A wide variety of nanomaterials have been used as core materials for the subsequent construction of nanomedical systems. The core material is important in terms of the detection technologies that can be used for diagnostics. The core building blocks of a nanomedical system can have both structural and functional attributes. Structurally, it is a starting point for building multilayered nanomedical systems with a combination of genes or drugs, targeting molecules, and stealth molecules to evade the immune system in vivo. It is also the starting place in the manufacturing process.

Nanomaterials are potentially a nanotoxicity problem. One potential source of nanomaterial toxicity is the large surface-to-volume ratio inherent in materials on the nanoscale size range. Many chemical reactions are aided by surfaces that can bring together different molecules for potential interactions and aid in their reorientations for potential interactions. In this way, small nanoparticles can act as catalysts and like enzymes to amplify the effects of interactions between molecules. Reactivity of nanomaterials also varies widely with size. For all of these reasons, nanotoxicity should be measured using nanoparticles of specific size ranges. The same nanomaterials can be more or less cytotoxic depending on their size. Biocoatings may hide the true nanotoxicity.

This is the only chapter of the book devoted to the characterizations and measurements of the nanoparticles themselves, although it does include material related to the interaction forces between nanoparticles and cells. Zeta potential is probably the most important factor in determining whether nanoparticles will agglomerate in clusters. If you observe agglomeration happening to your nanoparticles (a very common problem), it is likely to be a problem with the zeta potential of your nanoparticles. The focus of the chapter is on the importance of “zeta potential,” which governs the fundamental electrostatic interactions of nanoparticles with each other as well as nanoparticle interactions with cells in an aqueous environment. Zeta potential is perhaps the single most important design consideration of nanomedical systems.

The normal paradigm for developing a new nanomedical system is to start with an in vitro cell line (usually human) system and then progress to excised, or biopsied , tissue from a human (ex vivo). Finally, to better simulate the effects of a total organism, we begin in vivo studies, usually on an animal system. This has been the general paradigm for decades. Now we have new “organ-on-a-chip” in vitro models that generate organ-like human tissue on an in vitro format. There have even been more recent promising efforts at generating “human-on-a-chip” technologies.

“Total design” of nanomedical systems means that you must take a total system-level design approach, but where the order in the design process matters – and each design step affects all preceding and subsequent design steps. The total design concept means that the essence of the design is a multilayered approach corresponding to a multistep targeting and drug delivery process. This chapter teaches how to design integrated nanomedical systems.

While nanomedical system design begins with the choice of core materials, the ultimate usefulness of these nanomedical systems is driven by the subsequent attachment of biomolecules in a series of layers. The initial attachment process (i.e., bioconjugation) requires biomolecules to be attached to a core material that is typically nonorganic and may consist of materials quite foreign to these biomolecules. Attachment strategies of biomolecules to the core depend on the composition of core materials.

Using our strict definition of Atomic Scale Analytical Tomography (ASAT), we explore the current landscape of materials characterization tools and discuss how electron microscopy, field ion microscopy, and atom probe tomography are each approaching ASAT. State-of-the-art electron microscopy can achieve sub-angstrom spatial resolution imaging in 2-D and small volumes in 3-D but lacks single-atom chemical sensitivity, especially in 3-D. Field Ion Microscopy can achieve 3-D imaging on small volumes but not for all materials. Atom probe tomography can achieve single-atom elemental quantification in 3-D but lacks the spatial resolution necessary for ASAT. The chapter concludes with a comparison of the different techniques and discusses how different techniques may be complementary.

The historical backdrop for the role of microscopy in the development of human knowledge is reviewed. Atomic-scale investigations are a logical step in a natural progression of increasingly more powerful microscopies. A brief outline of the concept of atomic-scale analytical tomography (ASAT) is given, and its implications for science and technology are anticipated. The intersection of ASAT with advanced computational materials engineering is explored. The chapter concludes with a look toward a future where ASAT will become common.

We discuss how ASAT has the potential to make important advances on critical frontiers in crystallography. These key frontiers include unequivocal quantification of the nearest-neighbour relationships in materials, compositional information, and details of the degree of both short-range order and long-range order. Interfaces represent a particular opportunity. We discuss the present challenges in experimental microscopy-based methods to incorporate both the structural crystallographic information at crystal interfaces with the local chemical compositional information. We anticipate that ASAT will drive forward the field of interface science and interface engineering.

We conclude our contribution with a prospective and optimistic look to the art of what might be possible with the advent of ASAT. We see a convergence between the digital or computational world and the experimental, and envisage ASAT as an enabler for the design and development of new materials. This potential arises because real-world 3D atomic-scale information will bring direct insights into thermodynamic, kinetic, and engineering properties. Moreover, when coupled with machine learning and other computational techniques, it may be envisaged that discovery-based procedures could follow that adjust the observed real-world atomistic configurations toward configurations that exhibit the desired engineering properties. This will fundamentally change the role of microscopy from a tool that provides inference to a materials behaviour to one that provides a quantitative assessment. This opens the pathway to atomic-scale materials informatics.

A complete, albeit brief review of the history of atoms and atomic-scale microscopy is offered. From the concept of the atom developed by Greek philosophers to the ultimate microscopy, the path of development is examined. Atomic-Scale Analytical Tomography (ASAT) is cited as the ultimate microscopy in the sense that the objects, atoms, are the smallest building blocks of nature. The concept of atoms developed as the scientific method grew in application and sophistication beginning in the Middle Ages. The first images of atoms were finally obtained in the mid-twentieth century. Early field ion microscopy evolved eventually into three-dimensional atom probe tomography. The crucial role of the electron microscope in atomic-scale microscopy is examined. Recently, combining atom probe tomography and electron microscopy has emerged as a path toward ASAT. The chapter concludes with the point that ASAT can be expected in the next decade.