Microsystems for Enhanced Control of Cell Behavior

The cell is the most basic functional, structural and biological unit of life as we understand it. Cells are able to perform coherent functions and make up all tissues and organs of all living multicellular organisms; in consequence, there are usually referred to as life’s building blocks. They can replicate independently and contain the hereditary information necessary for regulating cell functions, including growth, metabolism, apoptosis, protein synthesis, movement and replication, for transmitting information to the next generation of cells. As present handbook will focus on the development strategies for biomedical microsystems aimed at interacting with human cells, which constitute our tissues and organs and play a fundamental role in health and disease, it is important to provide a brief introduction to the cell as complex multi-scale and multi-physical/chemical living organism, to its structure and subunits and to its main functions, before focusing on the field of biomedical microsystems. In addition, as tissue repair and tissue engineering are directly connected to stem cells and several chapters of present Handbook will cover development strategies for biodevices linked to tissue engineering, which constitute a very relevant part of the biomedical microsystems designed for interacting at a cellular level, it is very important to provide an introductory note to cell types and to cell differentiation processes. This chapter pretends to serve as introduction to the handbook, as regards the nature, structure and main types and functions of cells.

Biomedical microsystems are reshaping the way researchers and physicians carry out their diagnostic, preventive, therapeutic and surgical tasks and, therefore, impacting Healthcare in a very relevant way. In general, the miniaturization of biomedical devices promotes the speed, sustainability and fiability of diagnostic tasks; prevents damages to surrounding tissues in surgical procedures, hence shortening recovery time; allows for the interaction at a cellular level for a better understanding of biological phenomena and supports advanced research, among other positive aspects. Although the handbook’s core topic is the more specific field of biomedical microsystems for interacting with cells, together with the use of advanced design and manufacturing strategies for their efficient development, it is important to provide a context for such microsystems within the whole ground of biomedical microdevices. This chapter provides a brief introduction to the more relevant types of biomedical microdevices, including microsystems for efficient diagnostic purposes, microsystems for personalized therapeutic purposes, microsystems for minimally invasive surgical procedures and the emerging microsystems for interacting with (and even controlling) cells. Main current research trends are also outlined.

Understanding how cells behave and interact with surrounding cells, tissues, microorganisms and all types of biological, biochemical and biomechanical cues from their environment, constitutes a relevant research challenge and requires the support, not only of advanced manipulation and imaging technologies, but also of specifically designed biomedical microsystems with micrometric and even nanometric details for enabling interactions at a cellular and molecular level. These types of microsystems, together with the use of advanced design and manufacturing strategies for their efficient development, constitute the core topic of present Handbook. Among the biomedical microsystems aimed at interacting with and studying the behavior of cells, it is important to mention the following areas of research and application: microsystems for disease management, microsystems for understanding cell activities, scaffolds for tissue engineering, cell-based sensors and actuators and microsystems for modeling life by controlling cells using microfluidic environments. This chapter provides an introduction to these different types of biomedical microdevices and to the related basic concepts, to which we will get back in subsequent chapters linked to design, manufacturing, biofunctionalization and testing strategies and to the complete development of different cases of studies linked to the aforementioned families of biomedical microdevices. Main current research trends are also outlined.

The detailed study of cell behavior and of the interactions between the cells and with their surrounding environment can be achieved by biomedical microdevices specifically designed to assess and even to control cellular responses, as explained in several chapters of present Handbook. In fact, the development and use of biomedical microsystems capable of interacting with cells and of helping researchers to obtain relevant information from cell behavior and interactions constitutes the central topic of the Handbook. However, for enabling such studies, a set of already common technologies for the micro-manipulation, culture, labelling, monitoring and visualization of cells and their (mutual) interactions are needed. This chapter provides a brief approximation to such technologies, as they are support resources for the developments detailed in forthcoming chapters. The use of supporting software and ad hoc developed programs for the real-time control and for the automated assessment of cell behaviors, on the basis of the images obtained by adequate labelling and visualization, also help to promote the development of more systematic studies for understanding cells and ultimately life.

The application of systematic engineering design methodologies, together with relevant advances in computer-aided design, engineering and manufacturing (CAD-CAE-CAM) technologies, novel materials and micro-/nano-manufacturing resources, have reshaped product development in the last three decades, greatly improving aspects such as time-to-market and overall project costs, as well as final product or device quality and overall performance. These methodological and technological improvements have also a remarkable impact in the development of novel medical devices and all kinds of products in the biomedical field, but very especially in the area of biomedical microsystems for interacting at a cellular and even a molecular level. This chapter is focused on providing a general description of the product development process, but taking into consideration specific aspects for the field of biomedical microsystems. The typical product development stages are covered: (detection of a relevant need, planning and specifications, conceptual design, basic engineering, detailed engineering, production and product market life) and the systematic methodologies commonly applied are also analyzed, providing a historical perspective, together with an overall view of additional methods for ensuring end-quality. The present introduction to modern product development is complemented by the several cases of study included in the Handbook, which have been developed following the proposed steps of systematic procedures. The overview of advanced design, modeling and manufacturing technologies provided in Chaps. 6–10 help to additionally support the methodological aspects of present chapter with very relevant resources used along the Handbook. This chapter constitutes and adapted and improved version of “Chap. 1: Introduction to modern product development”, from Springer’s “Handbook on Advanced Design and Manufacturing Technologies for Medical Devices” also by Andrés Díaz Lantada.

The degree of optimization achieved by biological materials and their very special properties, their hierarchical designs and their multi-scale structures, continue to be great sources of inspiration for engineers and materials scientists world-wide. Fortunately, the development, in the last decades, of advanced computer-aided design, engineering and manufacturing technologies and the groundbreaking manufacturing paradigm consequence of the advent of additive manufacturing technologies, which enable solid free-form fabrication, have provided extremely relevant resources for the development of new knowledge-based multifunctional materials following biomimetic approaches for enhanced performance. This chapter covers some of the new design and manufacturing strategies that promote biomimicry and their advantages will be also put forward by means of several cases of study included in the following chapters, linked to the complete development process of tissue engineering scaffolds, organs-on-chips and other microfluidic biomedical devices benefiting from bioinspired designs. Section 6.1 introduces the term biomaterial and compares it to the concept of biological material, also detailing main differences between synthetic and biological materials, which constitute challenges as well as sources of inspiration for materials scientists and engineers. Sections 6.2 and 6.3 cover different strategies for obtaining biomimetic designs using the information from imaging techniques as principal input, while Sects. 6.4 and 6.5 detail procedures based on direct modeling by means of advanced computer-aided design, recursive and Boolean operations and models based on precise mathematical descriptions of living organisms, tissues and biological structures.

Multidisciplinarity is intrinsic to Biomedical Engineering, as the products, processes and systems of the biomedical industry, aimed at continuously improving the diagnosis, treatment and prevention of pathologies, are normally developed by large teams of physicians, biologists, materials scientists and engineers. In the field of biomedical microsystems (bio-MEMS) for interacting at a cellular and even molecular level, several physical, chemical and biological phenomena are present and an adequate comprehension of the behaviour of such microdevices also requires studying interactions between the microdevices and the surrounding environments at different scale levels. In such complex systems, the use of modeling resources may be a key aspect towards a straightforward and successful development process. As modern (bio)engineering systems usually exploit phenomena at different scales for improving functionalities of traditional systems, linking the different scales and using multi-scale modeling approaches can increase the predictive capability and applicability of modeling to a wide range of applications. In addition, as modern (bio)engineering systems typically involve different areas of Physics and Chemistry, understanding and modeling their behavior requires the use of multi-physical/chemical modeling approaches. Only by being able to describe the behavior of such (bio)engineering systems at different scale levels and taking account of the physical and chemical phenomena involved in their operation, can we benefit from the advantages of (computer-aided) modeling regarding cost saving, reduction of time-to-market and overall understanding of the products, processes and systems under development. This chapter details methods and examples and provides some cases of study linked to the use of multi-scale and multi-physical/chemical modeling approaches in the field of biomedical microsystems for interacting at a cellular and even molecular level, as introduction to procedures used thoroughly along the Handbook.

The applications of microsystems in the biomedical field are indeed remarkable and continuously evolving thanks to recent extraordinary progresses in the area of micromanufacturing technologies, capable of manufacturing devices with details in the typical range of 1–500 μm. As living organisms are made up with cells, whose overall dimensions typically range from 5 to 100 μm, micro-manufactured devices (with details precisely in that range) are very well-suited to interacting at a cellular level for promoting innovative diagnostic and therapeutic approaches. This chapter provides an overview of the more relevant micromanufacturing technologies with special application to the development of advanced micro-medical devices and to the manufacture of rapid prototypes, as several of these manufacturing technologies will be applied thoroughly along the Handbook for the development of different cases of study linked to microfluidic biodevices for disease modeling, to cell culture platforms for understanding cell behavior, to labs-on-chips and organs-on-chips and to tissue engineering scaffolds. The different technologies detailed in present chapter are also illustrated by means of application examples related to the aforementioned types of biomedical microdevices aimed at interacting at a cellular level. The possibility of combining technologies for the promotion of multi-scale and biomimetic approaches is also analyzed in detail and some current research challenges are also discussed.

Surface biofunctionalization techniques are essential resources for improving the biological and biochemical response of several biomedical devices and provide the opportunity of interacting with cells, even at a molecular level, by means of controlling matter in the range of nanometers. Applications of nanomanufacturing technologies, in many cases applied as post-processes, include: the improvement of biocompatibility, the promotion of wear resistance, the incorporation of special tribological (contact) phenomena linked to controlling adhesion, wettability or friction, the incorporation of anti-bacterial properties and the overall improvement of (bio)mechanical properties and aesthetics, among others. This chapter provides an overview of the more relevant nanomanufacturing technologies with special application to the development of advanced micro-medical devices with surface biofunctionalizations for optimal performance, as several of these manufacturing technologies will be applied thoroughly along the Handbook for the development of different cases of study. The different technologies detailed in present chapter are also illustrated by means of different application examples related to enhancing the biological response of different cell culture platforms and tissue engineering scaffolds aimed at interacting at a cellular level. The possibility of combining technologies for the promotion of multi-scale and biomimetic approaches is also analyzed in detail and some current research challenges are also discussed.

The rapid prototyping of biomedical microsystems, which is usually based on additive manufacturing processes, is very well suited for single prototypes with complex geometries, but in many cases inadequate for mass production, due to the excessive cost and time involved, in comparison with replication technologies, such as injection molding and compression molding. In addition, the polymers used in the most precise additive manufacturing technologies, which are based on photo-polymerization processes, are typically toxic or inadequate for biomedical applications, what limits enormously the span of final applications. Exploring cooperative strategies, for taking advantage of the complexity of geometries attainable via rapid prototyping, while also benefiting from the possibility of manufacturing large low-cost series using mass replication techniques, is a relevant industrial need and can be a source of novel procedures for supporting research and innovation in several fields. The issue is of special relevance in biomedical applications, as mass production enables the democratization of Healthcare and helps researchers to carry out more systematic studies for addressing the problems of disease and for finding improved therapeutic solutions. This chapter provides an introduction to the more relevant mass-production technologies with application in the field of biomedical microdevices. Illustrative examples linked to the complete development and mass production of different cell culture platforms and biodevices for studying cell behavior are provided to further analyze the advantages and potentials of using this kind of manufacturing procedures. Main current research trends, linked to the progressive convergence between subtractive and additive manufacturing approaches and to the combined use of technologies for the promotion of multi-scale and biomimetic approaches, are also discussed.

The modern and integrated study of biomechanical and biochemical issues in disease is usually carried out with the fundamental support of fluidic microdevices and of microfluidic diagnostic platforms, as fluids allow for the transport of nutrients, gases, debris, pathogens and drugs to and from cells, help to control the movement of microorganisms in vitro and make the application of controlled stresses in culture systems possible. In consequence, biomimetic responses are promoted and in many cases results obtained in vitro are more accurate than those obtained from animal models. In fact the field of microfluidic systems for diagnosis has experienced an explosive growth in the last two decades, promoted by the convergence of clinical diagnostic techniques, computer-aided modeling and mature micro- and nano-fabrication technologies capable of producing submillimeter-size fluidic channels, reservoirs and nanometric features in several materials, structures and devices. This chapter provides and introduction to the field of biomedical devices for disease study and management, with examples of systems devoted to purposes such as: in vitro drug screening, disease modeling and diagnosis, disease modeling and prediction, and modeling of tumors, among the most important and already well-established applications. The application of computer-aided design and rapid prototyping resources to the complete development of a capillary actuated microfluidic platform, as versatile framework for the potential point-of-care testing of different diseases and their eventual response to different antibiotics, is detailed as additional case of study.

Understanding how cells behave and interact with surrounding cells, tissues, microorganisms and all types of biological, biochemical and biomechanical cues from their environment, constitutes a relevant research challenge and requires the support, not only of advanced manipulation and imaging technologies, but also of specifically designed biomedical microsystems with micrometric and even nanometric details for enabling interactions at a cellular and molecular level. These types of microsystems, together with the use of advanced design and manufacturing strategies for their efficient development, constitute the core topic of present Handbook. Biomedical microsystems aimed at interacting with and studying the behavior of cells, include: dishes for 2D culture, microsystems for studying cells under chemical gradients, electrophoretic microsystems, multi-culture platforms and devices for cell co-culture and dynamic bioreactors or cell culture platforms. This chapter provides an introduction to these different types of biomedical microdevices, illustrating them by means of different cases of study. Main current research trends are also outlined. Other emerging and possibly more complex microsystems for interacting with cells and controlling their behavior and fate, even with the potential of constructing whole tissues and organs from cultured cells, are covered in depth in Chaps. 13–23.

The fact that cellular development and fate is very dependent, not just of the biochemical signals of the environment and of their own genetic background, but also of the mechanical properties and mechanical stimuli acting within the extra cellular matrix, has promoted the birth of a new field of science and technology at the interface of biology and engineering, that of mechanobiology. Such novel field focuses on the way that physical forces, stresses and strains, and changes in cell or tissue mechanics contribute to tissue development, to the success of physiological interactions and even to the appearance of disease. A major challenge in the field is linked to understanding the complex mechanisms by which cells sense and respond to mechanical signals: the mechanotransduction properties of cells. Although completely understanding how cells respond to mechanical stimuli and learning about their mechano-sensitive properties and about the mechanical forces they can develop is a complex task, the use of biomedical microdevices with controlled microstructures and microtextures can be a useful strategy for the progressive comprehension of single and collective cell behavior. This chapter provides some introductory examples of microsystems developed for generating knowledge for the field of mechanobiology. The cases of study include cell culture platforms for obtaining different types of cell aggregations, biomedical microsystems for studying the impact of surface texture on cell behavior and some final textured surfaces with details reaching nanometric details.

Cells and tissues respond to several mechanical properties and mechanical stimuli of their extra cellular matrix and surrounding environment, as well as to gradients of them, including Young’s modulus, surface topography, hardness, presence of vibrations, among other external influences studied in the evolving field of cell mechanobiology. Interestingly, clear differences are perceived between cell culture processes carried out in static and dynamic conditions and even cell differentiation and fate can be controlled by means of such dynamic cultures. The use of fluid flows for the generation of dynamic culture conditions is common, as detailed in the chapters devoted to labs-on-chips and organs-on-chips. Here we focus on the use of mechanical vibrations for the promotion of dynamic cell culture processes and detail main challenges linked to producing such types of actuations upon devices with micrometric features. Issues linked to the design, modeling, manufacture and testing of microdevices for achieving resonant behaviors for dynamic cell cultures are detailed. The difficulties of using micro-resonators working at MHz frequencies, especially regarding experimental validation, are detailed and some proposals for successful results and further research are provided.

Even though pioneer studies in the field of tissue engineering, either for disease study or for tissue repair, were performed on flat 2D substrates (normally Petri dishes), more recent research has helped to highlight the relevance of three-dimensional systems in cell culture. In fact, even one-dimensional patterns upon have been found more adequate, for mimicking actual cell migration in three-dimensional environments, than conventional two-dimensional scaffolds for cell culture, what puts forward the need for alternative development procedures aiming at a more adequate reproduction of the 3D environment, taking account of both biochemical and biomechanical approaches. The combined employment of computer-aided design, engineering and manufacturing resources, together with rapid prototyping procedures, working on the basis of additive manufacturing approaches, allows for the efficient development of knowledge-based functionally graded scaffolds for effective and biomimetic three-dimensional cell culture in a wide range of materials. Applications of such tissue engineering scaffolds for cell culture include the repair, regeneration and even biofabrication of hard tissues, soft tissues and osteochondral constructs, as well as the modeling of disease development and management, as detailed in forthcoming chapters. In this chapter we present some design and manufacturing strategies for the development of knowledge-based functionally graded tissue engineering scaffolds aimed at different types of tissues. We also detail some prototyping approaches towards low-cost rapid prototyped scaffolds and tumor growth models, as cases of study for illustrating the complete development process of these types of medical devices.

Hard tissue repair is a very relevant and challenging area for the emerging fields of tissue engineering and biofabrication due to the very complex three-dimensional structure of bones, which typically include important variations of porosities and related mechanical properties. The need of porous and rigid extra cellular matrices, of structural integrity, of functional gradients of mechanical properties and density, among other requirements, has led to the development of several families of biomaterials and scaffolds for the repair and regeneration of hard tissues, although a perfect solution has not yet been found. Further research is needed to address the advantages of different technologies and materials for manufacturing enhanced, even personalized, scaffolds for tissue engineering studies and extra cellular matrices with outer geometries defined as implants for tissue repair, as the niche composition and 3D structure play an important role in stem cells state and fate. The combined employment of computer-aided design, engineering and manufacturing (also CAD-CAE-CAM) resources, together with rapid prototyping procedures, working on the basis of additive manufacturing approaches, allows for the efficient development of knowledge-based functionally graded scaffolds for hard tissue repair in a wide range of materials and following biomimetic approaches. In this chapter we present some design and manufacturing strategies for the development of knowledge-based functionally graded tissue engineering scaffolds aimed at hard tissue repair. A complete case of study, linked to the development of a scaffold for tibial repair is also detailed to illustrate the proposed strategies.

Medical implants for bone repair are starting to benefit from advanced design and (micro-)manufacturing technologies that promote a precise control of final geometries and allow for the incorporation of design-controlled and in some cases personalized features for enhanced interaction at a cellular level. Recent advances in additive manufacturing technologies and available materials support solid free-form design and fabrication approaches, hence helping with device personalization and enabling a real 3D control of device geometry. Furthermore, the vast knowledge generated during last decades in the field of tissue engineering can be used as a source for redesigning all types of implants, pursuing improved biomechanical and biomimetic solutions, especially in the area of bone repair. Hybridizations between conventional compact bone implants and trabecular tissue engineering scaffolds can help to adjust the mechanical performance of bone repair solutions to that of real bone, thus promoting long-term stability and preventing bone resorption thanks to a more adequate stress distribution in service. The increased surface to volume ratio of such lattice or trabecular implants, based on the tissue engineering scaffold concept, helps with cellular attachment to the implant, improves cell motility due to the presence of irregularities that help them to “crawl”, enhances osseointegration in the case of implants aimed at bone repair and promotes drug incorporation for disease prevention. The potential of dental scaffolds for the in vitro development of artificial teeth is also remarkable. The general aspects and main design and manufacturing strategies linked to these advanced scaffold-based implants for bone repair have been introduced in previous chapter. Here we focus on the area of dental implants, detailing novel concepts, describing the development process of a scaffold library for dental applications, modeling and discussing dental implant interactions with bone and also analyzing the more remarkable technologies capable of providing adequate results for the manufacture of high-precision dental solutions, when compared with other state-of-the-art manufacturing approaches.

Soft tissue repair is a very relevant and challenging area for the emerging fields of tissue engineering and biofabrication due to the complex three-dimensional structure in form of interwoven fibres and the relevant variations of mechanical properties present in these tissues. The need of elasticity, of structural integrity, of functional gradients of mechanical properties, among other requirements, has led to the development of several families of biomaterials and scaffolds for the repair and regeneration of soft tissues, although a perfect solution has not yet been found. Further research is needed to address the advantages of different technologies and materials for manufacturing enhanced, even personalized, scaffolds for tissue engineering studies and extra cellular matrices with outer geometries defined as implants for tissue repair, as the niche composition and 3D structure play an important role in stem cells state and fate. The combined use of computer-aided design, engineering and manufacturing resources together with rapid prototyping procedures, working on the basis of additive manufacturing approaches, allows for the efficient development of these types knowledge-based functionally graded scaffolds for soft tissue repair in a wide range of materials. In this chapter we present some design and manufacturing strategies for the development of knowledge-based tissue engineering scaffolds aimed at soft tissue repair. Complete cases of studies, linked to the development of several scaffolds for the repair of articular cartilage, tendons and muscles, with an example of a complete heart-valve scaffold and a set of scaffolds for artificial sphincters, are also detailed to illustrate the proposed strategies.

Articular repair is a very relevant and challenging area for the emerging fields of tissue engineering and biofabrication, as expertise regarding the repair of both soft and hard tissues is required. The need of significant gradients of properties, for the promotion of osteochondral repair, has led to the development of several families of composite biomaterials and scaffolds, using a wide range of potentially effective approaches, although a perfect solution has not yet been found. Further research is needed to address the advantages of combining different technologies for manufacturing enhanced, even personalized, scaffolds for tissue engineering studies and extra cellular matrices with outer geometries defined as implants for tissue repair, as the niche composition and 3D structure play an important role in stem cells state and fate. In this chapter we present some design and manufacturing strategies for the development of knowledge-based tissue engineering scaffolds with radical variations of mechanical properties, aimed at complex articular tissue engineering applications. These functionally graded scaffolds constitute a key development in the areas of tissue engineering and biofabrication, as their mechanical properties can be tuned to those of the tissues and biological structures being repaired. A couple of complete cases of studies, one linked to a composite scaffold for osteochondral repair, focused on the repair and regeneration of the extremes of large bones, and one linked to a composite scaffold for spine injuries, oriented to the repair and regeneration of both vertebrae and inter-vertebral discs, are also presented to illustrate the proposed strategies.

Lab-on-chip microfluidic devices or “labs-on-chips” are aimed at integrating the complex operations and procedures typical from biochemical and biological laboratories in just a few cm², by taking advantage of microfluidic operation, which promotes reaction speed, sustainability due to the use of low fluid and sample volumes, and repeatability, thanks to multiplexing and automation, as already mentioned. Even if further research in the field will promote additional miniaturization and integration of capabilities, lab-on-chip microdevices incorporating cells and tissue samples are already very interesting for disease modeling, for studying in depth the biomechanical and biochemical aspects of disease and for obtaining models of physiological structures of the human body, normally by co-culturing different cell types, for final in vitro assessment of drugs and for a better understanding about the mechanisms of life. This chapter provides an introduction to labs-on-chips aimed at cell culture stimulated by means of microfluidic stimuli. Design, modeling and manufacturing strategies, for the development of labs-on-chips capable of helping researchers with cell co-culture for studying the interactions of different cell types and for the development of in vitro models of physiological structures, are covered. In addition, a complete case of study of a versatile lab-on-a-chip for cell co-culture is detailed. These types of microfluidic systems constitute the basic infrastructures for the development of other more complex devices such as cell-based sensors, cell-based actuators and organs-on-chips, covered in detail in the following chapters.

Cells and tissues can be seen, from the perspective of Materials Science and Engineering, as “smart materials and structures”. In fact, cells and tissues are able to perceive and respond to several environmental stimuli and gradients of them, including the presence of biochemical cues and microorganisms, the mechanical and topographical properties of the extra cellular matrix and surfaces upon which they lie, the application of vibrations and the surrounding electromagnetic fields, to cite just a few, as already detailed in several chapters of the Handbook. Advances in technologies for manipulating, culturing and monitoring single cells, together with progress in the fields of modeling, simulation, prototyping and testing, have led to a better understanding of how cells respond to several types of stimuli and accurate predictions about the behavior of cells and tissues are already possible. In consequence, cells and tissues can be employed as living transducers for the development of (micro-)sensors and (micro-)actuators, as it is possible to predict and control their responses. This chapter provides and introduction to the development of cell-based sensors and actuators and to current main challenges in this novel area. Once such challenges are solved, the frontiers between biological systems, machines and synthetic engineering systems in general will start to fade away. An approach for a more rapid solution of the aforementioned challenges, towards a wide-spread use of cell-based sensors and actuators, may rely on the use of systematic libraries with CAD models of conceptual cell-based sensors and actuators, both for modeling and prototyping strategies, as proposed in a final case study included in present chapter.

The artificial production of complete three-dimensional vascularized functional organs is still a research challenge, although recent advances are opening up new horizons to the treatment of many diseases by combining synthetic and biological materials to produce portions of veins, capillaries, arteries, skin patches and parts of bones and soft organs. Counting with artificially obtained completely functional replicas of human organs will constitute a benchmark for disease management, but there is still a long way to achieve the desired results and produce complete organs in vitro. In the meantime, having at hand simple biomimetic microsystems capable of mimicking the behaviour of complete complex organs, or at least of some of their significant functionalities, constitutes a realistic and very adequate alternative for disease modeling and management, capable of providing even better results than the use of animal models. These simplified replicas of human organ functionalities are being developed in the form of advanced labs-on-chips generically referred to as “organs-on-chips” and are already providing interesting results. This chapter provides an introduction to this emerging area of study and details different examples of organs-on-chips and their development process with the aid of computer-aided design and engineering technologies and with the support of rapid prototyping and rapid tooling resources.

The artificial production, in laboratories, of biological structures and even complete organs, by adequately placing and combining ex vivo cells, synthetically produced tissue patches and supporting biomaterials, including but not limited to tissue engineering scaffolds, is no more a matter of science fiction but a present relevant research challenge already providing promising results, included under an innovative area called “biofabrication”. If larger biological structures and complete organs could be synthetically obtained, patients would benefit from more rapid surgical interventions, compatibility would be highly promoted, as they would be produced ex vivo from the own patient’s cells, and aspects such as organ piracy would be limited. It is important to highlight that nowadays around 10 % of organs used for transplantation worldwide comes from illegal activities. The socio-economical impact of synthetic organ production is comparable to that of the whole pharmaceutical industry, what explains the interest it has arisen in the last decades, with several new companies and research centres worldwide aiming at improving state-of-the-art tissue engineering procedures for starting 3D tissue construction and organ biofabrication. In addition novel scientific journals and book series are being devoted to these advances and related concepts and techniques are starting to be included in the syllabuses of teaching programs at universities, what will for sure be very positive for the evolution of this area. This chapter provides a brief introduction to this field of research, discussing most relevant advances on materials science, design tools and manufacturing technologies that being combined for making biofabrication a viable alternative to conventional therapeutic procedures. Main present difficulties and remarkable research challenges are also discussed. It constitutes an updated version of “Chap. 14: Biofabrication: Main advances and Challenges” from Springer’s “Handbook on Advanced Design and Manufacturing Technologies for Medical Devices” also by Andrés Díaz Lantada (Díaz Lantada 2013).

In this chapter we present the complete development of a novel course on “Biomedical Devices”, in the framework of the “Biomedical Engineering” Degree at Universidad Politécnica de Madrid (TU Madrid). The course is based on the “CDIO: Conceive, Design, Implement, Operate” approach, as we consider it a very remarkable way of promoting student active learning and of integrating, with impact, novel concepts into ongoing curricula. During the course, groups of students live through the complete development process of different biomedical devices aimed at providing answers to relevant social needs. Computer-aided engineering and rapid prototyping technologies are used as support tools for their designs and prototypes, so as to rapidly reach the implementation and operation phases. Main benefits, lessons learned and challenges, linked to this CDIO-based course, are analyzed, considering the results from 2014–2015 academic year. Some of the most remarkable biodevices developed by students are linked to the field of biomedical microdevices for interacting at a cellular level, the central topic of present Handbook. The complete development of two bioreactors, which have led to Master’s Degree Theses, after additional tasks carried out in parallel to the course, is also schematized and presented as one of the most remarkable results of the teaching-learning strategy.