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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: 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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