© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1 REVIEW Nanomaterials for Engineering Stem Cell Responses Punyavee Kerativitayanan, James K. Carrow, and Akhilesh K. Gaharwar* P. Kerativitayanan, J. K. Carrow, Prof. A. K. Gaharwar Department of Biomedical Engineering Texas A&M University College Station, TX 77843, USA E-mail: gaharwar@tamu.edu Prof. A. K. Gaharwar Department of Materials Science and Engineering Texas A&M University College Station, TX 77843, USA DOI: 10.1002/adhm.201500272 biomedical research emanate from similar length scales with the majority of biolog- ical moieties such as structural protein, deoxyribonucleic acid (DNA), signaling molecules, antibodies, and extracellular matrices (ECMs). A cell itself is essentially a multifunctional particle comprised of nano compartments such as cell mem- branes, surface proteins, cytoskeletons, and nuclear membranes containing DNA. Owing to their small size, nanomaterials can widely interact with the physiological environment and enable the develop- ment of systems that mimic structural complexity and functions of ECMs. [7,8] For example, an ECM is a dynamic struc- ture that consists of different nanofibers (such as collagen, actin filaments, etc.), nanocrystals, and signaling molecules. Because nanomaterials are small enough to interact and alter cellular-level func- tions, they are expected to provide a new framework for medical intervention and diagnosis. Stem cells are unspecialized precursor cells with self-renewal capacity and the potential to differentiate into different lineages given the appropriate signals. [9] Stem cells can be classified into two types: embryonic stem cells (ESCs) obtained from the inner cell mass of the blastocyst, and adult stem cells, found in postnatal tissues such as the umbil- ical cord, bone m arrow, dental pulp, adipose, and neuron tis- sues. [10] ESCs are an ideal cell source for regenerative medicine due to their indefinite self-renewal and pluripotency. However, there are some ethical questions concerning the use of embryos to obtain ESCs. Multipotent adult stem cells are an alternative with fewer ethical issues, but they have limited differentia- tion and self-renewal capacity, limiting their applications. [11,12] Hence, researchers have attempted to reprogram somatic cells into pluripotent stem cells by somatic cell nuclear transfer (SCNT) and by inducing the expression of embryonic transcrip- tion factors to generate induced pluripotent stem cells (iPSCs). Still, the reprogramming efficiency and the epigenetic abnor- malities of the cells differentiated from SCNT and iPS cells are debatable. [13] Because of the confluence of nanomaterials and stem cells, the restoration and regeneration of diseased cells and tissues are becoming a clinical possibility that will result in therapies for currently incurable diseases. However, certain challenges must be addressed before stem cells can be fully applied to medical treatments. These include controlling self-renewal processes, proliferation, and regulating the differentiation of stem cells. [14,15] Nanomaterials have the ability to control stem cell behavior due to their small size Recent progress in nanotechnology has stimulated the development of multi- functional biomaterials for tissue engineering applications. Synergistic inter- actions between nanomaterials and stem cell engineering offer numerous possibilities to address some of the daunting challenges in regenerative medicine, such as controlling trigger differentiation, immune reactions, lim- ited supply of stem cells, and engineering complex tissue structures. Specifi- cally, the interactions between stem cells and their microenvironment play key roles in controlling stem cell fate, which underlines therapeutic success. However, the interactions between nanomaterials and stem cells are not well understood, and the effects of the nanomaterials shape, surface morphology, and chemical functionality on cellular processes need critical evaluation. In this Review, focus is put on recent development in nanomaterial–stem cell interactions, with specific emphasis on their application in regenerative medi- cine. Further, the emerging technologies based on nanomaterials developed over the past decade for stem cell engineering are reviewed, as well as the potential applications of these nanomaterials in tissue regeneration, stem cell isolation, and drug/gene delivery. It is anticipated that the enhanced under- standing of nanomaterial–stem cell interactions will facilitate improved bio- material design for a range of biomedical and biotechnological applications. 1. Introduction Advances in nanotechnology have resulted in the develop- ment of advanced biomaterials with custom property com- binations. A range of biomedical nanomaterials have been developed to mimic tissue complexity and modulating stem cell functions, resulting in many therapeutic benefits. [1] In this Review, we focus on nanomaterials that possess at least one physical dimension between 1–100 nm utilized in tissue engineering. Nanomaterials are not a simple miniaturization of macroscopic counterparts; they exhibit distinctive physical, chemical, optical, and mechanical properties due to a high specific surface area. [2–4] The unique properties of nanoma- terials offer implementation in nanoelectronic devices to bio- medical applications. [4–7] The applications of nanomaterials in Adv. Healthcare Mater. 2015, DOI: 10.1002/adhm.201500272 www.advhealthmat.de www.MaterialsViews.com