**3. Use of placenta mesenchymal stem/stromal cells (PMSC) and nanotechnology for tissue regeneration**

The goal of cell-based regenerative medicine is to repair, replace, or regenerate cells, tissues, or organs when damaged. However, there are still some unresolved issues such as engraftment of transplanted cells onto the injured tissue and the survival for the time needed to repair the damage. Nanotechnology can be very helpful since nanomaterials can be used as scaffolds to improve the engraftment of stem cells onto the damaged tissue. In addition, the use of nanoparticles (NPs) for gene/drug delivery can complement the therapeutic benefits of transplanted stem cells, and allow the tracking of the cells inside the body [90].

Several reports described the therapeutic application of PMSC combined with biomaterials. PMSC proliferation and differentiation into myocardial and neuronal cells improved when the cells were grown on top of gold-coated collagen nanofibers (GCNFs) [91]. The peptide hydrogel PuraMatrix® (PM; 3-D Matrix, Ltd) was used to support PMSC in rat models of both acute MI and post-MI ischemic cardiomyopathy. The peptide hydrogel and the PMSC create a film to coat the heart. The epicardial "coating" method has advantages with respect to intramyocardial injection such as higher survival of the transplanted cells and lower complications [92].

In bone regenerative medicine, the RKKP glass ceramic has been proposed as a biocompatible support for PMSC. RKKP exhibits a higher osteointegration rate compared to other ceramic materials mainly in osteopenic bone. Additionally, the biology of PMSC is not affected when grown over this support while maintaining their osteogenic potential [93] PMSC seeded over poly-L-lactic acid (PLLA) nanofibrous scaffolds and subjected to osteogenic conditions have been successfully grafted in a rabbit model of sternal defect closure [94].

**2.6. Use of placental mesenchymal stem/stromal cells in intestinal inflammatory** 

These benefits were greater when NOD2-activated PMSC were used [88].

sphincter to apparently normal histology and function [89].

**nanotechnology for tissue regeneration**

**2.7. Use of placental mesenchymal stem/stromal cells in urological diseases**

**3. Use of placenta mesenchymal stem/stromal cells (PMSC) and** 

transplanted stem cells, and allow the tracking of the cells inside the body [90].

Stress urinary incontinence (SUI) is a widespread disorder, commonly associated with childbirth, with a detrimental impact on the quality of life. SUI triggers a weakening of muscles and ligaments causing involuntary leakage of urine during physical activity, sneezing, or coughing. Surgical intervention to place a tissue sling that provides support to the urethra is

Animal models of SUI have been employed to prove the benefits of cell therapy in this pathology. Periurethral injection of myogenic differentiated PMSC in SUI mice restored the urethral

The goal of cell-based regenerative medicine is to repair, replace, or regenerate cells, tissues, or organs when damaged. However, there are still some unresolved issues such as engraftment of transplanted cells onto the injured tissue and the survival for the time needed to repair the damage. Nanotechnology can be very helpful since nanomaterials can be used as scaffolds to improve the engraftment of stem cells onto the damaged tissue. In addition, the use of nanoparticles (NPs) for gene/drug delivery can complement the therapeutic benefits of

Several reports described the therapeutic application of PMSC combined with biomaterials. PMSC proliferation and differentiation into myocardial and neuronal cells improved when the cells were grown on top of gold-coated collagen nanofibers (GCNFs) [91]. The peptide hydrogel PuraMatrix® (PM; 3-D Matrix, Ltd) was used to support PMSC in rat models of both acute MI and post-MI ischemic cardiomyopathy. The peptide hydrogel and the PMSC create a film to coat the heart. The epicardial "coating" method has advantages with respect to intramyocardial injection such as higher survival of the transplanted cells and lower complications [92].

Crohn's disease (CD) and ulcerative colitis (UC) are chronic conditions caused by a sustained inflammation of the intestinal epithelium that ends in tissue destruction throughout the gastrointestinal tract. It is believed that these disorders are the result of an abnormal host immune response to intraluminal antigens in genetically predisposed individuals. Several genetic variants of nucleotide-binding oligomerization domain 2 (NOD2) are associated with the development of Crohn's disease [86]. Both pathologies have a major impact on the quality of life and there is no curative treatment. Furthermore, many patients are not responsive to current therapy. Intraperitoneal administration of conditioned medium from PMSC ameliorated clinical parameters in a mouse model of dextran sulfate sodium (DSS)-induced colitis [87]. Intraperitoneal injection of PMSC also prevented the loss of body weight and decreased the mortality of mice.

**diseases**

238 Stromal Cells - Structure, Function, and Therapeutic Implications

the usual therapeutic action.

Some systems have shown suitable behaviors as recipients of PMSC for cartilage regeneration. Collagen sponge allowed the formation of a cartilage-like tissue both, in vitro and in vivo, under chondrogenic-inducing conditions [95]. Similarly, PMSC embedded in alginate incorporating nanosized calcium-deficient hydroxyapatite (nCDHA) and/or a recombinant protein containing arginine-glycine-aspartate (RGD) and seeded over poly(D,L-lactide-co-glycolide) (PLGA) gave rise to cartilage formation [96].

The use of nanoparticles for gene/drug delivery can significantly contribute to the advance of regenerative medicine. The use of stem cells as carriers of NPs containing biologically active molecules (e.g., pro-survival, anti-inflammatory) or chemicals such as anticancer drugs is very promising. PMSC have been employed as a platform to load mesoporous silica nanoparticles. NP loading did not affect the chemotactic ability of PMSC toward tumors in vitro and in vivo. When carrying doxorubicin-loaded NP, PMSC promoted breast cancer cells death in a coculture system [97]. In a proof of concept, ultrasound-responsive NPs loaded with antitumor drugs were transported to tumor tissues by PMSC, and the cargo was released by NPs only after ultrasound application [98].

In vivo monitoring of cells, after transplant, is needed and NP-based probes are useful for this purpose. They offer the possibility of tracking the bio-distribution and engraftment of cells into the body with minimally invasive techniques. However these probes have to ensure minimal changes in cell phenotype [97]. PMSC have been efficiently labeled with albuminconjugated fluorescent nanodiamonds (FNDs) [99], with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, MNPs@SiO2(RITC) [100], with rhodamine B labeled mesoporous silica nanoparticles [98] and with human serum albumin coated iron oxide nanoparticles (HSA-IONPs) [101] without any detrimental effect.
