REVIEW Nanotechnology for regenerative medicine: nanomaterials for stem cell imaging Aniruddh Solanki1, Although stem cells hold great potential for the treatment of many injuries and John D Kim1 & degenerative diseases, several obstacles must be overcome before their therapeutic Ki-Bum Lee1,2,3† application can be realized. These include the development of advanced techniques to †Author for correspondence 1Rutgers, The State University understand and control functions of microenvironmental signals and novel methods to of New Jersey, Department of track and guide transplanted stem cells. The application of nanotechnology to stem cell Chemistry & Chemical biology would be able to address those challenges. This review details the current Biology, Piscataway, NJ 08854, USA challenges in regenerative medicine, the current applications of nanoparticles in stem cell 2Institute for Advanced biology and further potential of nanotechnology approaches towards regenerative Materials, Devices & medicine, focusing mainly on magnetic nanoparticle- and quantum dot-based applications Nanotechnology, 607 Taylor in stem cell research. Road, Piscataway, NJ 08854, USA 3The Rutgers Stem Cell Why nanotechnology for microenvironments. Conventional experimental Research Center, Rutgers, regenerative medicine? The State University of New studies for specific cellular responses are typically Jersey, Piscataway, NJ 08854, The recent emergence of nanotechnology has set conducted on large cell populations, which inev- USA high expectations in biological science and medi- itably produce data measured from an inhomo- Tel.: +1 732 445 0281; cine; many scientists now predict that nanotech- geneous distribution of cellular responses. Unless Fax: +1 732 445 5312; E-mail: [email protected] nology can solve many key questions concerning cellular responses and processes are isolated from biological systems that transpire at the nanoscale. inhomogeneous signals at the single cell level, it Nanomedicine, defined broadly as the approach of would be extremely difficult to elucidate the science and engineering at the nanometer scale intricate cellular systems and to analyze the com- towards biomedical applications, has been drawing plex dynamic signaling transductions. Further- considerable attention in the area of nanotechnol- more, conventional biomedical approaches reveal ogy [1]. Given that the sizes of functional elements very little concerning genotypic aspects that tran- in biology are in the nanometer scale range, it is scend into cell phenotypes. Thus, to better not surprising that nanomaterials interact with understand and control the responses of cells biological systems at the molecular level [2]. In towards external stimuli at the single cell or sin- addition, nanomaterials have novel electronic, gle molecule level, it is imperative to characterize optical, magnetic and structural properties that the full range of cell behaviors (e.g., self-renewal, cannot be obtained from either individual mole- differentiation, migration and apoptosis). cules or bulk materials. These unique features can Recently, stem cells have gained much atten- be tuned precisely to explore biological phenom- tion for the treatment of devastating injuries ena through numerous innovative techniques. and damage caused by degenerative diseases, One of the major goals of biology is to address the diabetes and aging [4]. Stem cells self-renew for spatial–temporal interactions of biomolecules at long periods of time and then further differenti- the cellular and integrated systems level [3]. How- ate into specialized cells and tissues on stimula- ever, to apply nanotechnology to biology and tion by appropriate microenvironmental cues. medicine, several conditions must be considered: They are typically categorized as embryonic • Nanomaterials must be designed to interact stem cells (ESCs) or tissue-specific adult stem with proteins and cells without interfering cells, depending on their origin and differentia- with their biological activities tion capability. ESCs, which originate from the inner-cell mass of the blastocyst-stage embryo, • Nanomaterials must maintain their physical Keywords: magnetic are able to differentiate into all cell lineages nanoparticle, quantum dots, properties after surface modification regenerative medicine, stem found in the three primary germ layers of the cell imaging • Nanomaterials must be nontoxic embryo (e.g., endoderm, mesoderm and ecto- Cells are single living units of organisms that derm) [5]. Although it has been shown that part of receive the input signals from disease and injury human ESCs (hESCs) can differentiate into and then return the output signals to their many interesting cell types, such as cells of 10.2217/17435889.3.4.567 © 2008 Future Medicine Ltd ISSN 1743-5889 Nanomedicine (2008) 3(4), 567–578 567 REVIEW – Solanki, Kim & Lee heart, brain or bone [5], the therapeutic poten- Nanomaterials for molecular tial of hESCs has not been fully realized owing & cellular imaging to numerous restrictions, including biological Although nanoparticles can be synthesized from issues concerning immunogenicity and rejection various materials using several methods, the cou- and social issues concerning ethics and pling and functionalization of nanoparticles with morality [6,7]. Adult stem/progenitor cells (e.g., biomolecules should be carried out in controlled mesenchymal [MSCs], hematopoietic and neu- conditions, such as a specific salt concentration ral stem cells [NSCs]) reside in mature tissue or pH. For this purpose, interdisciplinary knowl- compartments and are known to function as the edge from molecular biology, bioorganic chemis- replication resources for cell renewal during nor- try, bioinorganic chemistry and surface mal homeostasis of tissue regeneration. In con- chemistry must be used to functionalize nano- trast to ESCs, adult stem cells can only particles with biomolecules. With significant proliferate for a few passages and their differen- advancements in synthetic and modification tiation ability is limited to certain cell types, methodologies, nanomaterials can be modified depending on where they are located (e.g., bone to desired sizes, shapes, compositions and prop- marrow, brain or epithelial tissues) [8]. erties [10,11]; they can then be functionalized Intrinsic regulators (e.g., growth factors and readily with biomolecules through combined signaling molecules) and cellular microenviron- methodologies from bioorganic, bioinorganic ments, such as extracellular matrices (ECMs), and surface chemistry. are two prime factors that have critical roles in the regulation of stem cell behaviors. To harness Magnetic nanomaterials: the unique potential of stem cells, it is important iron oxide nanoparticles to understand the functions of intrinsic regula- Inorganic nanoparticles, especially iron oxide tors and extracellular microenvironments during nanoparticles and quantum dots (QDs), are stem cell fate [9]. Furthermore, to fully achieve one of the most promising materials for stem the therapeutic promise of stem cells, several cell research because they can be synthesized critical issues (Box 1) need to be addressed. easily in large quantities from various materials Nanostructures and nanomaterials can inter- using relatively simple methods. The dimen- act intrinsically with biological systems at the sions of the nanoparticles can be tuned from single molecular level with high specificity. The one to a few hundred nanometers with a mono- unique properties of nanomaterials and nano- dispersed size distribution. Moreover, they can structures can be particularly useful in control- comprise different metals, metal oxides and ling intrinsic stem cell signals and in dissecting semiconducting materials, whose compositions the mechanisms underlying embryonic and and sizes are variable. adult stem cell behavior (Figure 1). Iron oxide nanoparticles can either bind to Herein, we have summarized nanotechnology the external cell membrane or can be internal- approaches for stem cell research and have fur- ized into the cytoplasm. Particles that are ther addressed some of the challenges concerning bound externally do not affect cell viability, these research efforts. Owing to the extensive although, they may interfere with cell-surface scope of the topic and space limitations, we have interactions or may simply detach from the cell focused primarily on cellular imaging from the membrane [12]. However, iron oxide nano- numerous applications of nanotechnology in particles that can be internalized within cells stem cell biology. have their surfaces modified to ensure high uptake efficiency with minimum deleterious effects on the cells [13]. For example, coating the Box 1. Critical issues for the therapeutic applications of surface of superparamagnetic iron oxide nano- stem cells. particles (SPIONs) with dextran or other poly- • The long-term behavior of transplanted stem cells in the target tissues mers enhances stability and solubility [14] and • The pluripotency/multipotency of stem cells to differentiate towards also prevents aggregation [15]. The coated SPI- homogeneous populations of specific cell types ONs are useful for tracking and studying • The control of transplanted stem cells to migrate to the correct stem/progenitor cells with MRI. In this regard, microenvironmental places magnetic iron oxide nanoparticles and their • The tracking of transplanted stem cells by labeling techniques composites are emerging as novel contrast • The optimal time