Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 299-330). / More than one million joint replacements are performed in the USA annually. However, around 10 % of patients require revision surgery within 10 years with prosthetic joint infections (PJI) as a common reason. PJI has a recurrence rate of 16 %, a mortality rate of 2.5 %, and end-stage treatments involving arthrodesis and amputation. Most drug eluting polymers that were in development to address this problem failed due to toxic degradation products, insufficient drug release, and insufficient mechanical strength. The gold standard of treatment uses antibiotic eluting bone cement which has a mechanical failure rate of 26-60 % within 49-54 months if used under load bearing conditions. Therefore, despite advances in orthopedic materials, development of drug-eluting devices with effective, sustained delivery with the necessary mechanical strength for a fully load bearing joint implant has been elusive. Here, we report the synthesis and application of a drug eluting, fully load bearing, and articulating joint prosthesis that has superior mechanical strength and drug elution profile compared to the clinical gold standard, antibiotic eluting bone cement. We modified the eccentricity of drug clusters and percolation threshold in the polymeric matrix of Ultra-High Molecular Weight Polyethylene (UHMWPE), which resulted in maximized drug elution and mechanical strength retention. The optimized antibiotic eluting UHMWPE elutes antibiotic at a higher concentration for a longer period of time than antibiotic eluting bone cement while retaining the mechanical and wear properties of clinically used UHMWPE joint prosthesis. After drug elution, the empty drug clusters in the polymer were filled with biological lubricants during articulation, which through a combination of weeping and elastohydrodynamic lubrication, reduced the overall wear rate of the UHMWPE. Treatment of Staphylococcus aureus infected lapine knee with the antibiotic eluting UHMWPE showed complete bacterial eradication without any detectable systemic side effect. Taken together, our study showed that the drug-eluting UHMWPE joint implants in this study are promising candidates for further clinical trial and as the next generation prosthetic joints. / by Vincentius Jeremy Suhardi. / Ph. D. in Medical Engineering and Medical Physics

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / MIT Institute Archives copy: Pages 101-130 bound in reverse order. / Includes bibliographical references (p. 123-130). / Cardiac arrhythmias are characterized by a disruption or abnormal conduction of electrical signals within the heart. Treatment of arrhythmias has dramatically evolved over the past half-century, and today, minimally-invasive catheter-based therapy is the preferred method of eliminating arrhythmias. Using an electroanatomical (EA) mapping system, which precisely tracks the position of catheters inside the patient's body, it is possible to construct three-dimensional maps of the ventricular and atrial chambers of the heart. Each point of these maps is annotated based on bioelectrical signals recorded from the electrodes located at the tip of the catheter. These maps are then used to guide catheter ablation within the heart. However, the electroanatomical mapping procedure results in relatively sparse sampling of the heart and a significant amount of time and skill are require to generate these maps. In this thesis, we present our software system for the integration of pre-operative, patient-specific magnetic resonance (MR) or computed tomography (CT) imaging data with real-time electroanatomical mapping (EAM) information. / (cont.) Following registration between the EAM and imaging data, the system allows for real-time catheter navigation within patient-specific anatomy. We then evaluate candidate registration strategies to rapidly and accurately align the pre-operative imaging data with the intra-operative mapping data using simulated electroanatomical mapping data using the great cardiac vessels including the aorta, superior vena cava, and coronary sinus. Based on these in vitro results, we focus on a registration strategy which is constrained by the ascending and descending aorta. In vivo prospective evaluation of the resulting image integration was then performed (n>200) in both experimental and clinical electrophysiology procedure. To compensate for residual error following registration or patient movement during a procedure, we present and evaluate warping strategies for deforming the pre-operative imaging data into agreement with the intra-operative mapping information. / by Zachary John Malchano. / M.Eng.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaf [39]). / Introduction: In the medical device space, a large proportion of the breakthrough inventions are developed by small firms that use private equity to bring their technologies from concept to varying stages of development. Medical Device companies spend a large proportion (11.4 % in 2002) of their sales on R&D, second only to Pharmaceutical companies. Smaller companies, in the meanwhile, spent 343 % of their sales in the same year'. [The Lewin Group (AdvaMed), 2004]. Private Equity financing is a critical factor that enables small start-ups to develop new technologies without a viable revenue stream to support the necessary R&D expenditure. In the medical device space, it has been noted that Venture Capital firms (VC's) use high risk capital to invest in early stage companies, and look for "exits" through either an Initial Public Offering (IPO) or through the sale of the start-up to an established firm. Corporations are also involved in varying degrees in early venture investments, through what is sometimes called Corporate Venture Capital (CVC), mainly for strategic reasons. Through CVC investments, some corporations hope, that as an insider, they would be able to judge better whether a particular company is a good target for acquisition. In this paper I review the exits through acquisition, from the perspective of venture backed start-ups, and hypothesize that factors related to the nature of investors, the type of investment, the impact of capital markets and the Intellectual Property of the company are associated with a higher exit valuation. / Ganesh R. Nair. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / "June 2007." / Includes bibliographical references (leaves 153-157). / A classic finding in asthma is a change in the structural organization of the airway epithelium. This complex process known as airway remodeling is not fully understood, and we believe that the forces accompanying airway constriction activate the epithelium and contribute to airway remodeling. To better understand this mechanotransduction mechanism we used an in vitro system of cultured normal human bronchial epithelial cells that could simulate compressive stresses experienced by the epithelium during bronchoconstriction. The application of a transcellular pressure gradient (10-50cmH20) for 10 minutes resulted in transient activation of the epidermal growth factor receptor (EGFR) - MAP kinase (ERK) signaling pathway. Furthermore, specialized real-time high-speed imaging revealed an exponential decrease in the volume of the compliant lateral intercellular space (LIS) separating neighboring cells. The measured LIS volume collapse curves were directly inputted into 2-D and 3-D numerical finite element models, whose output was EGFR-ligand concentration dynamics in the LIS. / (cont.) During the first three minutes under pressure, the calculated increase in ligand concentration (specifically HB-EGF, which is made by the cells and shed into the LIS, thereby constituting an autocrine loop with the EGFR) matched the measured phosphorylated EGFR (pEGFR) dynamics. The model thus provided crucial insight into how an observed change in LIS geometry esulted in activation of the EGFR signaling pathway. This insight, coupled to EGFR signaling models, could one day be applied to the design of novel pharmacogenetic therapeutics aimed at preventing airway over-activation and potentially hindering airway remodeling progression in asthmatic patients. / by Nikola Kojić. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / 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. 51-54). / Background: If we are to successfully treat cancer, we must understand the biologic underpinnings in conjunction with early diagnosis. Genome-wide expression studies have advanced the research of many cancers. Nevertheless, understanding which genes are expressed in a tumor is not equivalent to knowing which proteins are being produced. Proteomics hold great promise for careful examination of the proteins in complex biologic fluids and tissues, and it may be possible to detect disease from a patient's serum, long before it would otherwise be clinically evident. Although there have been steady advances in all the steps of a proteomic analysis, much remains to be standardized. Because of some high-profile problems with the initial analysis of ovarian cancer proteomic data, early exuberance has now been tempered and replaced by a more methodical approach to these studies. Hypothesis: My hypothesis in this thesis is that proteomics is a valuable tool in the diagnosis and study of cancer, as will be demonstrated in several steps. Methods: First, I describe the current field of proteomics, specifically as it applies to early detection of cancer and biomarker discovery. / (cont.) I lay out the current state-of-the-art technologies for preparing samples and enumerating the proteins in complex fluids and tissues, giving special treatment to the main threats to validity-chance and bias. I also describe the bioinformatic tools necessary for analyzing the large amounts of data produced. Through the example of a mouse model of colorectal carcinoma, I demonstrate the steps involved in a proteomic study, from procuring samples to peptide and protein determination to bioinformatic analysis. Finally, I discuss these findings in light of the proteomic considerations discussed earlier. Results: From this work, I discovered that proteomic profiling can describe the proteins in serum from mice both with and without colon cancer. Furthermore, I developed a naive Bayes classifier that could distinguish between the serum of mice with colorectal carcinoma and their normal litter-mates. Contributions: Through this work, I have contributed the following. I described the field of proteomics with special emphasis on cancer biomarker discovery and early detection. I enumerated the challenges and pitfalls to developing early detection schemes for cancer based on high-dimensional proteomic analyses. / (cont.) I described a set of experiments on mice harboring a gene mutation that predisposes them to colorectal carcinoma. I detailed the bioinformatic analysis of this data, including the development of a naive Bayes classifier to differentiate the cancerous state from the normal state. Finally, I discussed the caveats of the current work, in reference to the initial discussion on the challenges and pitfalls of early detection schemes and cancer biomarker discovery. / by Samuel Louis Volchenboum. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 38-39). / The task of gathering detailed patient information from narrative clinical text presents a significant barrier to clinical research. A prototype information extraction system was developed to extract pre-specified findings from narrative echocardiogram reports. The system which uses a Unified Medical Language System compatible architecture is very simple and takes advantage of canonical language use patterns to identify sentence templates with which concepts and their values can be identified. The data extracted from this system will be used to enrich an existing database used by clinical researchers in a large university healthcare system to identify potential research candidates fulfilling clinical inclusion criteria. The system was developed and evaluated using ten pre-determined clinical concepts. Concept-value pairs extracted by the system related to these ten conditions were compared with findings extracted manually by the author. The system was able to recall 78% of the relevant findings (CI, 76% to 80%), with a precision of 99% (CI, 98%-99%). Because data acquired from the system will ultimately be used in document and patient retrieval, preliminary analysis was done to evaluate document retrieval effectiveness. Median recall across the ten conditions was 36% (range, 0% to 93%). The system retrieved no documents for two of the ten conditions; median precision for the remaining eight conditions was 100% (range, 92% to 100%). / by Jeanhee Chung. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1999. / Includes bibliographical references. / Age-related vertebral fractures are a common public health problem for the elderly with an estimated 27 percent of U.S. women aged 65 years and over thought to have at least one vertebral fracture. It is important, therefore, to characterize the "at risk" patient and to find methods of reducing that risk. Fracture risk has been defined as the ratio of applied loads to the force required to fracture a bone. Although studies have examined the force required to fracture, few studies have tried to assess the applied loads associated with fractures. Epidemiological studies have found that as many as 30 to 50 percent of vertebral fractures are associated with falls. This work examines the forces on the spine during a backward fall. Models of a passive fall, without tension in the torso musculature, were constructed in order to examine the peak axial forces on the spine as a result of a passive fall. Muscle tension elements were added to examine the effect of pre-compression of the spine by the musculature. Three experimental and observational studies were performed to examine the input parameters of these models. This included an experimental measurement of the stiffness and damping of the spine segments, measurement and modeling of the fall dynamics in a backward fall, and measurement of the geometry of the torso musculature. The peak axial forces on the spine were found to range from 1100 Newtons to 3500 Newtons depending on a number of factors including the fall impact dynamics (fall velocity and torso angle), the body weight of the individual, the properties of the soft tissue of the pelvis and spine, and the amount of muscle tension in the torso musculature. These forces can be compared to a mean compressive failure force around 2000 N in elderly thoracolumbar vertebrae. This puts a portion of the elderly population at risk for a fracture simply from an upright passive fall of average velocity. The highest forces were found in upright, fast falls in which the individual had a high upper body weight and very tense torso musculature and little damping in the spine. / by Sara E. Wilson. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (p. 286-290). / by Kelly Lynn Poort. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 61-64). / Genetic testing companies have come under fire lately for an array of reasons. Many direct-to-consumer outfits are being challenged by the federal regulatory authorities, by the physicians' community and by the public itself. The desire to derive utility from the existing mass of genetic research is only outpaced by the sheer amount of new information being added to our understanding daily. These genetic testing companies are simultaneously trying to apply the existing knowledge, build a base for further study and be credible, going concerns from a business perspective. It is a worthy but difficult objective. The direct-to-consumer genetic initiatives face resistance from physicians who are the traditional intermediaries between medical insight and application of this insight. The companies also face a strong adversary in a government that wants to protect its constituents from fraudulent marketing claims and misinformation. Recent, informal studies have also exposed flaws in the product offerings and delivery of information by these companies. Finally, these are all for-profit entities which are struggling to become profitable. The objective of this thesis is to identify an attractive consumer base and opportunity that would allow for successful deployment of genetic diagnostic capability. I postulate that the success of a direct-to-consumer company would depend on finding a customer that values the genetic insight deeply and is able to take action from such insight. Based on those two fundamental criteria-perceived value and actionable utility-I build a profile of place, person and disease to test my hypothesis. Driven by the findings of my research, I anchored my hypothesis around an Indian consumer who pays for health care out-of-pocket, is vulnerable to certain genetic diseases due to narrow, endogamous customs and has grown up in a culture of arranged marriages. If this individual's religious and moral code forbids early termination of pregnancy or if financial and logistical circumstances make abortion impossible, I posit the desire for this cohort to use pre-marital genetic testing will increase. My research showed that people born in India and people who had considered arranged marriage as a viable option (the two groups overlapped but not completely) did display a greater likelihood of using genetic tests at the pre-marital and pre-natal stage to make informed decisions about family planning. These groups also showed a greater inclination towards early termination of pregnancy as well as reconsidering partner choice based on the outcome of genetic testing. However, the data also showed that those groups that did not believe in abortion still did not preferentially want a pre-marital genetic test. / by Ridhi Tariyal. / S.M.

Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 75-76). / While much is known about the process of how airborne sound is conducted to the inner-ear via the outer ear and middle ear, so-called air conduction (AC), the mechanisms by which vibrations of the head and body, so-called bone conduction (BC), produce an auditory response are not well understood. It is clear that the inner ear is the sensory site of auditory stimulation by bone conduction, and that the resultant activation of the inner ear has many features in common with air-conduction stimulation; however, bone conduction is known to stimulate the inner ear through multiple pathways. The relative significance and frequency dependence of these different pathways have not been well defined. Our previous work on bone conduction in chinchillas suggested inner-ear mechanisms are the dominant sources in BC. This thesis builds upon the early work by investigating inner ear mechanisms with stapes fixation and ear canal occlusion. Results of stapes fixation show a decrease in scala vestibuli sound pressure Psv and little change in scala tympani sound pressure PST in bone conduction. Ear canal occlusion produces an increase in ear canal sound pressure PEC with a similar amount of increase in Psv, but almost no change in Pst. We attributed the differences in the change between Psv and PST in bone conduction after these manipulations to the existence of compressible cochlear structures or third window pathways, e.g. the cochlear aqueduct. While ear canal compression and middle ear inertia sources may contribute to the total bone conduction response (a 10 dB decrease in Psv after middle ear interruption and stapes fixation, and a 10 dB increase after ear canal occlusion), inner ear mechanisms are still the most significant sources in bone conduction because the changes in Psv and Pst in BC are much smaller than the changes in AC. / by David Chhan. / S.M.