Seeking the right context for evaluating nanomedicine: from tissue models in petri dishes to microfluidic organs-on-a-chip.

Engineering predictive tissue models The field of tissue engineering and regen­ erative medicine has seen tremendous prog­ ress over the past few decades through a wide spectrum of engineering innovations in biomaterials, biomolecule delivery, bio­ mechanics, biophysics and biomedicine. For example, scaffolds are fabricated to possess controllable structures, porosities, hierarchies, degradability along with well­ controlled spatial and temporal presentation of bioactive molecules (e.g., growth factors, antagonists, DNAs and micro/siRNAs) that aid in regulating cellular behavior [1]. Moreover, it is increasingly appreciated that biomechanical cues of the materials can be employed to direct the differentiation of stem cells into specific lineages [2]. Alterna­ tively, cellular behaviors may also be tuned by other biophysical cues including surface roughness and topography [3]. However, since its conception, tissue engi­ neering has always focused on the generation of tissue substitutes to replace those damaged or diseased in the body. Only recently has the area started to enter an emerging paradigm of building physiologically relevant minia­ ture human tissue and organ models. The increasing awareness in animal welfare has further expedited such efforts in generating human tissue models that may eventually replace animal models from the ethical per­ spective as well as to provide more accurate predictions of human body responses. Indeed, there have been tremendous progress on developing functional human healthy/diseased organoids from vari­ ous human cell sources including induced pluripotent stem cells (iPSCs), genetically modified cell lines and diseased cells derived from patients. For example, Helmrath and colleagues showed that through iPSC dif­ ferentiation and subsequent maturation by transplanting under the kidney capsules of immunocompromised mice, human small intestinal organoids could form that contain mature intestinal epithelium with crypt­villus architecture and a laminated mesenchyme [4]. Also, Knoblich and colleagues demonstrated the potential to generate human brain regions that recapitulated the structure and develop­ ment of cerebral cortex in 3D iPSC­derived cerebral organoids [5]. In another example, Kim and colleagues created a model of famil­ ial Alzheimer’s disease (FAD) using a 3D cul­ ture system of differentiated neuronal cells expressing FAD mutations, which expressed amyloid­β and phosphorylated tau proteins, similar to those of FAD in human brains [6]. While these examples are still preliminary, the findings have undoubtedly provided sig­ nificant excitement about generating predic­ tive human tissue models for drug testing. More interestingly, realistic human tumor Seeking the right context for evaluating nanomedicine: from tissue models in petri dishes to microfluidic organs-on-a-chip