One possible solution to common running related injuries is to transition runners from a rearfoot strike during initial contact to a midfoot strike. Natural rearfoot strike runners were studied to see if a modified elliptical trainer could be used to alter their running pattern to that of a midfoot strike runner. Their results were compared to subjects who ran on a non-modified elliptical trainer. After training on the modified elliptical trainer, subjects demonstrated a decrease in foot angle at initial contact when attempting to run with a midfoot strike. Training did not affect all kinetic metrics or stride frequency. However, the kinematic change suggests that there may be an impact on running energetics. Training on the modified elliptical trainer resulted in improved midfoot strike kinematics in natural rearstrike runners when they attempted run in a midfoot strike pattern.

Peripheral nerve stimulation (PNS) is commonly used to promote use-dependent cortical plasticity for rehabilitation of motor function in spinal cord injury. Pairing transcranial magnetic stimulation (TMS) with PNS has been shown to increase motor evoked potentials most when the two stimuli are timed to arrive in the cortex simultaneously. This suggests that a mechanism of timing-dependent plasticity (TDP) may be a more effective method of promoting motor rehabilitation. The following thesis is the result of applying a brain-computer interface to apply PNS in closed-loop simultaneously to movement intention onset as measured by EEG of the sensorimotor cortex to test whether TDP can be induced in incomplete spinal cord injured individuals with upper limb motor impairment. 4 motor incomplete SCI subjects have completed 12 sessions of closed-loop PNS delivered over 4-6 weeks. Benefit was observed for every subject although not consistently across metrics. 3 out of 4 subjects exhibited increased maximum voluntary contraction force (MVCF) between first and last interventions for one or both hands. TMS-measured motor map volume increased for both hemispheres in one subject, and TMS center of gravity shifted in 3 subjects consistent with studies in which motor function improved or was restored. These observations suggest that rehabilitation using similar designs for responsive stimulation could improve motor impairment in SCI.

Glaucoma is the leading cause of blindness in the United States accounting for 9-12% of all cases of blindness. Currently, the front line treatment for glaucoma are prostaglandins that may have to be taken up to several times a day. Even with proper treatment, roughly 11% of the patients using the treatment are non-compliant and lose their vision. In this project, ForSight Laboratories has developed a pharmaceutical drug delivering implant with the capability of sustaining long-term release of a prostaglandin as a new way to treat the condition. This project reports the product development of a polymer drug matrix with a controlled release in order to better treat glaucoma. Accompanying product development, a mathematical model was created in order to strengthen the understanding of the dosage profile and to predict long term dosages.

The application of high frequency ultrasound is the key to higher resolution intravascular ultrasound (IVUS) images. The need to further improve the IVUS spatial resolution may drive the transducer center frequency even higher than the current 40 MHz range. However, increasing the center frequency may be challenging as it leads to stronger scattering echoes from blood. The high level of blood scattering echoes may obscure the arterial lumen and make image interpretation difficult. Blood backscatter levels increase with transmission center frequency at a much greater rate compared to arterial tissue. These different frequency dependencies provide a potential method to distinguish blood from tissues by means of multi-frequency processing techniques. To obtain a good blood-tissue contrast with sufficient signal-to-noise ratio, a system with a wider bandwidth is highly desirable. The method described in this paper is based on the ratio of the received signal power between the high (60 MHz) and low (25 MHz) frequency ranges from a novel 40 MHz wideband IVUS catheter. In this paper we will present our in vitro experiment work on porcine blood and a tissue-mimicking arterial wall. Results of multi-frequency processing indicate that blood, at higher frequencies, has a greater backscatter power that is 8X greater than arterial tissue, suggesting this technique will provide a greater contrast between the blood-wall lumen boundary for coronary imaging.

Spinal fusion is used to treat diseases or disorders of the spine by fusing together two or more vertebrae. Two associated risks with spinal fusion are infection and blood loss. Administration of tranexamic acid is used to prevent blood loss, and transfusions are given following blood loss. Surgical site infections are prevented with vancomycin powder spread into the surgical wound, while established infections are treated by debridement and delivery of antibiotics for 4 to 6 weeks. The present research explored an alternate method to prevent and treat blood loss or infection in spinal fusion. Poly(lactic-co-glycolic acid) (PLGA) microspheres was used to encapsulate vancomycin for 42 days to treat infection. Vancomycin encapsulated in gelatin microspheres had a controlled release of 7 days to prevent infection. Tranexamic acid was dissolved into phosphate-buffered saline or carboxymethylcellulose to provide a release of 6 hours to prevent blood loss after surgery. The microspheres and tranexamic acid were delivered to a target region using a water based spray system. The spray system demonstrated the delivery and distribution of drugs to a target region. The microsphere spray system is capable of spraying drugs onto a target region to prevent or treat blood loss and infection over time.

Changes in the biomechanical properties of cells accompanying the development of various pathological conditions have been increasingly reported as biomarkers for various diseases and as a predictor of disease progression stages. For instance, cancer cells have been found to be less stiff compared to their healthy counterparts due to the proteomic and lipidomic dysregulations conferred by the underlying pathology. The separation and selective recovery of cells or extracellular vesicles secreted from such cells that have undergone these changes have been suggested to be of diagnostic and prognostic value. This dissertation first describes the implementation of a stiffness-based separation of phosphatidylcholine-based vesicles using a method first introduced based on the research in this work and was dubbed thermally-assisted acoustophoresis, or thermo-acoustophoresis. By tuning the temperature, we achieved the separation of vesicles of the same size, shape, and charge but with different stiffness values. It was observed that at a specific transition point, the acoustic contrast factor of vesicles changed sign from positive to negative. This change was mainly due to change in the compressibility of the vesicles, which is inversely proportional to stiffness. The acoustic contrast temperature (Tϕ), corresponding to the temperature at which the contrast factor switches sign, was determined to be unique to the composition of the vesicles. This unique temperature signature allowed us to develop this separation method of vesicles with distinct membrane stiffness with target outlet purities exceeding 95%. We have further explored the functionality of this method by experimenting with cholesterol-containing vesicles. In cells, the cholesterol content plays a crucial role in determining stiffness. Changes in the cholesterol content in cellular membranes can be an indication of pathological disorders. We evaluated the Tϕ of vesicles at different cholesterol molar ratios (Xchol) and developed a multi-stage lab-on-a-chip method to accomplish for the first time the separation of a three-vesicle mixture. Using Xchol = 0.1, 0.2, and 0.3 vesicles, we obtained efficiencies exceeding 93%. The simplicity, rapidity, and label-free nature of this approach holds promise as a diagnostic and separation tool for cells affected by diseases that affect the stiffness and extracellular vesicles such as exosomes and microvesicles.

Animal models of ocular hypertension are important for glaucoma research but come with experimental costs. Available methods of intraocular pressure (IOP) elevation are not always successful, the amplitude and time course of IOP changes are unpredictable and irreversible, and IOP measurement by tonometry is laborious. This dissertation focuses on the development and implementation of two novel systems for monitoring and controlling IOP without these limitations. The first device consists of a cannula implanted in the anterior chamber of the eye, a pressure sensor that continually measures IOP, and a bidirectional pump driven by control circuitry that can infuse or withdraw fluid to hold IOP at user-desired levels. A portable version was developed for tethered use on rats. The system was fully characterized and deemed ready for cage- or bench-side applications. The results lay the foundation for an implantable version that would give glaucoma researchers unparalleled knowledge and control of IOP in rats and potentially larger animals. Moreover, a novel mathematical technique was developed to efficiently analyze IOP records obtained using the pressure controlling device. The algorithm successfully yields the value of several parameters that influence ocular physiology and are commonly linked to glaucoma development. This unique methodology uses information regarding the amount of volume necessary to maintain IOP at different levels to quantify the outflow facility of perfused eyes. The use of this technology largely simplifies the investigator’s experimental set-up and cuts procedural times in half. The second device is an implantable pressure sensor for continuously monitoring IOP. The miniature system is equipped with pressure and temperature transducers, on-board amplifiers and a powerful microcontroller that ensure data quality. The sensor is able to obtain measurements with twice the accuracy and precision of any other IOP sensor used to date, avoid electronic drifts commonly seen in commercial sensing devices, and can potentially be used in a variety of animal models. The sensor was characterized and tested in alert rats for weeks on end. Data obtained with this device showed the presence of previously reported circadian rhythms, with IOP significantly increasing during nocturnal cycles. This technology provides researchers with an unprecedented tool to analyze IOP dynamics over time. The characterization of the amplitude, period and phase of the IOP profiles of normal and glaucomatous eyes may help establish a definitive correlation between ocular hypertension and glaucoma progression. While implantable systems provide investigators with essential physiological data, their implementation can be difficult. Challenges such as reduced operational lifetimes and limited data acquisition capabilities are commonly faced by most bio-devices. These limitations are frequently linked to small battery capacities, however the implementation of bigger batteries is not usually viable due to size requirements. Energy harvesting technologies have surfaced in recent years in an attempt to replace battery applications; however, most technologies provide low power densities and cannot deliver continuous telemetric operation. An innovative wireless powering system was developed to overcome these limitations. The technology uses radio frequency (RF) energy transfer to continuously harvest high energy levels. Taking advantage of the controlled environment under which most research animals are housed, RF transmitters are placed around the cage to form strong, omnidirectional electric fields. An especial antenna was designed to be worn by the animal and collect large energy levels, irrespective of animal movements and positioning. The system was tested on the implantable IOP sensor for weeks, providing robust performances and allowing the sensor to collect data continuously with high precision. The device consistently generated power densities much greater than those required by the sensor. The surplus of energy could be used to operate multiple sensors simultaneously, greatly increasing the investigator’s leverage. The technology is easily adaptable to other bio-sensors and has the potential to revolutionize the biomedical field.

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.