Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references. / Cancer mortality still remains high despite significant investments in diagnostics, drug development, and treatment. The systemic route is convenient both for routine monitoring and for drug administration. Local cancer biomarker concentrations, however, are more indicative of the state of solid tumors and their response to therapy. Furthermore, local drug delivery can achieve efficacy where systemic treatments fail. This dissertation describes two reservoir-based devices to enable such local approaches. We are applying superparamagnetic crosslinked iron oxide nanoparticles (CLIO) for the quantitative measurements of soluble cancer biomarkers. These nanoparticles are functionalized to react specifically in the presence of their target analyte. An implanted device with a size-exclusion membrane was used to contain the CLIO and to expose them to the cancer milieu. The system was designed to be deployed deep within the body and indirectly detect cancer cells and their activity by their secreted products, which are produced at a very high copy number by each cell. A reservoir-based polymeric device has also been applied for local chemotherapy. A biodegradable polymer microchip was designed in our group to independently deliver more than one therapeutic agent. Only in vitro release of active compounds had been previously demonstrated. The work in this thesis achieves local drug therapy from the polymer microchip and demonstrates efficacy against an in vivo tumor model of brain cancer. The reservoir-based device approach has the potential to enable early detection of cancer recurrence, personalized drug treatments, and localized multi-drug therapy. / by Grace Young Kim. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 59-61). / Diseases affecting the retina, such as Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), result in the degeneration of the photoreceptor cells and can ultimately lead to blindness in patients. There is currently no cure for AMD or RP, and only a few methods exist for slowing the progression of these diseases. Although there has been much recent headway in cell replacement therapy to restore vision loss, a number of challenges still remain. More specifically, there is a need for the development of a device that can deliver a large number of cells to the posterior segment of the eye, while promoting cell survival, differentiation and integration into the retina following transplantation. This research focuses on designing a device to meet these demands and improve the vision of those afflicted with blinding diseases. The specific hypothesis behind the proposed research is that a MEMS-based strategy to engineer a device can provide precisely defined spatial and chemical cues to influence retinal progenitor cells (RPCs) attachment, promote differentiation, and provide physical guidance in a more normal anatomical organization for their integration as neurosensory retina after transplantation to the subretinal space. Therefore, the specific aims of this research are to design, fabricate, and evaluate in vitro a novel ultrathin 3-D device made of polycaprolactone (PCL) for retinal cell replacement synthesized by the stacking, aligning, and bonding of three uniquely designed layers. / (cont.)Photolithography, standard replica molding, and soft lithography techniques are used to fabricate the device elements. The 3-D device is designed with a defined cage structure to encapsulate a large number of cells. Another layer of the design allows for unidirectional cell migration out of one end into the subretinal space with the aid of contact guidance ridges. The third design layer allows for nutrient infiltration from the retinal pigment epithelium into the cell cages. The ultimate goal is to provide an environment compatible with the normal retinal tissue and conducive to the formation of functional synapses under the appropriate conditions, thereby restoring proper vision. With demonstration of efficacy and cell retention in vitro, the scaffold has the potential to reverse retinal degeneration due to disease or trauma and improve retinal function and integrity in vivo. / by Sonal Sodha. / M.Eng.

Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 141-148). / Pitch variations are used in different languages in a variety of communicative ways, from cueing lexical item identity to conveying meaning through phrasing and accentuation. Previously, linguistic theories of intonation and tone which have sought a unifying account for tonal phenomena have not defined a clear and systematic relation between phonological representations and phonetic output in terms of acoustically observable fundamental frequency (FO) variations. This is problematic, because meaningful pitch patterns cannot be related to underlying phonological primitives in any clear way, so that it is difficult to empirically verify or falsify the theory. This thesis addresses this problem by proposing a phonological description of intonation and tone for which there is a clear and systematic relationship between observed FO variations and underlying phonological primitives. The theory is based on a construct called the tone interval, which represents an abstraction of a ratio of two fundamental frequencies. A syntagmatic tone interval relates two sequentially-ordered tones, while a paradigmatic tone interval relates a tone and a speaker-specific referent level. Tone intervals define one of three relations: a tone may be higher, lower, or the same level as its referent. Additional language-specific categories may be formed which restrict the pitch distance between a tone and its referent. Tones in syntagmatic tone intervals are assumed to be arranged at the phrasal level with respect to a metrical grid, which represents the relative prominence and timing of syllables. / (cont.) This permits interactions between nonsequential tones occupying metrically prominent syllables, accounting for cross-linguistic observations involving control of relative height relations on nonadjacent syllables. Six experiments tested the predictions of tone interval theory and other phonological theories for English. Experiments 1 and 3 involved discrimination of pairs of stimuli in which the timing of an FO extremum had been varied along a continuum with respect to segments, while Experiments 2 and 4 involved imitation of these stimuli. Experiments 5 and 6 involved imitating stimuli in which absolute FO level had been varied along a continuum. Consistent with the tone interval theory, these results demonstrate the importance of relative pitch level for phonological representations. In particular, discrimination maxima and discreteness in production data were observed for positions in stimulus series in which either (i) the timing of an FO extremum was varied across a vowel onset, or (ii) the FO level of one syllable switched from higher than another syllable to lower than that syllable. / by Laura Christine Dilley. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 92-95). / Breath analysis has potential to become a new medical diagnostic modality. In this thesis, a method for the analysis of human expired breath was developed using gas chromatography-mass spectroscopy. It was subsequently adopted for gas chromatography-differential mobility spectroscopy, a modality not previously applied to this problem. Tedlar bags and solid-phase microextraction were used for breath sampling and concentration prior to analysis. Four fiber coatings were evaluated with respect to selectivity and sensitivity; extraction time, gas chromatography temperature programming, and sample storage stability were explored for optimization. The method entails extraction and preconcentration with a polydimethylsiloxane-divinylbenzene coated fiber for 30 min at 37⁰C, and extraction profiles for several compounds demonstrate competitive adsorption. 120 compounds were identified in breath with response variability between 23 - 117% about mean values. Feasibility of differential mobility spectroscopy for breath analysis was established, and this method will be the basis for future investigations on the diagnostic potential of breath analysis. / by William Merrick. / M.Eng.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (p. 167-171). / Advanced laryngeal cancer is often treated by surgical removal of the larynx (laryngectomy) thus rendering patients unable to produce normal voice and speech. Laryngectomy patients must rely on an alternative means of producing voice and speech, with the most common method being the use of an electrolarynx (EL). The EL is a small, hand-held, electromechanical device that acoustically excites the vocal tract when held against the neck or at the lips. While the EL provides a serviceable means of communication, the resulting speech has several shortcomings in terms of both intelligibility and speech quality. Previous studies have identified and tried to correct different single selected acoustic properties associated with the abnormal quality of EL speech, but with only limited success. There remains uncertainty about: 1) which components of the EL speech acoustic signal are contributing most to its abnormal quality and 2) what kinds of acoustic enhancements would be most effective in improving the quality of EL speech. Using a combination of listening experiments, acoustic analysis and acoustic modeling, this thesis investigated the perceptual and acoustic impacts of several aberrant properties of EL speech, with the overall goal of using the results to direct future EL speech improvement efforts. Perceptual experiments conducted by having 10 listeners judge the naturalness of differently enhanced versions of EL speech demonstrated that adding pitch information would produce the most benefit. Removing the EL self-noise and correcting for a lack of low frequency energy would also improve EL speech, but to a lesser extent. However, / (cont.) this study also demonstrated that monotonous, normal speech was found to be more natural than any version of EL speech, indicating that there are other abnormal properties of EL speech contributing to its unnatural quality. An acoustic analysis of a corpus of pre- and post-laryngectomy speech revealed that changes in vocal tract anatomy produce narrower formant bandwidths and spectral zeros that alter the spectral properties of EL speech. Vocal tract modeling confirmed that these spectral zeros are a function of EL placement and thus their effects will vary from user to user. Even though the addition of pitch information was associated with the greatest improvement in EL speech quality, its implementation is not currently possible because it would require access to underlying linguistic and/or neural processes. Based on these findings it was concluded that an enhancement algorithm that corrects for the low frequency deficit, the interference of the EL self-noise, the narrower formant bandwidths, and the effect of the source location, should produce EL speech whose quality surpasses what is currently available. / by Geoffrey Seth Meltzner. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (leaves 43-49). / Electronic prescription software is replacing traditional handwritten medication orders. This development however doesn't come without a cost and speed has been one of the most complained about issues. It is important to address this problem and develop methods to reduce the time spent entering medication orders into computerized prescription software. The objective of this study was to understand the structure of prescription patterns and explore the possibility of designing a method that will predict prescription patterns with only the knowledge of past prescription history. Various machine-learning methods were used and their performance measured by the accuracy of prediction as well as their ability to produce desirable results, within practical time limits. This paper presents a method to transform prescription data into a stochastic time series for prediction. The paper also presents a new nonlinear local algorithm based on nearest neighbor search. In analyzing the database the drug patterns were found to be diverse and over 30% of the patients were unique, in the sense that no other patient had been prescribed the same set of active ingredients. In spite of this diversity, it was possible to create a list of 20 drugs that contained the drug to be prescribed next for 70.2% of patients. This suggests that probabilistically created pick lists, tailored specifically for one patient at the time of prescription, might be used to ease the prescription process. However, further research is needed to evaluate the impact of such lists on prescription habits. / by Ívar S. Helgason. / S.M.

Thesis (Ph. D. in Medical and Engineering Physics)--Harvard-MIT Program in Health Sciences and Technology, June 2013. / "May 2013." Cataloged from PDF version of thesis. / Includes bibliographical references (pages 121-127). / Sepsis is a systemic inflammatory response that results the presence and persistence of microorganisms or their toxins in the bloodstream and it is diagnosed by detecting the presence of pathogens in blood. Despite improvements in modem medicine, sepsis has a high mortality rate that increases rapidly with every hour the patient does not receive optimal antibiotic therapy. Thus, there is a great demand for technologies that can accelerate pathogen detection and sepsis diagnosis. Our lab previously developed a micromagnetic-microfluidic pathogen isolation technology that can selectively remove pathogens from flowing whole human blood with high efficiency using micro- or nano-sized magnetic beads coated with microbe-specific antibodies [1, 2]. However, the identity of the pathogen is not known when a patient first presents with the clinical symptoms of sepsis, and currently, it can take days to a week to identify the specific pathogen type. The goal of this dissertation is to develop a generic pathogen collection technology that can be used to pull bacteria and fungi out of blood or other fluids without first knowing their identity, and to concentrate them for analysis and rapid identification. In Chapter 1, 1 will review the field of sepsis diagnostics and methods that have been employed to confront this challenge. In Chapter 2, I describe the development of a natural human opsonin - Mannose Binding Lectin (MBL) - as a generic pathogen capture molecule. MBL is found in human blood and is part of the innate immune system; it has been previously shown to bind over 90 different types of pathogens, including gram negative and positive bacteria, fungi, viruses and parasites [3-5]. The studies described in this chapter include development and optimization of methods to coat magnetic beads with MBL and demonstration that MBL beads bind to wide range of pathogens with high efficiency in saline and blood. The binding of MBL beads to sample pathogens is tested under a wide range of conditions to determine optimal bead concentration, binding time and sample treatments to maximize binding in blood. In Chapter 3, 1 describe development of a device that efficiently concentrates and visualizes fungi tagged with the magnetic MBL micro beads. Visualization is made possible by controlling the balance of fluidic shear stress and magnetic force on the tagged pathogens in the device, which enables spreading of the beads and bound fungi into a uniform layer that can be quickly quantified with fluorescent microscopy. Chapter 4 describes tools that I have developed to rapidly concentrate and purify magnetically tagged bacteria from blood and other complex samples for polymerase chain reaction (PCR) detection. The MBL-bead approach is used to pull out and concentrate pathogens from large sample volumes, and to remove contaminating human DNA, so that sensitive detection can be carried out using PCR amplification. The efficiency of this new MBL-based, sample pre-concentration method is compared to existing commercial isolation methods for analysis of both blood and food samples. Finally, I discuss the implications of these findings in Chapter 5. / by Ryan Mcomber Cooper. / Ph.D.in Medical and Engineering Physics

Thesis (S.M.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1999. / Includes bibliographical references (leaves 42-44). / The functionality of prosthetic limbs is restricted by the limited availability of sensory feedback. This research aims to develop a technology to allow the presentation of sensory information directly to the sensory afferent neurons of the transected peripheral nerve in the stump of the amputee. lntraneural implants of several designs were developed and implanted in rabbit animal models and monitored for chronic functionality evaluated using both neurophysiological and behavioral tests. Animal studies have demonstrated single channel implant functionality of up to 129 days. The relative merit of the designs is assessed, and future directions for implant design and behavioral testing are suggested. / by Daniel DiLorenzo. / S.M.

Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2016. / 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 (pages 115-124). / Clinical predictive models are useful in predicting a patient's risk of developing adverse outcomes and in guiding patient therapy. In this thesis, we explored two different ways to apply domain knowledge to improve clinical predictive models. We first applied knowledge about the heart to engineer better frequency-domain features from electrocardiograms (ECG). The standard frequency domain (in Hz) quantifies events that repeat with respect to time. However, this may be misleading because patients have different heart rates. We hypothesized that quantifying frequency with respective to heartbeats may adjust for these heart rate differences. We applied this beat-frequency to improve two existing ECG predictive models, one based on ECG morphology, and the other based on instantaneous heart rate. We then used machine learning to find predictive frequency bands. When evaluated on thousands of patients after an acute coronary syndrome, our method significantly improved prediction performance (e.g., area under curve, AUC, from 0.70 to 0.75). In addition, the same bands were found to be predictive in different patients for beat-frequency, but not for the standard frequency domain. Next, we developed a method to transfer knowledge from published biomedical articles to improve predictive models when training data are scarce. We used this knowledge to estimate the relevance of features to a given outcome, and used these estimates to improve feature selection. We applied our method to predict the onset of several cardiovascular diseases, using training data that contained only 50 adverse outcomes. Relative to a standard approach (which does not transfer knowledge), our method significantly improved the AUC from 0.66 to 0.70. In addition, our method selected 60% fewer features, improving interpretability of the model by experts, which is a key requirement for models to see real-world use. / by Yun Liu. / Ph. D. in Medical Engineering

Thesis: Ph. D. in Speech and Hearing Bioscience and Technology, Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 107-118). / Nearly all information about the acoustic environment is conveyed to the brain by auditory nerve (AN) fibers. While essential for hearing, these fibers may also be the most vulnerable link in the auditory pathway: moderate noise exposure can cause loss of AN fibers without causing hair cell damage or permanent threshold shift. This neuropathy is undetectable by standard clinical examination, but post-mortem evidence suggests that it is widespread in humans. Its impact on suprathreshold hearing ability is likely profound, but is not well understood. An essential tool for evaluating the impact of neuropathy is a non-invasive test useable in humans. Since noise-induced neuropathy is selective for high-threshold AN fibers, where phase locking to envelopes is particularly strong, we hypothesized that the envelope following response (EFR) might be a more sensitive measure of neuropathy than the more traditional auditory brainstem response (ABR). We compared ABRs and EFRs in mice following a neuropathic noise exposure. Changes to EFRs were more robust: the variance was smaller, thus inter-group differences were clearer. Neuropathy may be the root cause of a number of deficits that can occur in listeners with normal audiograms, such as speech discrimination in noise and ability to use envelope cues. We searched for neural correlates of these deficits in the mouse auditory midbrain following exposure. Consistent with reductions in EFRs, synchronization to envelopes was impaired. Neural detectability of tones in background noise was impaired, but only for cases when noise level changed every 600 milliseconds. When noise level changed every minute, responses were equal to those of unexposed mice, implicating changes to adaptation. In quiet, tone-evoked rate-level functions were steeper, indicating that neuropathy may initiate a compensatory response in the central auditory system leading to the genesis of hyperacusis. In sum, we found compensatory effects on coding in the midbrain beyond the simple direct effects expected by peripheral neuropathy. / by Luke A. Shaheen. / Ph. D. in Speech and Hearing Bioscience and Technology