Improving medical aerosols is the multifaceted objective that is the overarching theme of this work. This thesis is the culmination of many hours of academic research. It details the current mechanical and physiological obstacles of state of the art drug inhalation technology, as well as provides a detailed guide of the experimental set up, procedure, analysis and background for the charge neutralization experiments performed by the author. The findings of this research are that inhalation devices need to become personalized; meaning adjustable flow rates, particle sizes, and charge levels. To improve the efficiency of lung deposition they could use MRI to take advantage of 3D modeling software to make transport models of an individual patient's lungs. This model would allow an engineer to calculate the air velocity in each passage of the respiratory system and would account for any pulmonary obstructions that would completely alter the deposition pattern from the average healthy patient. With the velocity profile of the lung a doctor could formulate an aerosol with the perfect attributed for the most targeted delivery. For the experiments performed in this work the following results were obtained. The ionization of air by polonium 210 alpha particles is dependent on the distance from the alpha emitting source and the strength of the electric field. Furthermore discharge of aerosol droplets is possible through volume conduction however the mass of the polonium 210 isotope must be proportional to the ionization current demand.

Abstract: Purpose: The dose-dependent effects of isoflurane anesthesia on insulin inhibition and insulin resistance were compared in rats. Methods: Three rats were entered into the procedure with each rat being subjected to 3 different doses of steady state concentrations of isoflurane (1.75%, 2.0%, and 2.50%). A surgical plane of anesthesia was induced by continuous infusion of isoflurane via an induction box at 4.0% isoflurane and when anesthesia was achieved the infusion of anesthesia was lowered to the steady state concentrations of isoflurane. Plasma glucose concentrations were measured every 10 minutes until two or three consistent peak values were observed. After assurance of reaching peak values sub-cutaneous insulin (0.75 units/kg) was injected between the scapulas. Following the insulin injection plasma glucose concentrations were obtained every 10 minutes via pinprick until peak minimal glucose values were reached. If the plasma glucose of any animal reached a level approximately 50 mg/dL, subcutaneous glucose was injected (2.0 grams/kg) to prevent adverse effects of hypoglycemia. Results: For absolute plasma glucose post-anesthetic values a comparison of multiple mean glucose concentrations (single factor ANOVA) yielded p=8.06 x 10-6. A post-hoc analysis revealed significant p values between 3 pairs of means: 1.75%/2.0%= 0.004; 1.75%/2.5%= 0.03; 2.0%/2.5%= 0.02 . For normalized plasma glucose values post-anesthetic a comparison of multiple means (ANOVA) yielded a p value of 0.03. Post-hoc analysis indicated that the peak response was at 2.0% with significant difference between 1.75%/2.0% =0.03 and 2.0%/2.5%=0.02. There was no significance between glucose values 1.75%/2.50%=0.68. For plasma glucose values post-insulin both absolute and normalized a mean comparison analysis (ANOVA) concluded that during post insulin the data was not statistically significant as p=0.68. Conclusions: When absolute plasma glucose concentrations were normalized by the baseline taken at conscious state the dose-dependency disappeared and concluded the largest change in plasma glucose at 2.0%. Although the data post-insulin injection was not statistically significant it can be concluded that there was normal glucose uptake and that there was no impaired insulin action on the skeletal muscle.

The use of a non-invasive form of energy to modulate neural structures has gained wide spread attention because of its ability to remotely control neural excitation. This study investigates the ability of focused high frequency ultrasound to modulate the excitability the peripheral nerve of an amphibian. A 5MHz ultrasound transducer is used for the study with the pulse characteristics of 57msec long train burst and duty cycle of 8% followed by an interrogative electrical stimulus varying from 30μsecs to 2msecs in pulse duration. The nerve excitability is determined by the compound action potential (CAP) amplitude evoked by a constant electrical stimulus. We observe that ultrasound's immediate effect on axons is to reduce the electrically evoked CAP amplitude and thereby suppressive in effect. However, a subsequent time delayed increased excitability was observed as reflected in the CAP amplitude of the nerve several tens of milliseconds later. This subsequent change from ultrasound induced nerve inhibition to increased excitability as a function of delay from ultrasound pulse application is unexpected and not predicted by typical nerve ion channel kinetic models. The recruitment curve of the sciatic nerve modified by ultrasound suggests the possibility of a fiber specific response where the ultrasound inhibits the faster fibers more than the slower ones. Also, changes in the shape of the CAP waveform when the nerve is under the inhibitive effect of ultrasound was observed. It is postulated that these effects can be a result of activation of stretch activation channels, mechanical sensitivity of the nerve to acoustic radiation pressure and modulation of ion channels by ultrasound.

The neuromodulatory capabilities of ultrasound in tandem with electrical stimulation has a significant potential for development of neural interfaces to peripheral nerve.

Tracking microscale targets in soft tissue using implantable probes is important in clinical applications such as neurosurgery, chemotherapy and in neurophysiological application such as brain monitoring. In most of these applications, such tracking is done with visual feedback involving some imaging modality that helps localization of the targets through images that are co-registered with stereotaxic coordinates. However, there are applications in brain monitoring where precision targeting of microscale targets such as single neurons need to be done in the absence of such visual feedback. In all of the above mentioned applications, it is important to understand the dynamics of mechanical stress and strain induced by the movement of implantable, often microscale probes in soft viscoelastic tissue. Propagation of such stresses and strains induce inaccuracies in positioning if they are not adequately compensated. The aim of this research is to quantitatively assess (a) the lateral propagation of stress and (b) the spatio-temporal distribution of strain induced by the movement of microscale probes in soft viscoelastic tissue. Using agarose hydrogel and a silicone derivative as two different bench-top models of brain tissue, we measured stress propagation during movement of microscale probes using a sensitive load cell. We further used a solution of microscale beads and the silicone derivative to quantitatively map the strain fields using video microscopy. The above measurements were done under two different types of microelectrode movement – first, a unidirectional movement and second, a bidirectional (inch-worm like) movement both of 30 μm step-size with 3min inter-movement interval. Results indicate movements of microscale probes can induce significant stresses as far as 500 μm laterally from the location of the probe. Strain fields indicate significantly high levels of displacements (in the order of 100 μm) within 100 μm laterally from the surface of the probes. The above measurements will allow us to build precise mechanical models of soft tissue and compensators that will enhance the accuracy of tracking microscale targets in soft tissue.

There is a strong medical need and important therapeutic applications for improved wireless bioelectric interfaces to the nervous system. Multichannel devices are desired for neural control of robotic prosthetics that interface to remaining nerves in limb stumps of amputees and as alternatives to traditional wired arrays used in for some types of brain stimulation. This present work investigates a new approach to ultrasound-powering of implantable microelectronic devices within the tissue that may better support such applications. These devices are of ultra-miniature size that is enabled by a wireless technique. This study investigates two types of ultrasound-powered neural interfaces for multichannel sensory feedback in neurostimulation. The piezoceramics lead zirconate titanate (PZT) ceramic and polyvinylidene fluoride (PVDF) polymer were the primary materials used to build the devices. They convert ultrasound to electricity that when rectified by a diode produce a current output that is neuro stimulatory to peripheral nerve or the neurons in the brain. Multichannel devices employ a form of spatial multiplexing that directs focused ultrasound towards localized and segmented regions of PVDF or PZT that allows independent channels of nerve actuation. Different frequencies of ultrasound were evaluated for best results. Firstly, a 2.25 MHz frequency signal that is reasonably penetrating through body tissue to an implant several centimeters deep and also a 5 MHz frequency more suited to application for actuation of devices within a less than a centimeter of nerve. Results show multichannel device performance to have a complex inter-relationship with frequency, size and thickness, angular incidence, channel separations, and number of folds (layers connected in series and parallel). The output electrical port impedances of PVDF devices were examined in relationship to that of stimulating electrodes and tissue interfaces. Miniature multichannel devices were constructed using an unreported method of employing state of the art laser cutting systems. The results show that PVDF based devices have advantages over PZT, because of better acoustic coupling with tissue, known better biocompatibility, and better separation between multiple channels. However, the PZT devices proved to be better overall in terms of compactness and higher outputs for a given ultrasound power level.

Noninvasive neuromodulation could help treat many neurological disorders, but existing techniques have low resolution and weak penetration. Ultrasound (US) shows promise for stimulation of smaller areas and subcortical structures. However, the mechanism and parameter design are not understood. US can stimulate tail and hindlimb movements in rats, but not forelimb, for unknown reasons. Potentially, US could also stimulate peripheral or enteric neurons for control of blood glucose.

To better understand the inconsistent effects across rat motor cortex, US modulation of electrically-evoked movements was tested. A stimulation array was implanted on the cortical surface and US (200 kHz, 30-60 W/cm2 peak) was applied while measuring changes in the evoked forelimb and hindlimb movements. Direct US stimulation of the hindlimb was also studied. To test peripheral effects, rat blood glucose levels were measured while applying US near the liver.

No short-term motor modulation was visible (95% confidence interval: -3.5% to +5.1% forelimb, -3.8% to +5.5% hindlimb). There was significant long-term (minutes-order) suppression (95% confidence interval: -3.7% to -10.8% forelimb, -3.8% to -11.9% hindlimb). This suppression may be due to the considerable heating (+1.8°C between US
on-US conditions); effects of heat and US were not separable in this experiment. US directly evoked hindlimb and scrotum movements in some sessions. This required a long interval, at least 3 seconds between US bursts. Movement could be evoked with much shorter pulses than used in literature (3 ms). The EMG latency (10 ms) was compatible with activation of corticospinal neurons. The glucose modulation test showed a strong increase in a few trials, but across all trials found no significant effect.

The single motor response and the long refractory period together suggest that only the beginning of the US burst had a stimulatory effect. This would explain the lack of short-term modulation, and suggests future work with shorter pulses could better explore the missing forelimb response. During the refractory period there was no change in the electrically-evoked response, which suggests the US stimulation mechanism is independent of normal brain activity. These results challenge the literature-standard protocols and provide new insights on the unknown mechanism.

Cardiac tissue engineering has major applications in regenerative medicine, disease modeling and fundamental biological studies. Despite the significance, numerous questions still need to be explored to enhance the functionalities of the engineered tissue substitutes. In this study, three dimensional (3D) cardiac micro-tissues were developed through encapsulating co-culture of cardiomyocytes and cardiac fibroblasts, as the main cellular components of native myocardium, within photocrosslinkable gelatin-based hydrogels. Different co-culture ratios were assessed to optimize the functional properties of constructs. The geometry of the micro-tissues was precisely controlled using micro-patterning techniques in order to evaluate their role on synchronous contraction of the cells. Cardiomyocytes exhibited a native-like phenotype when co-cultured with cardiac fibroblasts as compared to the mono-culture condition. Particularly, elongated F-actin fibers with abundance of sarcomeric α-actinin and troponin-I were observed within all layers of the hydrogel constructs. Higher expressions of connexin-43 and integrin β1 indicated improved cell-cell and cell-matrix interactions. Amongst co-culture conditions, 2:1 (cardiomyocytes: cardiac fibroblasts) ratio exhibited enhanced functionalities, whereas decreasing the construct size adversely affected the synchronous contraction of the cells. Therefore, this study indicated that cell-cell ratio as well as the geometrical features of the micropatterned constructs are among crucial parameters, which need to be optimized in order to enhance the functionalities of engineered tissue substitutes and cardiac patches.

Bioimpedance measurements have been long used for monitoring tissue ischemia and blood flow. This research employs implantable microelectronic devices to measure impedance chronically as a potential way to monitor the progress of peripheral vascular disease (PVD). Ultrasonically powered implantable microdevices previously developed for the purposes of neuroelectric vasodilation for therapeutic treatment of PVD were found to also allow a secondary function of tissue bioimpedance monitoring. Having no structural differences between devices used for neurostimulation and impedance measurements, there is a potential for double functionality and closed loop control of the neurostimulation performed by these types of microimplants. The proposed technique involves actuation of the implantable microdevices using a frequency-swept amplitude modulated continuous waveform ultrasound and remote monitoring of induced tissue current. The design has been investigated using simulations, ex vivo testing, and preliminary animal experiments. Obtained results have demonstrated the ability of ultrasonically powered neurostimulators to be sensitive to the impedance changes of tissue surrounding the device and wirelessly report impedance spectra. Present work suggests the potential feasibility of wireless tissue impedance measurements for PVD applications as a complement to neurostimulation.

Peripheral Vascular Disease (PVD) is a debilitating chronic disease of the lower extremities particularly affecting older adults and diabetics. It results in reduction of the blood flow to peripheral tissue and sometimes causing tissue damage such that PVD patients suffer from pain in the lower legs, thigh and buttocks after activities. Electrical neurostimulation based on the "Gate Theory of Pain" is a known to way to reduce pain but current devices to do this are bulky and not well suited to implantation in peripheral tissues. There is also an increased risk associated with surgery which limits the use of these devices. This research has designed and constructed wireless ultrasound powered microstimulators that are much smaller and injectable and so involve less implantation trauma. These devices are small enough to fit through an 18 gauge syringe needle increasing their potential for clinical use. These piezoelectric microdevices convert mechanical energy into electrical energy that then is used to block pain. The design and performance of these miniaturized devices was modeled by computer while constructed devices were evaluated in animal experiments. The devices are capable of producing 500ms pulses with an intensity of 2 mA into a 2 kilo-ohms load. Using the rat as an animal model, a series of experiments were conducted to evaluate the in-vivo performance of the devices.

During the past five decades neurosurgery has made great progress, with marked improvements in patient outcomes. These noticeable improvements of morbidity and mortality can be attributed to the advances in innovative technologies used in neurosurgery. Cutting-edge technologies are essential in most neurosurgical procedures, and there is no doubt that neurosurgery has become heavily technology dependent. With the introduction of any new modalities, surgeons must adapt, train, and become thoroughly familiar with the capabilities and the extent of application of these new innovations. Within the past decade, endoscopy has become more widely used in neurosurgery, and this newly adopted technology is being recognized as the new minimally invasive future of neurosurgery. The use of endoscopy has allowed neurosurgeons to overcome common challenges, such as limited illumination and visualization in a very narrow surgical corridor; however, it introduces other challenges, such as instrument "sword fighting" and limited maneuverability (surgical freedom). The newly introduced concept of surgical freedom is very essential in surgical planning and approach selection and can play a role in determining outcome of the procedure, since limited surgical freedom can cause fatigue or limit the extent of lesion resection. In my thesis, we develop a consistent objective methodology to quantify and evaluate surgical freedom, which has been previously evaluated subjectively, and apply this model to the analysis of various endoscopic techniques. This model is crucial for evaluating different endoscopic surgical approaches before they are applied in a clinical setting, for identifying surgical maneuvers that can improve surgical freedom, and for developing endoscopic training simulators that accurately model the surgical freedom of various approaches. Quantifying the extent of endoscopic surgical freedom will also provide developers with valuable data that will help them design improved endoscopes and endoscopic instrumentation.