Delivery of Stem Cells

The major drawback to using an intravenous route of cell delivery would be the possibility that the therapeutic cells would become trapped in the microvasculature of the lungs, liver, and lymphoid tissues. This theoretical limitation of systemic transvenous delivery of stem cells has been confirmed experimentally. In a study by Toma et al. [97], human MSCs were injected into the left ventricular cavity of experimental mice 4 days later, an estimated 0.44% of the injected cells remained in the myocardium, and the rest had localized to the spleen, liver, and lungs. Other studies using the systemic delivery approach have produced similar results, with very low local cell retention rates of less than 5% [98, 99]. Thus, the transvenous delivery route appears unlikely to achieve the local cell concentration needed to produce a significant therapeutic benefit. 

Our group performed the first clinical trial of transendocardial injection of ABMMCs to treat heart failure patients [26]. This study, performed in collaboration with physicians and scientists at the Hospital Pro-Cardiaco in Rio de Janeiro, Brazil, used EMM-guided transendocardial delivery of stem cells. The results of 2- and 4-month noninva-sive and invasive follow-up evaluations [26] and of 6- and 12-month follow-up evaluation [129] have already been published. 

Bakshi, A., Hunter, C., Swanger, S., Lepore, A., Fischer, I. (2004). Minimally invasive delivery of stem cells for spinal cord injury advantages of the lumbar puncture technique. JNeurosurg Spine, 1,330-7. 

Chitosan microspheres are also combined with porous scaffold for the delivery of stem cells with high efficiency [171]. ADSCs are not only able to attach and infiltrate into the pores of the microspheres, but can also maintain multipotency after being released from the microspheres and into a collagen gel scaffold. This investigation provides a new approach for incorporation of stem-cell-loaded microspheres into suitable scaffolding architecture and for construction of tissue-engineered composite biomaterials. 

Our laboratory has also reported the combination delivery of stem cells with growth factor delivery. We looked specifically at the codelivery of HGF and MSCs in a mouse model of myocardial ischemia [89]. We demonstrated that delivery of both cells and HGF from PEGylated fibrin resulted in a 15-fold increase in cell retention with reduced fibrosis and enhanced ejection fraction as a measure of cardiac performance. An important conclusion of this study was that increases in blood vessel density could be produced through the release of the growth factor alone which was not necessarily correlated with improved cardiac output. While many growth factors are known to stimulate angiogenesis, the stabilization and maturation of newly formed vessels may be more complex and necessary for functional recovery. 

Li, Y.H., Feng, L., Zhang, G.X., Ma, C.G., 2015c. Intranasal delivery of stem cells as therapy for central nervous system disease. Exp. Mol. Pathol. 98, 145-151. 

In application of stem cells for tissue regeneration, support cells are often committed cell types that can be co-cultured with the stem cells to direct specific differentiation [143, 144]. In this instance, hydrogels serve as a platform to control the interactions between the stem and support cells [145] and as a delivery system to enable delivery of multiple cell types for regeneration of complex tissues [146]. It has been shown in several studies that co-delivery of stem cells and support cells have synergistic effects in tissue regeneration [146,147]. 

The current understanding of stem cell biology and kinetics gives important clues as to how one should deliver them. The efficacy of therapeutic stem cells will obviously depend largely on successful delivery. Stem cells have been delivered indirectly through peripheral and coronary veins and coronary arteries. Alternatively, they have been delivered... 

Results of recent studies have challenged the safety and effectiveness of intraeoronary delivery. There is growing evidence of very low retention of stem cells in target regions and of increased restenosis rates associated with this delivery method. 

Despite many unresolved issues related to treatment dose, timing, and delivery, the clinical potential of stem cell therapy for cardiovascular disease is enormous. The expectations of both patients and clinicians for this new therapeutic modality, however, are high and to achieve the full potential stem cell therapy has to offer will require continued cooperation and future close collaboration between basic and clinical scientists. 

Another novel cardiovascular therapy that has recently come into play is the use of stem cell delivery. These approaches have thus far involved the use of gene delivery mechanisms to essentially force embryonic stem cells into cardiomyocyte differentiation with the goal of producing a cardiac pace-making cell (Arruda et al., 2004). Researchers are also developing methods for utilizing seeded adult mesenchymal stem cells as an implanted base to act as a depot for the delivery of localized gene therapies (Arruda et al., 2004). 

This review firstly focuses on modification of the chitosan molecule to obtain desired properties and functions. The most important material forms (porous scaffolds, hydrogels, and rods) and delivery vectors fabricated from chitosan and its derivatives will be introduced. Particularly, the interaction and modulation of stem cell behavior by chitosan will be discussed. Finally, the applications of chitosan-based materials for repair and regeneration of various tissues and organs such as skin, cartilage, and bone will be summarized. 

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