Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaf 98). / Companies must receive marketing authorization by the Food and Drug Administration (FDA) before they can begin commercial distribution of a new type of medical device in the United States. The premarket approval application (PMA) is the process by which this occurs. Companies submit a PMA after they have completed laboratory test, animal studies and human clinical trials to demonstrate the safety and effectiveness of the device for a specific condition, or therapeutic indication. Despite legislation in the early part of this decade to reduce the timeframe for FDA review of PMAs, these timeframes continue to vary dramatically and unpredictably from months to many years. The focus of this thesis is to examine factors which influence this timeframe. Hypotheses about factors that impact PMA review timeframes were developed by analyzing the review process and through interviews with industry representatives and FDA officials. The following factors were evaluated: year of submission to FDA, size of firm seeking approval, presence of prior approved PMAs by firm seeking approval, product category, first-of-a-kind device, number of amendments, expedited review status, advisory panel review, unanimous advisory panel vote, and confirmation of primary efficacy endpoints in pivotal clinical trials. The year of submission was considered a control variable. The other factors fall into one of three categories: applicant characteristics, device characteristics, and process characteristics. Analysis was limited to PMAs received by FDA from 2000 through 2005. Two levels of analysis were conducted. / (cont.) First, the directional impact of each factor on PMA review time was evaluated. Second, regression analysis was used to develop predictive models for PMA review time, in days, and to test which factors have meaningful associations when controlling for other factors. Factors that have highly statistically significant associations with longer review timeframes include: a larger number of amendments, and designation as an orthopedic device. Designation as an orthopedic device has a particularly dramatic impact on PMA review time. Orthopedic devices have a mean PMA review time of 647 days, 240 days longer (66% more) than the average for all other categories combined. Even after controlling for process, device, and applicant factors, the impact of an orthopedic designation remains large, increasing the review time by 175 days (p<0.01). In a univariate regression model, each additional amendment is associated with 20.2 additional days (p<0.0001) of review time. After controlling for other factors, each additional amendment is associated with 17.5 additional days (p<0.0001) of review time. Although the number of amendments cannot be known - or predicted - in advance of PMA submission, its significance (R-squared of 0.25 in a univariate regression model) in predicting PMA review timeframes reinforces the notion that quality - primarily of the dossier, in terms of its organization, clarity and completeness, but also of the adequacy of the underlying data to substantiate safety and effectiveness - is critically important to the achieving a shorter PMA review time. Only one factor has an association that in the opposite direction to that hypothesized. PMAs with an expedited review status have mildly longer PMA review times, by 37 days, than those that were not expedited. / (cont.) This result can be explained in part by the larger number of amendments on these PMAs (corr=0.32). When controlling for the number of amendments and other important factors, an expedited review designation has a significant impact on PMA review timeframes in the opposite, but hypothesized direction - it shortens PMA review times by 146 days (p<0.01). / by Inder Raj Singh. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Page 150 blank. / Includes bibliographical references. / Current clinical practice calls for the development of techniques to diagnose diseases in its early stages, when treatment is most effective and significant irreversible damage can either be prevented or delayed. Optical coherence tomography (OCT) is an emerging medical diagnostic technology being investigated for applications in a number of medical fields including ophthalmology, cardiology, and gastroenterology. OCT is analogous to ultrasound except that it uses light waves rather than sound waves. OCT can achieve a much higher resolution than ultrasound in measuring the underlying tissue microstructures. Another advantage of OCT is that it can achieve imaging in a non-contact and non-invasive manner. With typical axial resolution of 10 [mu]m, OCT already provides significantly more detailed structural information than any other conventional clinical imaging technique. The development of OCT with even higher resolution would potentially have significant impact in diagnosing diseases in such fields as ophthalmology, cardiology, gastroenterology, and oncology. Ultrahigh resolution OCT systems have been developed for animal research and clinical ophthalmology. Ultrahigh resolution OCT improves the axial resolution of OCT from the standard 10 [mu]m to 1 [mu]m for animal studies and 3 [mu]m for clinical studies. This improved imaging resolution approaches that of histopathology. Therefore, OCT can potentially function as "optical biopsy" since it permits the imaging of tissue microstructure with resolutions approaching that of histopathology except that imaging can be performed in real time, without the need of tissue removal. / (cont.) Using ultrahigh resolution OCT systems, animal imaging studies have been performed on mouse and rat models of retinal diseases and clinical imaging studies have been performed on more than 800 patients at the ophthalmology clinic. The results from patient imaging studies on a wide variety of retinal diseases suggest that ultrahigh resolution OCT can improve the diagnosis and management of retinal diseases as well as possibly increase the understanding of ocular disease pathogenesis. Therefore, ultrahigh resolution OCT has the potential to become an important tool in ophthalmology research and clinics. / by Tony Hong-Tyng Ko. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student submitted PDF version of thesis. / Includes bibliographical references (p. 120-128). / Oxygen consumption is an essential process of the functioning brain. The rate at which the brain consumes oxygen is known as the cerebral metabolic rate of oxygen (CMRO₂). CMRO₂ is intimately related to brain health and function, and will change in settings of disease and functional activation. Accurate CMRO₂ measurement will enable detailed investigation of neuropathology and facilitate our understanding of the brain's underlying functional architecture. Despite the importance of CMRO₂ in both clinical and basic neuroscience settings, a robust CMRO₂ mapping technique amenable to functional and clinical MRI has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity-selective spin labeling to isolate MR signal exclusively from post-capillary venular blood on a voxel-by-voxel basis. This isolated signal can be related to venular oxygen saturation, oxygen extraction fraction, and ultimately CMRO₂. This thesis first explores fundamental theory behind the QUIXOTIC technique, including design of a novel MRI pulse sequence, explanation of the principal sequence parameters, and results from initial human experiences. A human trial follows, in which QUIXOTIC is used to measure cortical gray matter CMRO₂ in ten healthy volunteers. / (cont.) QUIXOTIC-measured CMRO₂ is found to be within the expected physiological range and is comparable to values reported by other techniques. QUIXOTIC is then applied to evaluate CMRO₂ response to carbon-dioxide-induced hypercapnia in awake humans. In this study, CMRO₂ is observed to decrease in response to mild hypercapnia. Finally, pilot studies that show feasibility of QUIXOTIC-based functional MRI (fMRI) and so-called "turbo" QUIXOTIC are presented and discussed. / by Divya Sanam Bolar. / Ph.D.

Thesis (Ph. D. in Electrical and Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Ambulation is a very important part of everyday life and its absence has a detrimental effect on an individual's quality of life. While much is understood about the neurobiological systems involved in locomotion through detailed anatomical connectivity and lesion studies, it is not well understood how neurons across different regions of the nervous system share information and coordinate their firing activity to achieve ambulation. Moreover, while it is clear that understanding the processes involved in healthy ambulation are essential to understanding how diseases affect an individual's ability to walk, diseases such as stroke tend to "take out" large portions of the underlying system. Until technologies are developed to allow restoration of damaged neural tissue back to its original state, physical therapy (which aims to restore function by establishing new motor-cortical connections among the remaining neurons) remains the most viable option for patients. The aim of this thesis is to elucidate some of the underlying neurobiological mechanisms of walking and to develop tools for rehabilitation robotics that allow finer quantification of patient improvement. To elucidate the neural mechanisms of locomotion, we studied how task relevant information (e.g. positions, velocities, and forces) modulate single unit neural activity from hindlimb/trunk region of the rat motor cortex during adaptations to robot-applied elastic loads and closed-loop brain-machine-interface (BMI) control during treadmill locomotion. Using the Point Process-Generalized Linear Model (PP-GLM) statistical framework we systematically tested parametric and non-parametric point process models of increased complexity for 573 individual neurons recorded over multiple days in six animals. The developed statistical model captures within gait-cycle modulation, load-specific modulation, and intrinsic neural dynamics. Our proposed model accurately describes the firing statistics of 98.5% (563/573) of all the recorded units and allows characterization of the neural receptive fields associated with gait phase and loading force. Understanding how these receptive fields change during training and with experience will be central to developing rehabilitation strategies that optimize motor adaptations and motor learning. The methods utilized for this analysis were developed into an open source neural Spike Train Analysis Toolbox (nSTAT) for Matlab (Mathworks, Natick MA). Systematic analyses have demonstrated the effectiveness of physical therapy, but have been unable to determine which approaches tend to be most effective in restoring function. This is likely due to the multitude of approaches, diseases, and assessment scales used. To address this issue, we develop an extension of the Force Field Adaptation Paradigm, originally developed to quantitatively assess upper extremity motor adaptation, to the lower extremity. The algorithm is implemented on the Lokomat (Hocoma HG) lower extremity gait orthosis and is currently being utilized to assess short-term motor adaptation in 40 healthy adult subjects (ClinicalTrials.gov NCT01361867). Establishing an understanding of how healthy adults' motor systems adapt to external perturbations will be important to understanding how the adaptive mechanisms involved in gait integrate information and how this process is altered by disease. / by Iahn Cajigas González. / Ph.D.in Electrical and Medical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 33-35). / Introduction. Models for mortality prediction are traditionally developed from prospective multi-center observational studies involving a heterogeneous group of patients to optimize external validity. We hypothesize that local customized modeling using retrospective data from a homogeneous subset of patients will provide a more accurate prediction than this standard approach. We tested this hypothesis on patients admitted to the ICU with acute kidney injury (AKI), and evaluated variables from the first 72 hours of admission. Methods. The Multi-parameter Intelligent Monitoring for Intensive Care II (MIMIC II) is a database of patients admitted to the Beth Israel Deaconess Medical Center ICU. Using the MIMIC II database, we identified patients who developed acute kidney injury and who survived at least 72 hours in the ICU. 118 variables were extracted from each patient. Second and third level customization of the Simplified Organ Failure Score (SAPS) was performed using logistic regression analysis and the best fitted models were compared in terms of Area under the Receiver Operating Characteristic Curve (AUC) and Hosmer-Lemeshow Goodness-of-Fit test (HL). The patient cohort was divided into a training and test data with a 70:30 split. Ten-fold cross-validation was performed on the training set for every combination of variables that were evaluated. The best fitted model from the cross-validation was then evaluated using the test set, and the AUC and the HL p value on the test set were reported. Results. A total of 1400 patients were included in the study. Of these, 970 survived and 430 died in the hospital (30.7% mortality). We observed progressive improvement in the performance of SAPS on this subset of patients (AUC=0.6419, HL p=0) with second level (AUC=0.6639, HL p=0.2056), and third level (AUC=0.7419, HL p=0.6738) customization. The best fitted model incorporated variables from the first 3 days of ICU admission. The variables that were most predictive of hospital mortality in the multivariate analysis are the maximum blood urea nitrogen and the minimum systolic blood pressure from the third day. Conclusion. A logistic regression model built using local data for patients with AKI performed better than SAPS, the current standard mortality prediction scoring system. / by Leo Anthony G. Celi. / S.M.

Thesis: Ph. D. in Materials Science and Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, February 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 135-139). / Endothelial cells (EC) are ubiquitous - as vascular epithelial cells they line the inner surface of all vessels and are the contact surface with flowing blood. Macrovascular EC are the first line barrier between flowing blood and mural structures. The microvasculature includes EC-lined vessels that contact virtually every cell in the body. These EC are potent bioregulatory cells, modulating thrombosis, inflammation and control over mural smooth muscle cells and vascular health. The biochemical roles of EC can be retained when cells are embedded within three-dimensional matrices without recapitulation of the full vessel architecture. Within these matrices, surface and structural properties impose a set of forces on the embedded EC. Indeed, substrata pore size and modulus have profound effects on phenotype and function of a range of cell types. In the first part of this work, we examined the effect of pore size, matrix relative density and modulus on matrix-embedded EC growth and secretion and found a greater biological dependence on modulus than pore size or density. In the second part of this work, we examined the effect of isolated changes in modulus on BC growth, secretion of growth regulators, and modulation of smooth muscle cell growth. EC growth is maximal at intermediate moduli over a range from 50 Pa- 1500 Pa. Secretion of heparan sulfate proteoglycans (HSPGs), which inhibit smooth muscle cell growth, is maximal at low moduli and flat at high moduli. Secretion of growth factors such as FGF2 and PDGF-BB were also modulus responsive. Inhibition of smooth muscle cell growth rose as modulus decreased from 510 Pa to 50 Pa and was the result of a balance between increased HSPG secretion and reduced secretion of vasoactive growth factors. Changes in endothelial function correlated with extracellular matrix gene and integrin aP 3 and c41 expression. Changes in the forces experienced by the cell - a change in substrate modulus - cause the cell to alter its ECM and integrin expression in an effort to return the force balance to normal, leading to downstream effects on cell function. While growth stimulatory function largely conserved, growth inhibitory function was altered to a much larger degree. In the final part of this work, we examined the effect of scaffold modulus on EC response to inflammatory stimuli, and attempted to correlate it to changes in smooth muscle cell regulation and integrin expression. While cytokine secretion was independent of modulus, surface expression of ICAM- 1 and VCAM-1, and induction of CD4' T cell proliferation followed a similar pattern to smooth muscle cell inhibition, suggesting that similar mechanisms may be involved in their regulation by substrate modulus. Alteration of scaffold modulus has a profound impact on EC function including growth regulation and inflammatory response. The model offered in this thesis - wherein EC attempt to neutralize changes in environmental force balance by altering ECM and integrin expression, leading to changes in downstream function - offers insight into how environmental changes effect functional changes in ECs. / by Sylaja Murikipudi. / Ph. D. in Materials Science and Medical Engineering

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 221-232). / Cells are continuously sensing and processing information from their environments and responding to it in sensible ways. The communication networks on which such information is handled often consist of systems of chemical reactions, such as signaling pathways or metabolic networks. This thesis studies the dynamics of systems of chemical reactions in the context of biological cells. The first part of this thesis analyzes the osmo-regulation network in yeast, responsible for the regulation of internal osmolarity. We measure the system's step response in single cells, and find that the steady state is independent of the input, a property termed perfect adaptation that relies on integral feedback control. We then consider the signaling cycle, a pattern of chemical reactions that is often present in signaling pathways, in which a protein can be either active (e.g., phosphorylated) or inactive (e.g., unphosphorylated). We identify new regimes of static and dynamic operation, and find that these cycles can be tuned to transmit or digitize time-varying signals, while filtering input noise. The second part of this thesis considers systems of chemical reactions where stochastic effects are relevant, and simplifies the standard models. We develop an approximate model for the time-evolution of the average concentrations and their variances and covariances in systems with and without spatial gradients. We also describe a framework to identify and derive approximate models for variables that evolve at different time scales in systems without spatial gradients. These tools can help study the impact of stochastic and spatial effects on system behavior. / by Carlos Alberto Gómez Uribe. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1998. / Includes bibliographical references (leaves 219-232). / by Gerald C. Koenig. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 133-138). / Nanoparticle (NP)-mediated drug delivery typically relies on cargo release to occur passively or in response to environmental stimuli. In the first part of this work, we present a drug delivery method based on light-activated disruption of intracellular vesicles after internalization of bio-functionalized mesoporous silica nanoparticles loaded with cargo. We developed an improved synthesis method to optimize size control of mesoporous silica nanoparticles in the 20-200nm range while preserving porosity. We optimized surface bio-functionalization to obtain a highly stable and targetable nanocarrier, and used an embedded photosensitizer to combine the power of targeted delivery with the spatiotemporal control of light activation. NP-mediated endosomal disruption can be controlled at the single vesicle level. As an example, we delivered a cell-impermeable fluorescent compound exclusively to the cytosol of multidrug resistant cancer cells in a mixed population. The second part of this thesis investigated the use of both photosensitizer-coupled and magnetic nanoparticles as actuators of ion channels. While direct magnetic actuation was not found to promote activation of the receptors tested, several members of the transient receptor potential superfamily (TRP), notably TRPV3 and TRPA1, were found to be activatable by light in conjunction with photosensitizers, including the endogenously present all-trans retinal. The findings were established using a combination of calcium imaging with both chemical and genetically encoded indicators, in addition to whole cell patch clamping. Spontaneous activation of channels in heterologous expression systems was observed upon illumination at selective wavelengths, establishing an effective actuation method, potentially adding native channels to the current opto-genetic toolbox. / by Sébastien Febvay. / Ph. D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (leaves 125-135). / Outer hair cells (OHCs) are key elements of the mammalian hearing system, which amplify sound-evoked signals transmitted into the inner ear. OHCs are innervated by peripheral projections of olivocochlear (OC) and type-II spiral ganglion neurons. Type-II neurons innervate up to 100 OHCs, but their function is unknown. It has been suggested that type-II neurons interconnect neighboring OHCs through reciprocal synapses, which are bi-directional (afferent and efferent) synaptic interactions (Nadol, 1981). Since reciprocal synapses on the OHCs have been shown to be prevalent only in aged primates, they were thought to be a pathological finding. In addition to their interactions with OHCs, type-II neurons are also innervated by OC neurons. Synapses between OC and type-II neurons (OC/type-II synapses) have been described (Smith and Rasmussen, 1963), but these interactions have not been characterized in detail. Serial and semi-serial section transmission electron microscopy were used to study the synaptic interactions of type-II neurons with OHCs and OC neurons in a young human and in adult cats. A high prevalence of nerve terminals with reciprocal synapses was observed in the young human and in adult cats. These reciprocal terminals were processes of type-IIs, and not of OC neurons. Reciprocal type-II terminals were found in all frequency regions studied in cats, but were most prevalent below 4,000Hz. All the type-II fibers traced to more than one OHC in an adult cat had reciprocal interactions with OHCs. Type-II fibers/terminals were heavily innervated by OC neurons, which preferentially targeted terminals with reciprocal synapses that were predominantly afferent in an adult cat. / (cont.) The innervation patterns of type-IIs and OC neurons in the cat were similar to that found in comparable frequency regions of primates. Type-II neurons have reciprocal synaptic interactions with OHCs and form an "outer spiral network", which may functionally integrate the OHCs. The OC system may modulate this network through OC/type-II synapses. The outer spiral network and its innervation by the OC system seem to be relevant to OHC function, and further research is needed to determine their role in hearing. / by Fabio Albuquerque Theirs. / Ph.D.