Stem cells are usually found in the living organisms in specific anatomical locations called as a niche in a highly controlled and specific microenvironment. Such expressions allow for the stem cell to have specific interactions necessary for proper regulation. These niches play specialized roles of regulating stem cells due to the presence of other specialized cells. The presence of noncellular materials such as extracellular matrices as well as biomolecules can generate tissue matrices. Cells around the stem cells within the niche produce matrix biomolecules such as fibronectin, laminin, collagen, elastins, and proteoglycans that produce specialized structures that are necessary for the growth and maintenance of stem cells. The nanostructures formed by these biomolecules serve as anchorage points, facilitating cell adhesion molecules to bind as well as immobilization of soluble factors. The extracellular proteins on the stem cell surfaces interact with amino acids expressed on the extracellular matrices or specialized three-dimensional (3D) structures to activate/deactivate a cascade of signaling pathways within the cells. These structures end up regulating adhesion, proliferation, migration, and cell differentiation [9,39]. Other microenvironmental factors that control stem cell localization, proliferation, and differentiation are mineral components, i.e., calcium. Calcium sensors expressed on the hematopoietic stem cell surface allow them to find their niche and translocate from the fetal liver to the bone marrow [40]. Reproducing the structural complexities of nanostructures present in the extracellular matrices has significantly improved our understanding of the stem cell—matrix interactions. It has delineated interactions and regulation of various processes within the stem cells. This knowledge has also helped us better regulate the bioactive remodeling of the stem cells [41]. The biometric scaffolds made through nanotechnology satisfy the essential characteristic requirements of biocompatibility and biodegradability. It also provides appropriate bimolecular signaling to allow for proper proliferation and differentiation of the stem cells.

How the structure and properties of nanomaterials may impact the proliferation and differentiation of stem cells has in itself become a new scientific frontier especially in the field of regenerative medicine. Most of the early studies on the role of the microenvironment in stem cell differentiation were carried out with two-dimensional (2D) biomaterial structures. Two-dimensional approaches have their advantages such as low cost, high throughput, and capability of delineating multiple interactions at once. True interactions of the stem cells in vivo are 3D in nature [42]. Hence new investigation has been directed to nanofabrication to develop 3D biodegradable scaffolds. These constructs are designed to catalyze stem cells to differentiate into specific cells of the organ/tissue required [43,44]. The biodegradable matrices and nanoscaffolds allow the transplanted cells to eventually take the 3D structure of the tissue as the scaffold eventually disappears [45,46].

Giri et al. studied the telomerase activity of rat embryonic liver progenitor cells in nanoscaffold-coated model bioreactor. This protein is known to control cellular processes such as proliferation, differentiation, immortalization, cell injury, and aging [47]. The investigators cultured a rat embryonal liver progenitor cell line RLC-18 in a selfassembly nanostructured scaffold-coated bioreactor. The researchers compared this to 2D models of collagen-coated plates and uncoated plates. These studies reported low telomerase activity and limited cell proliferation. Scaffold interaction may play a significant role in controlling critical cellular functions in the bioartificial liver construction. Self-assembling peptide nanoscaffold has also been examined to study the influence of electrical stimulation on 3D cultures of adipose tissue—derived progenitor cells [48]. Studies revealed that the process of electrostimulation along with 3D scaffolding may eventually lead to development of effective cardiac cells. Tam et al. utilized a nanoscaffold impregnated with mesenchymal stem cells derived from the Wharton jelly of human umbilical cords. These investigators suggested that this system improves wound healing [49]. The authors utilized an aloe vera (due to its antibacterial properties) polycaprolac- tone nanoscaffold impregnated with green fluorescent protein—labeled stem cells for healing of excisional and diabetic wounds. The excisional and diabetic wounds in mice showed rapid wound closure, reepithelialization, and increased numbers of sebaceous glands and hair follicles compared with controls suggesting that the combination of stem cells with nanoscaffolding provide synergistic benefits in wound healing.

Other material examined as a nanoscaffold for potential bone tissue engineering is graphene. Elkhenany et al. contemplated the use of graphene as a nanoscaffold for goat mesenchymal stem cells. The researchers reported the effect of this material on the proliferation and differentiation of bone progenitor cells and compared it with polystyrene-coated tissue culture plates [50]. The results suggested that oxidized graphene films support in vitro proliferation and osteogenic differentiation even in medium containing fetal bovine serum without the addition of any glucocorticoid or specific growth factors. It has been suggested that graphene scaffold and goat mesenchymal stem cell combination may be a promising potential construct for bone tissue engineering. Mousavi et al. studied the expansion of human umbilical cord blood hematopoietic stem/progenitor cells in 3D polycaprolactone nanoscaffold coated with fibronectin to overcome the major obstacle of limited cell dose [51]. These studies suggested that 3D scaffold can result in greater expansion of total cells (58-fold expansion) compared with 2D cultures (38-fold expansion). More importantly, the CD34+ (stem cell marker) cells are also significantly higher in 3D scaffolds (40-fold) relative to 2D cell culture (2.66- fold). PuraMatrix hydrogel [52] and gelatin [53] are some of the other materials employed to generate nanoscaffolds for tissue engineering. Neural stem/progenitor cells cultured in PuraMatrix hydrogel following transplantation in rat brain injury resulted in significant reduction in lesion volume, lowering in neurological deficits, and higher cell survival, which may be another promising approach toward in reengineering.

Another method for controlling growth and differentiation of stem cells is to grow the stem cells on a lab-on-a-chip. It is a tool that incorporates numerous laboratory tasks onto a small device, usually only millimeters or centimeters in size [54]. Some of these chips contain nanoreservoirs. Each chip surface containing thousands of reservoir cavities with radius in the nanometer range. The reservoir can be filled with biomaterials such that a stem cell may be exposed to in a niche, including lipid bilayers as well as voltage-gated channels. The chip technology allows for electrical exposure at specific time points to specific cells under chemical environment in a controlled manner. Such controlled environment renders the stem cell to differentiate in a correct manner. It also allows the cells to grow in layers making a complex tissue. These microfluidics- based technologies create a new path forward both for further development in regenerative medicine as well as for the development of high-throughput screening platforms. Sciancalepore et al. generated a renal microdevice that resembles in vivo structure of a kidney proximal tubule by embedding a population of tubular adult renal stem cells into a microsystem. The stem cells were exposed to fluid shear stress in the chip, which led to the correct polarization of the cells. It is in contrast to static cultures resulting in an ideal platform for testing agents for therapeutic and toxicological responses [55]. Similar technologies have been utilized to develop other organs on a chip such as heart-on-a- chip platform for cardiac drug screening as well as heart regeneration [56,57]. Li et al. utilized custom-built microfluidic perfusion bioreactors. This apparatus was integrated with ultrasound standing wave traps for cartilage tissue engineering. This system involved the use of sweeping acoustic drive frequencies (890—910 kHz) along with continuous perfusion of chondrogenic culture medium at a low-shear flow rate. This technique provides improved mechanical stimulation and mass transfer rates. This process induced the generation of 3D agglomerates of human articular chondrocytes, which resulted in enhanced cartilage formation [58]. Similarly, Mooney et al. have reported unique properties of carbon nanotubes (CNTs) in synergy with human mesenchymal stem cells (hMSCs). By using a fluorescent dye, single-walled nanotubes (SWNTs) were found to migrate through the cell wall to a nuclear location after 24 h. In addition, SWNTs had no significant effect on adipogenesis, osteogenesis, or chondrogenesis. This indicates CNTs had no adverse effects on hMSC biocompatibility, proliferation, or differentiation and have tremendous potential for future approaches in tissue repair/regeneration (Fig. 5.3) [59].

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