation, differentiation, and chemotaxis of preadipocytes in inflammatory microenvironment. It was found that only TNF-alpha stimulates preadipocyte proliferation whereas IL-6 does not. However, both TNF-alpha and IL-6 inhibit differentiation of preadipocytes. Furthermore, preadipocytes did not have chemotactic responses towards both cytokines. Therefore this study concludes that these inflammatory microenvironments induce the preadipocytes proliferation in Crohn’s. However, they inhibit adipogenesis and recruitment of the preadipocytes in Crohn’s.
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Title: Ultrasensitive protein quantification using Rolling Circle Amplification
Creator: Hetzel, Laura Ann
Date: 2019
Description: There are several protein biomarkers that can aid in diagnosing and evaluating the progression of Alzheimer’s Disease (AD), including Amyloid...
Show moreThere are several protein biomarkers that can aid in diagnosing and evaluating the progression of Alzheimer’s Disease (AD), including Amyloid Beta-42 (Aβ42), Amyloid Beta-40 (Aβ40), and Tau proteins. The proteins are most prevalent in the brain and cerebral spinal fluid, becoming more diluted in the bloodstream. Since diagnosis and progression would require evaluating and comparing protein levels over time and identifying miniscule changes, an assay with high sensitivity is paramount. Similarly, evaluating how a drug treatment affects the levels of protein requires a highly sensitive assay. Currently, enzyme-linked immunosorbent assay (ELISA) is accepted as the most sensitive assay for protein detection and quantification. However, in the case of Aβ40 and Aβ42 proteins, oftentimes the levels of the proteins in patients are very close to the sensitivity of the commercial ELISA. The uncertainty in these measurements is very high, which results in reporting of conflicting outcomes. One of the challenges of quantifying proteins is that proteins, unlike nucleic acids, cannot be amplified. To overcome this limitation, we have cleverly pseudo-amplified proteins using rolling circle amplification (RCA). By doing so, we have demonstrated a ten to forty times improvement in sensitivity over ELISA and radioimmunoassays. In previous experiments, C-peptide has been used as the protein of interest, and ELISA reports the smallest detectable quantity is 0.01 ng in buffer. Using RCA, we have found that as little as 0.00075 ng C-peptide in buffer could be quantified, and 0.004 ng in 10% serum could be quantified. The same process can be applied to other proteins such as Aβ40 and Aβ42, and the results are expected to be similar. In fact, we have measured Type I Diabetes autoantibodies with approximately forty times improvement over the gold standard radioimmunoassay. With excellent results in buffer and 10% serum, expansion to human samples holds great potential. If the human experiments are as successful as anticipated, RCA could be used to precisely evaluate the effect of a drug on protein levels, contributing to the overall evaluation of the success of the drug.
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Title: Non-invasive quantification of cancer drug targets: Mathematical models for paired-agent molecular imaging
Creator: Sadeghipour, Negar
Date: 2017
Description: Cancer is among the leading causes of death worldwide. Incidence of cancer is rising at a rate that is almost completely nullifying...
Show moreCancer is among the leading causes of death worldwide. Incidence of cancer is rising at a rate that is almost completely nullifying improvements in cancer treatment and the heterogeneity of advanced disease poses significant complications for the development of effective therapies. With more aggressive cancers tending to display abnormally high expression of signaling receptors associated cell proliferation - receptors that tend to be expressed at very low levels by healthy cells in adulthood - many new cancer-specific “molecular therapies” have been developed to target and block these pathways. However, not all cancers overexpress the same proliferation pathways, so many have proposed molecular imaging as a non-invasive means of identifying on a patient-by-patient basis, which specific targets may be overexpressed to tailor therapies to the individual (“precision medicine”). The primary goal of this thesis was to develop and validate some of the first non-invasive means of measuring drug-target concentrations prior to therapy and the first measures of drug-target occupancy during therapy to ultimately predict and monitor the efficacy of cancer molecular therapy. All work was founded on paired-agent molecular imaging protocols that employ co-administration of two imaging agents: one agent that is targeted to the biomolecule of interest (e.g. a cell surface signaling receptor that may be overexpressed by a cancer), and a second, “control” (“untargeted”) agent that is as chemically similar to the targeted agent as possible, but that does not bind to the biomolecule of interest. In all paired-agent imaging strategies, the signal from the control agent is used to account for delivery and nonspecific retention effects that can confound the relationship between the targeted imaging agent concentration in a region-of-interest (ROI) and the targeted biomolecule concentration in that ROI.
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