Access to vaccine technologies in developing countries: Brazil and India

This study, conducted by visits, interviews, and literature search, analyzes how vaccine manufacturers in Brazil and India access technologies for innovative vaccines: through collaborations with academia and research institutions, technology transfer agreements with multinational corporations, public sector, or developing country organizations, or by importation and finishing of bulk products. Each has advantages and disadvantages in terms of speed, market, and ability to independently produce the product. Most manufacturers visited are very concerned about avoiding patent infringement, which might result in undeveloped or delayed products because of a lack of mastery of the patent landscape. Disregarding the patent picture could also threaten the market of a potential product. Although it is too soon to assess the effects of TRIPS on vaccine technology access in Brazil and India, a good understanding of intellectual property management will be useful. A case study on development of a new combination vaccine illustrates these findings.

Optimization of the treatment of hydrocephalus by the non-invasive measurement of the intra-cranial pressure

Alec Ginggen

This thesis work aims to optimize the treatment of hydrocephalus. It consists of two distinct objectives: the optimization of the diagnosis of patients implanted with a shunt system for the derivation of cerebro-spinal fluid (CSF) and the optimization of the treatment by a better understanding of the fluidic characteristics of shunts. The diagnosis optimization was addressed by a pressure sensor allowing for the measurement of the intra-cranial pressure (ICP). It has been characterized experimentally in vitro and in vivo in animals. The pressure sensor is integrated along a shunt system for the derivation of CSF and it can be interrogated by telemetry. The non-invasive access to the ICP will allow the physician to verify that the implantation of a shunt system has successfully restored a physiological ICP level. It will also provide a method to verify that the shunt is not blocked and fully functional. Simple mathematical models of the hydrodynamics of shunt systems used clinically are presented to address the second objective. These simple models are verified experimentally by characterizing the shunts on a setup developed for that purpose. This setup allows the characterization of non-bijective flow-pressure characteristics. The integration of mathematical models of shunt systems in a broader model describing the circulation of CSF in a patient implanted with a shunt will permit to predict the dynamics of the CSF circulation. It will also be a useful tool for shunt manufacturers to identify shunt characteristics critical to successfully restore a physiological condition after implantation. The results of this thesis work are presented in the form of an introduction, three scientific publications and a short conclusion. The motivations for the thesis work are presented in the introduction chapter along with background information about hydrocephalus and its treatment. A mathematical model describing the circulation of CSF is described in the same chapter. This model illustrates the interactions between the fluidic constituents of the cranial vault that lead to a physiological CSF circulation and ICP level. This model has been adapted to account for the implantation of a shunt system. The key technical characteristics of the pressure sensor are exposed in the subsequent section along with the experimental techniques and a short summary of the publications and patents. The pressure sensor is described in the first publication with a focus on the pressure transducer, the original sensor encapsulation technique, the electronics embedded in the sensor and the telemetry technique. A capacitive pressure transducer, which provides an accurate measurement of the absolute pressure, has been developed. The transducer technology guarantees a minimal drift of its characteristics with time. The design and the key manufacturing steps of the transducer are exposed. A hermetically closed capsule protects the sensor electronics. The effect of the packaging components and the assembly techniques on the sensor characteristics are analyzed. An analysis of the water diffusion through the walls of the capsule is presented since resistance to water permeation is a critical characteristics of the packaging. Minimal drift with time can only be achieved if the atmosphere in the capsule is extremely stable. The packaging provides a barrier to water diffusion in order to keep a constant low humidity level in the sensor. The telemetric link between the sensor and the external reading unit is provided by an inductive coupling between two loop antennas. The coupling allows the simultaneous transmission of power to the sensor and of the pressure data to the external unit. The fundamental characteristics of the telemetric link are described. The interfacing electronic components are integrated in an ASIC that consumes a minimal amount of energy. Lastly, the experimental characterization of the accuracy of the sensor and its thermal stability are presented. The second publication is focused on the in vivo characterization of the pressure sensor in animals. An animal model of hydrocephalus has been developed in order to characterize the correlation between the pressure measured by the sensor integrated into a shunt system and a reference provided by a direct measurement of the ICP in the ventricles of the brain. Hydrocephalus was induced in dogs by injection of kaolin and glue in the cisterna magna. The time course of hydrocephalus induction was followed by the measurement of the size of the ventricles by an ultrasonic imaging technique. Approximately 50 days after the injection of kaolin and glue, a shunt system integrating a pressure sensor was implanted between the brain ventricles and the peritoneum. A reference pressure sensor was also implanted in the ventricles. The pressure was then measured for up to 48 hours. The correlation between the pressure in the shunt and the intra-ventricular pressure is documented in the publication. The advantages associated with the measurement of the pressure in the shunt versus an intra-ventricular measurement technique are discussed and the pressure sensor is compared with other published sensors. The third publication describes three commonly used shunt systems by simple hydrodynamic mathematical models. A setup allowing the characterization of shunt systems having a non-bijective pressure-flow characteristics is presented. The experimental characteristics of the three shunt systems is compared to the theoretical models. The "pressure-controlled" and "flow-controlled" terminologies, which are frequently used in the clinical field, are discussed in the context of the hydrodynamic characteristics of shunts. Four patent applications have been submitted in the course of this thesis work. The three first applications have been granted, and the last one is filed. The first patent protects the pressure sensor encapsulation technique. The second patent protects the concept of a shunt system allowing the non-invasive adjustment of the resistance of the shunt valve. This concept has been developed as a result of the analysis of the critical parameters to successfully restore a physiological ICP level by the mathematical model of the CSF circulation. The third patent protects the use of the pressure sensor packaging technique for a flow sensor integrated in the shunt system. The last application protects the mechanism that regulates the power of the radio-frequency wave emitted by the external reading unit on the basis of the voltage induced in the sensor. The last chapter, entitled "Conclusion and Perspectives" summarizes the outcome of this thesis work in reference to the optimization of the treatment of hydrocephalus. This work laid the foundation for the use of the sensor in humans through a clinical study. The ICP data gathered during such a study would then allow the validation of the mathematical model of CSF circulation presented in this thesis.

EPFL2007

The sources of process innovation in user firms

Marcellus Bogers

Previous research has shown that innovation can have various sources and different forms. Innovation can thus be developed by different types of organizations or individuals for several reasons, and it can be related to product or process technologies. One particular stream of research has explored the role of users as a source of innovation. Examples of user innovations can be found in a variety of fields and settings such as mountain biking, snowboarding, open source software, scientific instruments, oil refining, semiconductor manufacturing, and even the World Wide Web. What these innovations have in common is that they were all initially developed by people or organizations that wanted to solve a specific need and benefited from using their innovation rather than selling it. A particular type of user innovator is a "user firm" which develops new or improved production technology for its own internal use. Such process innovation is characterized by determinants and outcomes, which are fundamentally different from for example product innovation. In particular, process innovation may be driven by learning-by-doing, which is a form of problem-solving or experimentation that takes place on the production floor rather than in research and development (R&D). However, the exact drivers and consequences of process innovation in general and learning-by-doing in particular are not yet fully explored. Therefore, the objective of this thesis is to increase the understanding of the antecedents and impact of process innovation in user firms by exploring the role of non-R&D activities and learning-by-doing. This thesis consists of four parts. Each of them addresses a specific aspect related to the sources of process innovation in user firms. The first paper particularly argues that process innovation relies on different learning mechanisms than product innovation. Using data from the Swiss Innovation Survey of the Swiss Institute of Business Cycle Research (KOF) at ETH Zürich, the paper shows which are the external and internal knowledge sources (related to R&D, manufacturing and marketing) that lead to innovation. The second paper further investigates R&D and non-R&D activities as sources of innovation and develops two measures to quantify the magnitude of non-R&D innovation. The results show that a substantial part of the firms develop innovations without R&D and that non-R&D process innovation has a very large impact on the overall cost reductions in the Swiss economy. In order to better understand the sources and attributes of process innovation in user firms, a questionnaire was conducted in a sample of Swiss manufacturing firms. Based on the results, the third paper shows the pervasiveness of major and especially minor process innovation. It also explores the sources of process innovation within the firms and identifies the practices related to the accounting, protection, appropriation, and monitoring of process innovation, which are often of an informal nature. The fourth paper investigates in more detail how such practices drive learning-by-doing and process innovation. The findings firstly show which complementary systems of practices are implemented in user firms to promote the innovative contribution of production floor workers and secondly how these practices drive learning-by-doing for either major or minor process innovation.

EPFL2009

Active origami platforms for human-robot interactions

Frédéric Henri Vaskin Giraud

Robots are employed to assist humans in lengthy, challenging, and repetitive tasks. However, the fields of rehabilitation, haptics, and assistive robotics have shown a significant need to support and interact with people in their everyday life. To facilitate these further needs, robots must overcome constraints in compactness, degrees of freedom (DoF), and mechanical performance. However, developing a robot with these characteristics is challenging for conventional mechanics. First, creating a meso-scale device requires the assembly of small components, which is laborious and increases manufacturing cost, time, and complexity. In addition, devices with several DoF and functionalities also require more parts to create numerous links and joints, actuators, and thus space, affecting the compactness of systems. Finally, aiming for mechanical performance in terms of force, speed, and motion range requires transmissions or bulky actuators, which also influence the size of the system. This thesis attempts to overcome the limitations of conventional mechanics by using origami robots, an alternative design approach for creating meso-scale structures with numerous folding joints. It consists in stacking layers of functional material to achieve low-profile and scalable structures that fold into 3D. Using this method, we developed three hybrid robots combining the decades of experience of conventional mechanics with the advantages of origami robotics. First, to enhance the performances of robots at the meso-scale, the creation of compact low-profile compliant transmissions benefiting from origami's minimal assembly of functional layers was explored. The transmissions obtained can reproduce conventional kinematics or generate unconventional motions using materials properties. Second, the development of multi-DoF compact robots was studied using the aforementioned low-profile compliant transmissions to create a multi-functional structure. The resulting robot is a fingertip haptic device called Haptigami that can render vibrotactile and three-DoF force feedback without compromising bulkiness. Then, this study aimed at creating a meso-scale, multi-DoF, and mechanically efficient robot. We combined the previous device contributions and developed Flexure Variable Stiffness Actuators (F-VSA), a novel compliant actuator that uses the origami flexure hinges' inherent stiffness to avoid hindering mechanical simplicity. Finally, we developed a software architecture that enables high-level control of the human-robot hardware and is compatible with multiple simulation engines. We used this architecture to control our robots and provide feedback to the user, based on interactions in a virtual environment. These novel robots rely on non-conventional structures, actuators, and kinematics that require exploring and testing suitable control strategies. Hence, kinematic and stiffness models were developed and used to tune the position, force, and stiffness of the end-effector. Several characterization platforms and experimental protocols suitable for testing our unique robotic systems were also developed to assess their precision and efficiency. Consequently, the results of this study pave the way for the development of robots that adapt to multiple environments, interactions, and application scenarios, compatible with the human bandwidth without hindering the user's motion and comfort in everyday life.

EPFL2022