A Software Toolchain for Physical System Description and Synthesis, and Applications to Microfluidic Design Automation

Microfluidic circuits are currently designed by hand, using a combination of the designer’s domain knowledge and educated intuition to determine unknown design parameters. As no microfluidic circuit design software exists to assist designers, circuits are typically tested by physically constructing them in silico and performing another design iteration should the prototype fail to operate correctly. Similar to how electronic design automation tools revolutionized the digital circuit design process, so too do microfluidic design packages have the potential to increase productivity for microfluidic circuit designers and allow more complex devices to be designed. Two of the primary software engineering problems to be solved in this space relate to design entry and design synthesis. First, the circuit designer requires a programming language to describe the behaviour and properties of the device they wish to build, and a compiler toolchain to convert this description into a model that can then be processed by other software tools. Second, once such a model is constructed, the remaining portions of the design toolchain must be constructed. It is necessary to implement software that can find unknown design parameters automatically to relieve the designer of much of the complexity that goes into creating such a circuit. Furthermore, automated testing and verification tools must be used to simulate the device and check for correctness and safety requirements before the engineer can have confidence in their design. In this thesis I outline work that has been done towards both of these goals. First, I describe a new programming language that has been developed for the purpose of describing and modelling physical systems, including but not limited to microfluidic circuits. This programming language, called “Manifold”, has been implemented following principles and features of modern functional programming languages, as well as drawing inspiration from VHDL and Verilog, the two industry-standard programming languages for EDA. The Manifold high-level language compiler carries out the process of translating a system description into a domain-agnostic intermediate representation. This representation is then passed to a domain-specific backend compiler which can perform further operations on the design, such as creating simulations, performing verification, and generating appropriate output products. Second, I perform a case study with respect to the creation of such a domain-specific backend for the domain of multi-phase microfluidic circuits. The process involved in taking a circuit description from design entry to device specification has a number of significant steps. I discuss in detail these steps with respect to the design of a multi-way droplet generator circuit. Such a circuit is difficult to design because of the behaviour of the key design parameter, the volume of generated droplets. The design goal is for each droplet generator on the device to produce droplets of a certain specified volume. However, the equation relating the properties of a droplet generator to the predicted droplet volume is complex and contains several nonlinearities, making it very difficult to solve by traditional methods. Recent advances in constraint solvers which can reason about nonlinear equations over real-valued terms make it possible to solve this equation efficiently for a given set of design constraints and goals, and produce many feasible specifications for droplet generators that meet the requirements. Another difficulty in designing these circuits is due to interactions between droplet generators. As the produced droplets have a significant hydrodynamic resistance, they affect the behaviour of the circuit by causing perturbations in the flow rates into the droplet generators. This has the potential to alter the volume of droplets that are being produced. Therefore, a means of regulating or controlling the flow rates must be found. I describe a potential solution in the form of a passive element analogous to a capacitor in an electrical circuit. Once an appropriate value for the capacitor is chosen, it remains to verify that it operates correctly under manufacturing variances in fabrication of the device. To perform this verification, a bounded model checker for real-valued differential equations is employed to demonstrate correctness or discover robustness issues. Furthermore, a simulation file for the MapleSim numerical simulation engine is generated in order to perform whole-design tests for further validation. The sequence in which these steps are performed closely follows the concept of “abstraction refinement” in formal methods, in which successively more detailed models are checked and a failure in one step can invoke a previous step with new information, allowing errors to be caught early and introducing the ability to iterate on the design. I describe such a refinement loop in place in the microfluidics backend that integrates these three steps in a coherent design flow, able to synthesize and verify many specifications for a microfluidic circuit, thereby automating a significant portion of the design process. The combination of the Manifold high-level language and microfluidics backend introduces a new design automation toolchain that demonstrates the effectiveness of constraint solvers in the tasks of design synthesis and verification. Further enhancements to the performance and capabilities of these solvers, as well as to the high-level language and backend, will in the future produce a general-purpose design package for microfluidic circuits that will allow for new, complex designs to be created and checked with confidence

Factories of the Future

Engineering; Industrial engineering; Production engineerin

A microfluidic platform for combinatorial synthesis and optimization of targeted polymeric nanoparticles for cancer therapy

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2013."November 2012." Cataloged from PDF version of thesis.Includes bibliographical references.The use of nanotechnology to engineer drug delivery vehicles comprised of controlled release polymers with targeting molecules has the potential to revolutionize cancer therapy, among other diseases. Although a myriad of nanotherapeutics have been developed at the bench side, many of them stay at the research stage due to their complexity and difficulty in their optimization. A key challenge for optimization of nanoparticles (NPs) for drug delivery is the ability to systematically and combinatorially create and screen libraries of NPs with distinct physicochemical properties, from which promising formulations can be moved forward to preclinical and clinical studies. In this work, the development of a controlled method to synthesize libraries of NPs with distinct properties is described. The procedure uses a microfluidic platform that rapidly mixes reagents and provides homogeneous reaction environments, resulting in the reproducible, single-step synthesis of NPs with well-defined properties and narrow size distributions. The microfluidic system is composed of a mixing unit and a NP assembly unit. The mixing unit consists of a multi-inlet, 2-layer mixer where different precursors such as polymers of different MW and charge, ligand- and drug-conjugated polymers, free drugs, and solvents are mixed at different ratios into a homogenous solution. In the assembly unit, the precursor solution is quickly mixed with an anti-solvent (i.e. water) using 3D hydrodynamic flow focusing where NPs self-assemble after complete mixing. With the microfluidic platform, a library of 100 NPs with different sizes (15-200nm), charge (-30 to +30mV), surface chemistry (i.e. PEG coverage), surface ligand density (0-2.510⁵ ligands/[mu]m²), and drug loading (0-5 w/w%) was producedd in a high-throughput manner by simply varying the flow ratios of precursors entering the system. This library was implemented for (i) screening for formulations (in vitro and in vivo) with optimal clinical properties for cancer treatment and (ii) deepening the understanding of how NP properties affect their biological behavior. The platform developed in this work would likely lead to better understanding of the design parameters for polymeric NPs and their smoother transition to the clinic.by Pedro M. Valencia.Ph.D

An Outlook on Design Technologies for Future Integrated Systems

The economic and social demand for ubiquitous and multifaceted electronic systems-in combination with the unprecedented opportunities provided by the integration of various manufacturing technologies-is paving the way to a new class of heterogeneous integrated systems, with increased performance and connectedness and providing us with gateways to the living world. This paper surveys design requirements and solutions for heterogeneous systems and addresses design technologies for realizing them

Factories of the Future

Engineering; Industrial engineering; Production engineerin

Service-oriented design of microfludic devices

Microfluidics is a relatively new and, with an estimation of the market for these devices exceeding $3 billion in 2014, it is considered a profitable domain. Constant development of new technologies and growing demand for more versatile products cause increasing complexity in this area. To address this, the current trends for the domain include automation, standardisation and customisation. At the same time, the society is moving from product types offering to services. Due to the customisation trend this transition appears beneficial for microfluidics. Taking advantage of these opportunities, an investigation of microfluidic design has been undertaken to address the issues at their origins. The literature review showed a lack of a general design methodology applicable for all microfluidic devices, identified existing approaches as technology driven and the domain as unique in terms of design. Also, it highlighted a number of automation and standardisation attempts in the area. In addition, microfluidics shows limited customer and service-orientation. Meanwhile, an investigation of complexity and its implications in microfluidics narrowed the study to sub-section interactions, which allowed standardisation and automation without compromising customisation. In response to these gaps, an aim of the research is to develop a guideline for service- oriented design of microfluidic devices that can deal with sub-section interactions. This research reviews: existing methodologies for design in micro-scale, their applicability to the domain, microfluidic practitioners’ approach to design, state of service-thinking and services in the area and how sub-section interactions are dealt with for these devices. The developed guideline and design enablers present a proposal for a general process for the design of microfluidics. The solution attempts to tackle the issue of sub- section interactions and brings the domain one step towards an ‘experience economy’ by incorporating service-considerations into the design process. The usefulness of this contribution has been confirmed by a variety of methods and numerous sources including experts in the field.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

PLANNING FOR AUTOMATED OPTICAL MICROMANIPULATION OF BIOLOGICAL CELLS

Optical tweezers (OT) can be viewed as a robot that uses a highly focused laser beam for precise manipulation of biological objects and dielectric beads at micro-scale. Using holographic optical tweezers (HOT) multiple optical traps can be created to allow several operations in parallel. Moreover, due to the non-contact nature of manipulation OT can be potentially integrated with other manipulation techniques (e.g. microfluidics, acoustics, magnetics etc.) to ensure its high throughput. However, biological manipulation using OT suffers from two serious drawbacks: (1) slow manipulation due to manual operation and (2) severe effects on cell viability due to direct exposure of laser. This dissertation explores the problem of autonomous OT based cell manipulation in the light of addressing the two aforementioned limitations. Microfluidic devices are well suited for the study of biological objects because of their high throughput. Integrating microfluidics with OT provides precise position control as well as high throughput. An automated, physics-aware, planning approach is developed for fast transport of cells in OT assisted microfluidic chambers. The heuristic based planner employs a specific cost function for searching over a novel state-action space representation. The effectiveness of the planning algorithm is demonstrated using both simulation and physical experiments in microfluidic-optical tweezers hybrid manipulation setup. An indirect manipulation approach is developed for preventing cells from high intensity laser. Optically trapped inert microspheres are used for manipulating cells indirectly either by gripping or pushing. A novel planning and control approach is devised to automate the indirect manipulation of cells. The planning algorithm takes the motion constraints of the gripper or pushing formation into account to minimize the manipulation time. Two different types of cells (Saccharomyces cerevisiae and Dictyostelium discoideum) are manipulated to demonstrate the effectiveness of the indirect manipulation approach

Novel Network Paradigms: Microfluidic and M2M Communications

The present thesis focuses on two appealing paradigms that are expected to characterize the next generation of communication systems: microfluidic networking and Machine to Machine (M2M) Communications. Concerning the former topic, we show how it is possible to introduce switching and routing mechanism in microfluidic systems. We define some simple mathematical models that capture the macroscopic behavior of droplets in microfluidic networks. Then, we use them to implement a simulator that is able to reproduce the motion and predict the path of droplets in a generic microfluidic system. We validate the simulator and apply it to design a network with bus topology. Finally, we prove the feasibility of attaining molecular communication in this domain by describing a simple protocol that exploits droplets length/interdistance modulation to send information. The research activity on M2M, instead, is aimed at the investigation of two critical issues that are expected to affect Machine-Type Communication (MTC), i.e. energy efficiency and massive access. Regarding energy efficiency, we address the problem of delivering a fixed data payload over a Rayleigh fading wireless channel with the purpose of minimizing the average total energy cost, given by the sum of the transmit energy and an overhead circuit energy, to complete it. This scenario is well suited for uplink cellular MTC in future 5G Internet of Things (IoT) use cases, where the focus is more on device energy efficiency than on throughput. We describe the optimal transmission policies to be used under various coordinated access scenarios with different levels of channel state information and transmitter/receiver capabilities, and show the corresponding theoretical bounds. In the last part of the work, we study the asymptotic performance of uncoordinated access schemes with Multi Packet Reception (MPR) and Successive Interference Cancellation (SIC) techniques for contention resolution at the receiver. The corresponding results in terms of throughput in a massive access M2M scenario are finally evaluated and discussed