This dissertation describes the development of a label-free, electrochemical immunosensing platform integrated into a low-cost microfluidic system for the sensitive, selective and accurate detection of cortisol, a steroid hormone co-related with many physiological disorders. Abnormal levels of cortisol is indicative of conditions such as Cushing’s syndrome, Addison’s disease, adrenal insufficiencies and more recently post-traumatic stress disorder (PTSD). Electrochemical detection of immuno-complex formation is utilized for the sensitive detection of Cortisol using Anti-Cortisol antibodies immobilized on sensing electrodes. Electrochemical detection techniques such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) have been utilized for the characterization and sensing of the label-free detection of Cortisol. The utilization of nanomaterial’s as the immobilizing matrix for Anti-cortisol antibodies that leads to improved sensor response has been explored. A hybrid nano-composite of Polyanaline-Ag/AgO film has been fabricated onto Au substrate using electrophoretic deposition for the preparation of electrochemical immunosening of cortisol. Using a conventional 3-electrode electrochemical cell, a linear sensing range of 1pM to 1µM at a sensitivity of 66µA/M and detection limit of 0.64pg/mL has been demonstrated for detection of cortisol. Alternately, a self-assembled monolayer (SAM) of dithiobis(succinimidylpropionte) (DTSP) has been fabricated for the modification of sensing electrode to immobilize with Anti-Cortisol antibodies. To increase the sensitivity at lower detection limit and to develop a point-of-care sensing platform, the DTSP-SAM has been fabricated on micromachined interdigitated microelectrodes (µIDE). Detection of cortisol is demonstrated at a sensitivity of 20.7µA/M and detection limit of 10pg/mL for a linear sensing range of 10pM to 200nM using the µIDE’s. A simple, low-cost microfluidic system is designed using low-temperature co-fired ceramics (LTCC) technology for the integration of the electrochemical cortisol immunosensor and automation of the immunoassay. For the first time, the non-specific adsorption of analyte on LTCC has been characterized for microfluidic applications. The design, fabrication technique and fluidic characterization of the immunoassay are presented. The DTSP-SAM based electrochemical immunosensor on µIDE is integrated into the LTCC microfluidic system and cortisol detection is achieved in the microfluidic system in a fully automated assay. The fully automated microfluidic immunosensor hold great promise for accurate, sensitive detection of cortisol in point-of-care applications.

For most of the patients with brain tumors and/or epilepsy, surgical resection of brain lesions, when applicable, remains one of the optimal treatment options. The success of the surgery hinges on accurate demarcation of neoplastic and epileptogenic brain tissue. The primary goal of this PhD dissertation is to demonstrate the feasibility of using various optical techniques in conjunction with sophisticated signal processing algorithms to differentiate brain tumor and epileptogenic cortex from normal brain tissue intraoperatively. In this dissertation, a new tissue differentiation algorithm was developed to detect brain tumors in vivo using a probe-based diffuse reflectance spectroscopy system. The system as well as the algorithm were validated experimentally on 20 pediatric patients undergoing brain tumor surgery at Nicklaus Children’s Hospital. Based on the three indicative parameters, which reflect hemodynamic and structural characteristics, the new algorithm was able to differentiate brain tumors from the normal brain with a very high accuracy. The main drawbacks of the probe-based system were its high susceptibility to artifacts induced by hand motion and its interference to the surgical procedure. Therefore, a new optical measurement scheme and its companion spectral interpretation algorithm were devised. The new measurement scheme was evaluated both theoretically with Monte Carlo simulation and experimentally using optical phantoms, which confirms the system is capable of consistently acquiring total diffuse reflectance spectra and accurately converting them to the ratio of reduced scattering coefficient to absorption coefficient (µs’(λ)/µa(λ)). The spectral interpretation algorithm for µs’(λ)/µa(λ) was also validated based on Monte Carlo simulation. In addition, it has been demonstrated that the new measurement scheme and the spectral interpretation algorithm together are capable of detecting significant hemodynamic and scattering variations from the Wistar rats’ somatosensory cortex under forepaw stimulation. Finally, the feasibility of using dynamic intrinsic optical imaging to distinguish epileptogenic and normal cortex was validated in an in vivo study involving 11 pediatric patients with intractable epilepsy. Novel data analysis methods were devised and applied to the data from the study; identification of the epileptogenic cortex was achieved with a high accuracy.

De nos jours, le domaine biomédical est en pleine croissance avec le développement de dispositifs thérapeutiques innovants, bas coût, pour le diagnostic, le traitement ou la prévention de maladies chroniques ou cardiovasculaires. Ces dernières années ont connu l’émergence des polymères semi-conducteurs, alternative intéressante aux matériaux inorganiques, présentant des propriétés uniques de conduction ionique et électronique. Tout d’abord, j’ai axé mes travaux de recherche sur le développement et l’optimisation d’une encre conductrice à base de PEDOT:PSS, parfait candidat comme matériau, pour la transduction des signaux biologiques en signaux électriques, compatible avec le process jet d’encre, pour la réalisation de dispositifs imprimés. Puis mes travaux se sont orientés vers la conception et l’étude d’électrodes imprimées sur supports papiers, tatous et textiles permettant des enregistrements long termes d’électrocardiogrammes (ECG) ou électromyogrammes (EMG), présentant des performances similaires aux électrodes commerciales, utilisant un système d’acquisition spécifique pour la mesure d’activités électriques de tissus musculaires. Puis dans un second temps, je me suis penchée sur l’impression sur support papier, de transistors organiques électrochimiques (OECTs) fonctionnalisés, afin de permettre la détection d’éléments biologiques ou chimiques comme l’alcool. Ces travaux proposent une nouvelle voie pour la conception de dispositifs innovants biomédicaux à bas couts, imprimés, permettant la personnalisation des produits pouvant être intégrés dans des dispositifs biomédicaux portables ou dans des vêtements « intelligents ». / With the evolution of microelectronics industry and their direct implementation in the biomedical arena, innovative tools and technologies have come to the fore enabling more reliable and cost-effective treatment. In this thesis I focus on the integration of the conducting polymer PEDOT:PSS with printing technologies toward the realization of performant biomedical devices. In the first part, I focus on the optimization of the conducting ink formulation. Following, I emphasize on the fabrication of inkjet printed PEDOT:PSS based biopotential electrodes on a wide variety of substrates (i.e., paper, textiles, tattoo paper) for use in electrophysiological applications such as electrocardiography (ECG) and electromyography (EMG). Printed electrodes on paper and printed wearable electrodes were fabricated and investigated for long-term ECG recordings. Then, conformable printed tattoo electrodes were fabricated to detect the biceps activity during muscle contraction and the conventional wiring was replaced by a simple contact between the tattoo and a similarly ink-jet printed textile electrode.In the last part, I present the potentiality of inkjet printing method for the realization of organic electrochemical transistor (OECTs) as high performing biomedical devices. A disposable breathalyzer comprised of a printed OECT and modified with alcohol dehydrogenase was used for the direct alcohol detection in breath, enabling future integration with wearable devices for real-time health monitoring. Their compatibility with printing technologies allows the realization of low-cost and large area electronic devices, toward next-generation fully integrated smart biomedical devices.

In this thesis, a passive exoskeleton spine was designed and evaluated by a series of biomechanics simulations. The design objectives were to reduce the human operator’s back muscle efforts and the intervertebral reaction torques during a full range sagittal plane spine flexion/extension. The biomechanics simulations were performed using the OpenSim modeling environment. To manipulate the simulations, a full body musculoskeletal model was created based on the OpenSim gait2354 and “lumbar spine” models. To support flexion and extension of the torso a “push-pull” strategy was proposed by applying external pushing and pulling forces on different locations on the torso. The external forces were optimized via simulations and then a physical exoskeleton prototype was built to evaluate the “push-pull” strategy in vivo. The prototype was tested on three different subjects where the sEMG and inertial data were collected to estimate the muscle force reduction and intervertebral torque reduction. The prototype assisted the users in sagittal plane flexion/extension and reduced the average muscle force and intervertebral reaction torque by an average of 371 N and 29 Nm, respectively.

The purpose of this study was to define a lower standard cuff occlusion time to induce reactive hyperemia in assessing endothelial dysfunction. In this study, strong evidence was found by a novel technique that used oscillometric methods, which supported that 3 minute reactive hyperemia was sufficient to elicit a significant difference in arterial compliance from baseline. Twenty healthy Cal Poly students were assessed, (n=12 female, n=8 male) aged 22 years old with a standard deviation of 2.04 years. Arterial compliance was estimated by measuring the peak-to-peak oscillations for baseline, 3 minute reactive hyperemia, and 5 minute reactive hyperemia tests, with the result being statistical evidence of an increase in arterial compliance after 3 minutes of cuff occlusion compared to baseline. The peak-to-peak mean for the 3 minute reactive hyperemia test was significantly greater than the baseline peak-to-peak mean with p-values less than 0.0001. These results support that 3 minute reactive hyperemia is sufficient to assess endothelial dysfunction using oscillometry techniques. Endothelial dysfunction is the most significant predictor of a major adverse cardiovascular event, so this test can be used as an early detection tool for cardiovascular disease and allow patients to find treatment before irreversible damage is done to the body. Implementing this test into routine doctor checkups has the potential to have a significant effect on cardiovascular disease, which is the leading cause of death globally. The currently accepted clinical benchmark performed in hospitals uses high-frequency ultrasound with a standard cuff occlusion time of 5 minutes. Although noninvasive, 5 minutes of cuff occlusion causes slight discomfort to the patient and is not desirable. This test was improved and shortened by using a system based on the oscillometric method of blood pressure measurement. By reducing the duration of the test from 5 minute reactive hyperemia to 3 minute reactive hyperemia, this will make the procedure practical for an increased number of patients, providing a noninvasive option to regularly check for early symptoms of cardiovascular disease.

Movement disorders are a group of syndromes that often arise due to neurological abnormalities. Approximately 40 million Americans are affected by some form of movement disorder, significantly impacting patients’ quality of life and their ability to live independently. Deep brain stimulation (DBS) is one treatment that has shown promising results in the past couple decades, however, the currently used open-loop system has several drawbacks. By implementing a closed-loop or adaptive DBS (aDBS) system, the need for expensive parameter reprogramming sessions would be reduced, side-effects may be relieved, and habituation could be avoided. Several biomarkers, for example signals or activity derived from electroencephalogram (EEG), could potentially be used as a feedback source for aDBS. Here, we attempted to characterize cortical EEG potentials in healthy subjects performing six tasks that are difficult for those with movement disorders. Using a 32-channel EEG cap with an amplifier sampling at 500 Hz, we performed our protocol on 11 college-aged volunteers lacking any known movement disorder. For each task, we analyzed task-related power (TRP) changes, spectrograms, and topographical maps. In a finger movement exercise, we found task-related depression (TRD) in the delta band at the F4 electrode, as well as TRD at the C3 electrode in the alpha band during a pencil-pickup task, and TRD at the F3 electrode in the beta band during voluntary swallowing. While delta-ERD in the finger movement exercise was likely due to ocular artifact, the other significant results were in line with what relevant literature would predict. The findings from the work, in conjunction with a future study involving movement disorder patients, can provide insight into the use of EEG as a feedback source for aDBS. Keywords: EEG, electroencephalography, neurostimulation, deep brain stimulation, movement disorders, closed-loop DBS, adaptive DBS, aDBS

Background: Over 700,000 patients per year undergo open-heart surgery. Healing complication rates can be up to 5% of patients who undergo this procedure, with a morbidity rate of 50% if mediastinitis supervenes. A secure and rigid fixation of surgically divided sternum is critical to avoid healing complications. The purpose of this study was to compare the yield load, construct stiffness, ultimate load, displacement at ultimate load, and post-yield behavior of three sternotomy closure methods (Peristernal wires or Sternalock titanium plates) when stressed in each of three directions: lateral distraction, rostro-caudal (longitudinal) shear distraction, and anterior-posterior (transverse) shear in a cadaveric model. Methods: Forty-two fresh cadaver models were divided into three test groups: group A, B, and C. A cardiothoracic surgeon divided each cadaveric sternum longitudinally and repaired peristernal wires or one of two Sternalock configurations. Tests were performed using a materials testing system that applied force at a constant displacement rate in a uniaxial direction until the construct catastrophically failed. Mechanical behavior was monitored using a 3D texture correlation system to create a real-time three-dimensional representation of strain directions. The resulting displacement pattern is analogous to a finite element contour plot of displacements, Lagrange Strain, or velocity. Statistical analysis was used to show the different mechanical properties of each closure method. Results: When loaded in lateral distraction, both Sternalock configurations surpassed the rigidity of peristernal wires by 600%. Some evidence was also found linking Sternalock with stiffer behavior in the rostro-caudal direction. Though not statistically significant, a trend was observed showing that constructs using the Sternalock also had higher yield loads, as well as, less post-yield displacement when compared to peristernal wires. Conclusions: Data gathered showed the superior performance of the Sternalock system in stiffness in both longitudinal distraction and rostro-caudal shear. Implications for use of the Sternalock system are faster healing times, lower complication rates, and success of the procedure.

The goal of this study is to design and manufacture a microfluidic device capable of measuring changes in impedance valuesof microfluidic cell cultures. Tocharacterize this, an interdigitated array of electrodes was patterned over glass, where it was then bonded to a series of fluidic networks created in PDMS via soft lithography. The device measured ethanol impedance initially to show that values remain consistent over time. Impedance values of water and 1% wt. saltwater were compared to show that the device is able to detect changes in impedance, with up to a 60% reduction in electrical impedance in saltwater. Cells were introduced into the device, where changes in impedance were seen across multiple frequencies, indicating that the device is capable of detecting the presence of biologic elements within a system. Cell measurements were performed using NIH-3T3 fibroblasts.

Fluorescence microscopy has revolutionized medicine and biological science with its ability to study the behavior and chemical expressions of living cells. Fluorescent probes can label cell components or cells of a particular type. Clinically the impact of fluorescence imaging can be seen in the diagnosis of cancers, AIDS, and other blood related disorders. Although fluorescence imaging devices have been established as a vital tool in medicine, the size, cost, and complexity of fluorescence microscopes limits their use to central laboratories. The work described in this thesis overcomes these limitations by developing a low cost integrated fluorescence microscope so single use fluorescence microscopy assays can be developed. These assays will enable at-home testing, diagnostics in resource limited settings, and improved emergency medicine.

Heart disease is one of the most prevalent diseases in the world. The survival chances for patients with ventricular fibrillation/ventricular tachycardia reduces significantly as time passes without treatment and even after getting timely treatment recurring episode are common. These patients can benefit from an Implantable Cardioverter Defibrillator (ICD) which can monitor heart rhythm and provide immediate treatment. Due to the ever changing physical conditions and disease progression, the ICD needs to collect diagnostic data as well as support programming by the physician. The ICD uses inductive telemetry and radio-frequency telemetry for the communication with the external devices such as a programmer or a monitor. Inductive telemetry uses less energy than RF telemetry but has a very short range of communication. In addition to inductive telemetry, the St. Jude Medical ICD supports 2.45 GHz band based asynchronized wakeup and 400 MHz MICS band based synchronized wakeup. The 2.45 GHz band based wakeup has limited wakeup range and the 400 MHz MICS based synchronized wakeup has limited availability for connection because it requires synchronization with the base station. The enhanced Medical Implant Communications Service (eMICS) algorithm is a firmware based algorithm which addresses the issues with other two wakeup schemes and provides fast, robust, and seamless wakeup. This thesis describes the design, implementation, and initial testing of eMICS algorithm on the Unity device platform in Technology Project Management (TPM) phase. The eMICS automated test tool developed at St. Jude Medical was used to test the eMICS algorithm under a controlled lab environment, typical home environment, typical hospital/clinic environment, and in the field. The project was successfully completed and transferred to Product Project Management (PPM) phase. However, the suggested duration of 60-90 seconds for sniff interval which will cause the least effect on the battery life was found unacceptable, and there is also a strong need for energy efficient hardware which draws minimal amount of current during each sniff. Therefore, St. Jude Medical is collaborating with the hardware vender to implement eMICS algorithm in the next version of hardware.