Scope

To screen biomaterials in a materiomics approach, libraries of materials are produced. Different materials are used, varying from metals and cements, to covalent polymers that can be either premixed or polymerized in situ, to supramolecular systems that can be applied in a modular approach. This chapter describes the generation of such libraries using different kinds of materials and chemistries. Additionally, the advantages and limitations of the application of these different systems/biomaterials in a materiomics approach are discussed.

Introduction

Different synthetic biomaterials are used for many biomedical applications, varying from metals and ceramic cements, to polymers and supramolecular systems. To screen these biomaterials in a materiomics approach, as said above, libraries of materials are produced. Variations in biomaterials are screened as continuous gradients or in a discrete fashion. The properties that are varied and methods used to create variation within these libraries depend on the type of biomaterial. For the hard metal and ceramic-based biomaterials, the surface interaction with tissue is the property of most interest, and therefore properties such as surface roughness and topography are varied. Covalent polymers are diversified using combinatorial chemistry. The dynamic and self-assembling nature of supramolecular systems allows for the development of material libraries using a modular approach by mixing and matching of different compounds modified with supramolecular moieties.

It’s that sense of unease when you step out of the airport terminal building and onto the streets of Kathmandu. Or the moment when you open the door to your new office to see unfamiliar faces waiting for you. Step out of your comfort zone and discover how exciting, thrilling and liberating it can be: a new world is waiting for you. This book is about stepping out of the comfort zone of your own scientific discipline and about exposing yourself to something new. Embrace all the scientific disciplines that build modern-day biomaterials research, in the cultural hotpot of materiomics. Don’t let the jargon and three-letter abbreviations of cell biology hold you back, nor the abracadabra of statistical models, nor the Latin terms for body parts and diseases. Learn a new language and a whole new culture is waiting for you.

The compilation of this book was initiated after an exciting conference termed ‘High throughput screening of biomaterials: shaping a new research area’, held beside the Amsterdam canals in April 2011. The meeting was attended by 50 selected scientists from all over the globe and across all the disciplines of biomaterials research, and the format of the conference took away that sense of unease. Chemists talked to clinicians, biologists listened to information scientists, engineers brainstormed with policy makers. We decided to bring this open and inviting atmosphere to the public through this book. Therefore, each chapter contains a tutorial on the topic for non-experts, gives an overview of the current status of that field and discusses how this technology will further shape the future of materiomics. The result of this exciting journey is presented here and was made possible only with the help of all the authors and those who contributed to the organization of the conference (Anouk Mentink), the editing of the book (Ruben Burer) or the chapters (Kristen Johnson). We hope that this book will be a scientific passport which lets you travel across the border of your discipline and helps you to learn to appreciate that of others. You won’t be disappointed. Enjoy your journey!

Scope

High-content imaging (HCI) plays a pivotal role in high-throughput screening (HTS) of biological responses to biomaterials. This chapter will give a brief introduction to its basic principles by explaining the most commonly used imaging techniques, describing the general structure of an image analysis pipeline and providing a summary of available HCI software. Special emphasis will be devoted to the initial steps of image analysis such as image correction, segmentation and feature extraction. Additionally we include a brief overview of relevant literature and description of promising new tools for HCI. Finally, two classic experiments will be described, which use state-of-the-art HCI in biomaterial science by experts in the field.

Origins of high-content imaging

The first person to observe micro-organisms with a microscopic device was the Dutchman Antoni van Leeuwenhoek (1), who was able to make and polish tiny lenses of high curvature which were the forerunners of the modern microscope. Robert Hooke, the English father of microscopy, later improved on the design and confirmed van Leeuwenhoek’s findings. Since then, light microscopy has evolved into its modern incarnation. The first use of fluorescence microscopy in biology was in 1881 when the bacteriologist Paul Ehrlich used fluorescin to observe the aqueous humour in the eye. The first immuno-staining was performed in 1950 by Melvin Kaplan (2). Green fluorescent protein (GFP) was the first fluorescent protein used in biology. It was isolated from jellyfish in 1961 by Shimomura and co-workers, and it was cloned by Prisher in 1992. The ability either to use antibody conjugated fluorophores or to clone GFP into chimaeric proteins led to the implementation of the fluorescence microscope in modern biology. High-content imaging (HCI) is the automation of fluorescence microscopy whereby the manual interpretation of images is replaced by computer algorithms.

Scope

Materiomics approaches may be applied broadly in the design and characterization of a wide range of materials, going beyond the biomedical focus. This chapter presents essential concepts relevant to the implementation of materiomics to physical and chemical properties not usually associated with biomedical materials. Recent progress in this area is reviewed briefly with several examples given in high-throughput measurement of organic and inorganic materials properties. The applications that are covered range from speciality coatings to membranes for fuel cells and metal–organic framework materials for carbon capture. Properties treated here include mechanical, spectroscopic and transport characteristics.

Tutorial on basic principles

Materials complexity

While previous chapters have focused on the application of materiomics concepts to biomedical materials, this chapter will emphasize how and why materiomics is being employed in materials research and development beyond the biomaterials field. The central challenge inherent to materials research and development is that most products consist of multiple components whose final properties are usually a sensitive function of composition and processing conditions. The complex interactions make it difficult, if not impossible, to design products a priori without significant experimentation. Academicians are often interested in characterizing fundamental phenomena, such as phase transitions or magnetization, and discovering how these phenomena can be used to develop novel materials functionalities.

Scope

Computational and statistical tools play an important role in materiomics, to provide insights in the underlying processes that allow certain materials to outperform other materials. In this chapter, we discuss numerous methods that allow the analysis of materiomics data. Specifically, we describe the use of statistical tests, ranking and data mining approaches, model learning and testing, as well as experimental design and the exchange of experimental results. Also, we review some of the important publications in this field from the past 15 years, organizing them according to the type of material descriptors that were used.

Basic principles of data analysis

Computational methods play an ever more important role in the study of material function. Partly, this is due to the increased scale of the experiments being performed, with an accompanying need for automated analyses. But the move from low-throughput towards high-throughput experiments entails more than just testing more materials simultaneously. The extra information these experiments produce is slowly catalysing a transition to a more rational approach to material discovery, in which not just material screening plays a role but also material modelling. Materials and their environments are approached as systems that can be modelled and thus explored in silico. This ‘systems approach to material research’ has been termed materiomics. This transition is certainly needed given the size of the materiome that one wants to explore: many material parameters can be varied and combined into a practically infinite palette of combinations. This far surpasses even the reach of high-throughput screenings. The question that will be addressed in this chapter is: how can we efficiently make use of our capability to perform high-throughput experiments, to explore and characterize such a large search space?

Scope

High-throughput and combinatorial research on biomaterials aims at the rapid development of new materials and the establishment of structure–function relationships. Therefore, knowledge of the chemistry of each material and its impact on physical properties is essential to understand the effect on its function as a biomaterial. A tutorial on basic physical and chemical properties of (polymeric) materials highlights these features and can be found in the first part of this chapter. The second part gives an overview of relevant techniques that can be used to screen these material properties in high throughput. In addition, several examples are described in which these methods are used to develop structure–function relationships between material properties and biological performance.

Basic principles: physical and chemical properties of polymeric biomaterials

Chemistry is a constant factor from which the performance of most (polymeric) biomaterials can be predicted, but this extrapolation becomes less obvious when numerous materials are mixed in huge combinatorial libraries. Therefore, researchers are becoming increasingly involved in high-throughput material research when successful correlations between biological performance and physico-chemical material properties are to be made. This accelerating trend can be extracted from many studies where high-throughput technologies are successfully applied to measure physical properties and biological performance of many different polymeric biomaterials. Physical properties such as hardness, topography and hydrophilicity are known to be important parameters in the biological evaluation of materials, because they allow or block the adhesion of biological compounds which is required to allow cell-spreading, migration, proliferation and differentiation. These properties are naturally different for every material or combination of materials, and relate primarily to the variable properties on the chemical level (molecular structure, functional groups and degradation). Therefore, the chemistry of a biomaterial directly contributes to its interaction with biological environments.

Scope

High-throughput screening (HTS) is carried out on two- (2D) and three-dimensional (3D) materials, with hundreds to thousands of conditions at various size scales. When hits are successfully found in HTS systems, upscaling to clinically relevant surfaces needs to be performed to validate whether the identified material and functionality can be replicated on the macroscale. In doing so, parameters such as surface chemistry, topography and sample dispensing must be controlled to maintain reproducibility. Here, we discuss the methods harnessed to replicate chemical and topographical features from the nano- to the macroscale in 2D and 3D systems. Technologies to control cell adhesion and 3D scaffold fabrication are introduced and discussed in terms of their potential for HTS.

Basic upscaling principles

HTS is a highly automated process that tests small amounts of large numbers of compounds for a desired function. In the previous chapters of this book, the general principles behind material chemistry and resulting physico-chemical properties, combinatorial chemistry, microfabrication technologies and development of tools to perform biological assays on HTS platforms have been described. These elements partly return here, where basic principles of polymer chemistry and surface topographies are introduced in the context of facing the technological challenges to upscale selected candidates to larger surfaces or medical devices with complex curved shapes. In addition, the basic principles behind implant fabrication technologies and precise cell deposition are discussed to illustrate the steps required to assimilate HTS into clinically relevant 3D systems.

Scope

Combinatorial chemistry and high-throughput synthesis of novel materials warrant a paradigm shift in current methods to analyse biological responses. This chapter will provide an overview on bioassay development and how novel assays amenable to high-throughput screening platforms can be adapted to more complex systems. Special emphasis will be devoted to the development of assays that can be used in platforms that closely mimic the in vivo complexity of tissues and organs. In that respect, assays that can cope with co-culture systems as well as 3D environments will be discussed. Moreover, modifications or development of new assays and techniques will be described as well as their respective advantages and disadvantages.

Basic principles of assay development

The ability to measure the speed of light changed the field of physics and the world. Chemical reactions led to the Big Bang and the creation of the Universe, but the ability to measure and control those reactions changed the face of the Earth. We can surely say that the need to see more, and in more detail, led to the development of technologies that made that possible and ultimately contributed to the advance of science and society.

Introduction to materiomics

The ability to regenerate and repair tissues and organs – using science and engineering to supplement biology – continuously intrigues and inspires those hoping that the frailty of our bodies can be ultimately avoided. From ancient times, a surprising range of unnatural materials have been used to (partially) substitute human tissues for medicinal purposes. For example, in the era of the Incas (c. 1500), moulded materials such as gold and silver were used for the ‘surgical’ repair of cranial defects. In addition, archaeological findings reveal a wide range of materials, such as bronze, wood and leather, being used to replace and repair parts of the human body. Continuous refinement led to the first evidence of materials successfully implanted inside the body, reportedly used to repair a bone defect in the seventeenth century (see Further Reading).

Even earlier than this, the relationships between anatomy (i.e. structure) and function of living systems had been explored by Leonardo da Vinci and Galileo Galilei, who were among the first few to apply fundamental science to biological systems. In the current age of technology, new materials for biomedical and clinical application have undergone a modern Renaissance, resulting in a surge in design and successful application (1–5). The concepts of tissue repair and substitution are constantly improving and becoming more accessible, as proven for example by the widespread occurrence (and popular approval) of total hip and knee replacements. But rather than replacement with synthetic analogues, can biological tissue(s) be directly engineered?