Product Development Resilience Through Set-Based Design

Often during a system Product Development program external factors or requirements change, forcing system design change. This uncertainty adversely affects program outcome, adding to development time and cost, production cost, and compromise to system performance. We present a development approach that minimizes the impacts, by considering the possibility of changes in the external factors and the implications of mid-course design changes. The approach considers the set of alternative designs and the burdens of a mid-course change from one design to another in determining the relative value of a specific design. The approach considers and plans parallel development of alternative designs with progressive selection of options, including time-versus-cost tradeoffs and the impact change-costs. The approach includes a framework of the development process that addresses design and integration lead-times, and their relationship to the time-order of design decisions, and the time-dependent burden of design changes

Generalized harmonic modeling technique for 2D electromagnetic problems : applied to the design of a direct-drive active suspension system

The introduction of permanent magnets has significantly improved the performance and efficiency of advanced actuation systems. The demand for these systems in the industry is increasing and the specifications are becoming more challenging. Accurate and fast modeling of the electromagnetic phenomena is therefore required during the design stage to allow for multi-objective optimization of various topologies. This thesis presents a generalized technique to design and analyze 2D electromagnetic problems based on harmonic modeling. Therefore, the prior art is extended and unified to create a methodology which can be applied to almost any problem in the Cartesian, polar and axisymmetric coordinate system. This generalization allows for the automatic solving of complicated boundary value problems within a very short computation time. This method can be applied to a broad class of classical machines, however, more advanced and complex electromagnetic actuation systems can be designed or analyzed as well. The newly developed framework, based on the generalized harmonic modeling technique, is extensively demonstrated on slotted tubular permanent magnet actuators. As such, numerous tubular topologies, magnetization and winding configurations are analyzed. Additionally, force profiles, emf waveforms and synchronous inductances are accurately predicted. The results are within approximately 5 % of the non-linear finite element analysis including the slotted stator effects. A unique passive damping solution is integrated within the tubular permanent magnet actuator using eddy current damping. This is achieved by inserting conductive rings in the stator slot openings to provide a passive damping force without compromising the tubular actuator’s performance. This novel idea of integrating conductive rings is secured in a patent. A method to calculate the damping ratio due to these conductive rings is presented where the position, velocity and temperature dependencies are shown. The developed framework is applied to the design and optimization of a directdrive electromagnetic active suspension system for passenger cars. This innovative solution is an alternative for currently applied active hydraulic or pneumatic suspension systems for improvement of the comfort and handling of a vehicle. The electromagnetic system provides an improved bandwidth which is typically 20 times higher together with a power consumption which is approximately five times lower. As such, the proposed system eliminates two of the major drawbacks that prevented the widespread commercial breakthrough of active suspension systems. The direct-drive electromagnetic suspension system is composed of a coil spring in parallel with a tubular permanent magnet actuator with integrated eddy current damping. The coil spring supports the sprung mass while the tubular actuator either consumes, by applying direct-drive vertical forces, or regenerates energy. The applied tubular actuator is designed using a non-linear constrained optimization algorithm in combination with the developed analytical framework. This ensured the design with the highest force density together with low power consumption. In case of a power breakdown, the integrated eddy current damping in the slot openings of this tubular actuator, together with the passive coil spring, creates a passive suspension system to guarantee fail-safe operation. To validate the performance of the novel proof-of-concept electromagnetic suspension system, a prototype is constructed and a full-scale quarter car test setup is developed which mimics the vehicle corner of a BMW 530i. Consequently, controllers are designed for the active suspension strut for improvement of either comfort or handling. Finally, the suspension system is installed as a front suspension in a BMW 530i test vehicle. Both the extensive experimental laboratory and on-road tests prove the capability of the novel direct-drive electromagnetic active suspension system. Furthermore, it demonstrates the applicability of the developed modeling technique for design and optimization of electromagnetic actuators and devices

Generalized harmonic modeling technique for 2D electromagnetic problems : applied to the design of a direct-drive active suspension system

The introduction of permanent magnets has significantly improved the performance and efficiency of advanced actuation systems. The demand for these systems in the industry is increasing and the specifications are becoming more challenging. Accurate and fast modeling of the electromagnetic phenomena is therefore required during the design stage to allow for multi-objective optimization of various topologies. This thesis presents a generalized technique to design and analyze 2D electromagnetic problems based on harmonic modeling. Therefore, the prior art is extended and unified to create a methodology which can be applied to almost any problem in the Cartesian, polar and axisymmetric coordinate system. This generalization allows for the automatic solving of complicated boundary value problems within a very short computation time. This method can be applied to a broad class of classical machines, however, more advanced and complex electromagnetic actuation systems can be designed or analyzed as well. The newly developed framework, based on the generalized harmonic modeling technique, is extensively demonstrated on slotted tubular permanent magnet actuators. As such, numerous tubular topologies, magnetization and winding configurations are analyzed. Additionally, force profiles, emf waveforms and synchronous inductances are accurately predicted. The results are within approximately 5 % of the non-linear finite element analysis including the slotted stator effects. A unique passive damping solution is integrated within the tubular permanent magnet actuator using eddy current damping. This is achieved by inserting conductive rings in the stator slot openings to provide a passive damping force without compromising the tubular actuator’s performance. This novel idea of integrating conductive rings is secured in a patent. A method to calculate the damping ratio due to these conductive rings is presented where the position, velocity and temperature dependencies are shown. The developed framework is applied to the design and optimization of a directdrive electromagnetic active suspension system for passenger cars. This innovative solution is an alternative for currently applied active hydraulic or pneumatic suspension systems for improvement of the comfort and handling of a vehicle. The electromagnetic system provides an improved bandwidth which is typically 20 times higher together with a power consumption which is approximately five times lower. As such, the proposed system eliminates two of the major drawbacks that prevented the widespread commercial breakthrough of active suspension systems. The direct-drive electromagnetic suspension system is composed of a coil spring in parallel with a tubular permanent magnet actuator with integrated eddy current damping. The coil spring supports the sprung mass while the tubular actuator either consumes, by applying direct-drive vertical forces, or regenerates energy. The applied tubular actuator is designed using a non-linear constrained optimization algorithm in combination with the developed analytical framework. This ensured the design with the highest force density together with low power consumption. In case of a power breakdown, the integrated eddy current damping in the slot openings of this tubular actuator, together with the passive coil spring, creates a passive suspension system to guarantee fail-safe operation. To validate the performance of the novel proof-of-concept electromagnetic suspension system, a prototype is constructed and a full-scale quarter car test setup is developed which mimics the vehicle corner of a BMW 530i. Consequently, controllers are designed for the active suspension strut for improvement of either comfort or handling. Finally, the suspension system is installed as a front suspension in a BMW 530i test vehicle. Both the extensive experimental laboratory and on-road tests prove the capability of the novel direct-drive electromagnetic active suspension system. Furthermore, it demonstrates the applicability of the developed modeling technique for design and optimization of electromagnetic actuators and devices

The Gut Microbiota and the Liver: Collaborators in Host Immunity and Metabolism

The gut microbiota consists of over one hundred trillion commensal bacteria required for proper gut immunity development. Commensals also augment the host’s ability to extract energy from the diet. Although restricted to the gut lumen by intestinal barrier epithelia, commensals shed microbial associated molecule patterns (MAMPs) into the circulation where they augment aspects of systemic immunity. Commensals also release fermentation byproducts into the portal blood stream. Since the liver receives 80% of its blood via the portal vein and contains a unique repertoire of immune cells particularly enriched in Kupffer Cells (KC) and Natural Killer T cells, we proposed that gut-derived MAMPs contribute to the development of residential hepatic leukocyte subsets. Because of the contributions of gut bacteria to digestion, we suspected that gut bacteria add an additional level of regulation to host metabolism and would generate a specific hepatic metabolic gene profile. Results showed that a cocktail of MAMPs translocate into the portal circulation of normal conventional (CL) mice stimulating KC expansion. ICAM1 expression, thought to be constitutive on sinusoidal endothelium, was significantly reduced without gut bacteria and was required for KC accumulation. The finding that constitutive ICAM1 expression by LSEC was dependent on gut bacteria lead us to investigate if the frequency of intra-hepatic lymphocytes known to bind ICAM1 were affected by gut bacteria. Results showed that intra-hepatic T lymphocyte populations including NKT (TCRβ+NK1.1+) cells and T helper (CD4+TCRβ+) cells were significantly reduced in GF mice and AVMN mice. In addition to the significant cellular composition changes of the liver related to gut bacteria density, notable changes in murine weight and metabolic gene profiles were observed. The average body mass of CL, GF, and AVMN mice was 37.8g, 33.4g, and 34.1g respectively. Our whole-liver gene array analysis included 217 probe sets mapped to 163 differentially expressed genes between groups, of which forty-eight have roles in lipid metabolism. In conclusion, gut bacteria affect both the hepatic metabolic gene profile and the inflammatory potential of the liver. These finding have implications for many hepatic pathologies including obesity, NAFLD, and autoimmune disease like PBC and AIH mediated by liver leukocytes

Ly6D+ Siglec-H+ precursor cells contribute to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage

Dendritic cells (DC) are antigen-presenting cells that form an indispensable part of the immune system. While conventional/classical dendritic cells (cDC) are largely involved in orchestrating T cell responses to extracellular pathogens and in anti-tumor immune responses, plasmacytoid dendritic cells (pDC) are the main driver of anti-viral defense through production of large amounts of type I interferons in response to viral infection. The origin and differentiation of these functionally distinct pDC and cDC has been studied extensively in the past decades, but the respective DC ontogeny is still subject to debate. In this study the CD11c+ Siglec-H+ CCR9low DC precursor fraction in murine bone marrow (BM) was studied in detail to unravel the heterogeneity of cells within this compartment and their commitment to cDC and/or alternative pDC fate. In steady state conditions, CD11c+ Siglec-H+ Ly6D+ Zbtb46- CCR9low B220high cells had almost exclusive pDC potential, while CCR9low B220low cells gave rise to pDC as well as cDC in vitro and after adoptive transfer in vivo. I further demonstrated that stimulating these cells with TLR9 agonists and type I interferons increased pDC output while limiting cDC output in vitro by driving pDC maturation and at the same time impeding pre-cDC proliferation and terminal differentiation. Data from single-cell RNA-sequencing of DC related cell populations and multiparameter spectral flow cytometry of steady-state BM and splenic cells of Zbtb46wt/ki mice were analyzed using powerful bioinformatic tools, leading to the discovery of a cDC-committed CD11c+ Siglec-H+ Zbtb46+ Ly6D+ precursor cell population that bridges the gap between CD11c+ Siglec-H+ Ly6D+ lymphoid-derived pDC-biased precursors and pre-cDCs. In vitro and in vivo differentiation assays further showed that cells with this phenotype mark a transitional state between advanced CD11c+ Siglec-H+ CCR9low lymphoid precursors and mature cDCs. The contribution of lymphoid precursors to cDCs may be relevant when cDCs are depleted and their regeneration from myeloid progenitor cells is impaired, such as during severe infections

Immune Activation by Novel Allobaculum Species Reveals Reciprocal Epistasis Among Human Gut Commensals

Gut commensal microbes that elicit human immune responses are noteworthy for their ability to influence both local mucosal inflammation and, more rarely, systemic antibody responses. Here we isolated and characterized novel strains belonging to genus Allobaculum from inflammatory bowel disease (IBD) stool samples. In defined gnotobiotic mouse models we recapitulated the inflammatory effects of Allobaculum sps. and their notable induction of systemic immune responses at baseline. A microbial ecology screen revealed that this taxon is inversely correlated with Akkermansia muciniphila, and co-colonization experiments uncovered microbe-dependent redirection of immune phenotypes, which we term reciprocal epistasis. These immunostimulatory gut commensal strains exemplify the remarkable effects microbial ecology can have upon inflammation and immunity, as well as present a framework for unraveling the complexity of the gut microbiota with more mechanistic insight

Characterizing the Role of the E3 Ligase ITCH in Gut Mucosal Homeostasis

The mucosal barrier of the small intestine is highly dynamic, enabling the passage of nutrients that are necessary for the body’s function while simultaneously preventing a breach by harmful microorganisms that are damaging to the host. The effectiveness of the mucosal barrier is dependent on the cohesive relationship established between the luminal mucosal epithelium and the underlying immune compartment in the small intestine. The epithelium provides the first line of defense against pathogens by establishing a physical barrier separating the external environment from the body’s internal milieu, while the immune system secondarily responds to clear bacteria that have breached the epithelial barrier. The HECT E3 ubiquitin ligase ITCH is known to regulate immune responses, and loss of function of ITCH has been associated with gastrointestinal inflammatory disorders. However, the high level of ITCH expression within the intestinal epithelium suggests that it may have an important function(s) in that tissue for maintaining gut homeostasis. Indeed, we identified that global loss of ITCH (Itcha18H/a18H) in young adult animals influenced intestinal architecture characterized by increases in both crypt and villus area that were more prominent in the distal part of the small intestine. Increased crypt area was found to result from expansion of both the proliferating transit amplifying progenitor population and terminally differentiated Paneth cells. Lack of ITCH also resulted in changes in numbers of goblet cells on the villus. Epithelial cell turnover was also accelerated in Itcha18h/a18H animals, as evidenced by increases in both proliferation and apoptosis within the crypt, as well a more rapid cell migration of bromodeoxyuridine-labeled epithelial cells along the crypt-villus axis. Consistent with the observed enhancement of cellular migration, Itcha18H/a18H mice carrying the Min mutation (Itcha18H/a18H; ApcMin/+) displayed a 76% reduction in tumor burden as compared to ApcMin/+ littermates with normal levels of ITCH. To identify which aspects of these changes were cell autonomous, intestinal organoids were generated from the crypts of ITCH sufficient and ITCH deficient animals. Interestingly, epithelial cell proliferation and differentiation were not perturbed in ITCH deficient organoids, in contrast to the in vivo phenotype of the Itcha18H/a18H small intestines. However, increased cell death was observed in organoids lacking ITCH, which was also consistent with increased cleavedcaspase 3 staining in the intestines of mice lacking ITCH exclusively in the intestinal epithelium. The failure to recapitulate the Itcha18H/a18H epithelial phenotype prompted us to investigate how loss of ITCH in immune cells impacts the intestinal epithelium. Animals lacking ITCH within the myeloid cell lineage have similar defects in crypt area, as well as increases goblet and Paneth cell numbers, as compared to the Itcha18H/a18H animals, albeit delayed. These finding highlight a cell autonomous as well as non-cell autonomous function for ITCH in mediating epithelial homeostasis, and emphasize the importance of ITCH in small intestinal barrier function

The 1981 NASA/ASEE Summer Faculty Fellowship Program: Research reports

Research reports related to spacecraft industry technological advances, requirements, and applications were considered. Some of the topic areas addressed were: (1) Fabrication, evaluation, and use of high performance composites and ceramics, (2) antenna designs, (3) electronics and microcomputer applications and mathematical modeling and programming techniques, (4) design, fabrication, and failure detection methods for structural materials, components, and total systems, and (5) chemical studies of bindary organic mixtures and polymer synthesis. Space environment parameters were also discussed

The role of the innate immune system in microbially induced intestinal inflammation and neoplasia

Inflammatory bowel disease (IBD) is one of the most common immune-mediated diseases in the United States costing the average patient tens of thousands of dollars annually, and greatly diminishing quality-of-life. While there is no universal cure for IBD, recently developed treatments targeting the immunological basis of disease have proven successful in managing clinical symptoms. However, these pharmaceutical therapies such as infliximab (Remicade[registered trademark]) carry several side effects and are not efficacious in all patients. Thus, more selective treatments are needed. One necessary step in the development of such agents is a more precise understanding of which cells in the gastrointestinal tract are primary contributors to the pathogenesis of IBD. We demonstrate that a rare subset of dendritic cells expressing CD8[alpha] is present in significantly different numbers in mouse strains considered susceptible or resistant to a microbially induced model of IBD. Additionally, we show that cells derived from the target organ of susceptible mice prior to and shortly after induction of the disease process are prone to production of greater levels of certain inflammatory mediators including IL-12/23p40, IP-10, RANTES, and TNF-[alpha]. Lastly, we describe the generation of a mouse strain susceptible to the disease model but selectively lacking the subset of dendritic cells expressing CD8[alpha], to be used in future studies. One of the most serious sequela to IBD is colitis-associated colorectal cancer (CAC). Diagnosis of colorectal cancer in general is reliant on tests that suffer from either poor sensitivity or specificity (such as fecal occult blood tests), or invasiveness (such as colonoscopy). Newer genetic tests have been developed for the identification of hereditary risk factors, however CAC follows a molecular pathway distinct from that of familial forms of colorectal cancer. Thus, the development of noninvasive screening assays for CAC with high sensitivity and specificity would increase compliance

Human Mononuclear Phagocyte Kinetics in Health and Inflammation

The mononuclear phagocyte system comprises three types of cells:: monocytes, macrophages and dendritic cells (DC). The kinetics underlying their generation, differentiation and disappearance are critical to understanding how these cells maintain tissue homeostasis as well as orchestrating the immune response. Currently, the circulating kinetics of these cells remain unknown in humans. The kinetic profiles of circulating monocyte subsets (classical, intermediate and non-classical) and DC subsets (pDC, pre-DC, cDC1 and cDC2) were examined in humans for the first time using stable isotope labelling in the form of deuterated glucose. Monocyte subsets appeared sequentially in the circulation which was demonstrated to be due to a developmental relationship between these cells. Pre-DC and cDC appeared prior to monocytes whereas pDC were observed later. After establishing the turnover of circulating mononuclear phagocytes under steady physiological conditions, the kinetics were then examined following experimental human endotoxemia. A temporary loss of circulating mononuclear phagocytes was observed at early time points, classical monocytes were the first to re-appear within the circulation due to an early emergency release from the bone marrow. Finally, in a human model of local inflammation, the infiltrating kinetics of monocyte and DC subsets were examined in the skin. Particularly, pre-DC were observed at higher concentrations compared to the blood which also expressed co-stimulatory molecules (CD80 and CD86). The infiltration of novel cDC2 subsets was also observed. In summary, this thesis illustrates the kinetic and developmental profiles of human mononuclear phagocytes under steady-state and experimental inflammation