5.3. CLINICAL TRIALS 59

MSCs transduced with GFP. The use of a scaffold promoted local cellular engraftment and survival. The number of residual GFP+ cells was greater with the scaffold than after cell suspension injection (9.7% vs. 5.1% at one month and 16.3% vs. 6.1% at two months, respectively). This concurred with a significant increase in mRNA VEGF level in the scaffold group. Clusters of GFP+ cells were detected in the peri-infarct area, mainly phenotypically consistent with immature MSCs. Functional assessment by echocardiography at two months post-infarct also showed a trend toward a lower left ventricular dilatation and a reduced fibrosis in the scaffold group in comparison to direct cell injection group [15].

5.2.3ADULT ADIPOSE TISSUE-DERIVED STEM CELLS

Adipose tissue is an appealing source of MSCs for clinical autologous cell therapies and tissue engineering [17]. Miyahara et al used the cell sheet technology (see Section 6.3 for more details) to regenerate the infarcted myocardium with autologous adipose tissue-derived MSCs in rats with chronic heart failure secondary to MI. In situ growth of the adipose tissue-derived monolayered MSCs developed into neovessel-rich stratum that also contained some undifferentiated cells and cardiomyocytes. The engrafted MSC tissue improved heart function and reversed wall thinning of the infarcted area when compared to control animals treated with a monolayer of dermal fibroblasts. The restorative effect of the stem cell monolayer was attributed to the MSC capacity to differentiate into vascular cells and to secrete angiogenic cytokines [8]. Hamdi et al used autologous adipose stem cell sheets for MI repair in rats. Epicardial deposition of cell sheets resulted in increased cell survival and engraftment (shown by larger number of eGFP-positive cells in the epicardial and intramyocardial layers), associated with better preservation of LV geometry, when compared to dissociated cell injection [18].

5.2.4CARDIAC STEM/PROGENITOR CELLS

Although several studies are already performed using direct injection of various CSC/CPC types in MI models, tissue engineering approaches utilizing these cells are still in their infancy. Zakharova et al used a cardiosphere-derived cell sheet approach to restore infarcted myocardium in a rat model. Delivery of rat or human cardiac progenitor cells as cell sheets had a very positive effect on cell survival and facilitated migration from the sheet to the area of ischemic injury. Moreover, cardiosphere-derived cell sheet transplantation promoted cardiomyogenic and vascular differentiation, and significantly reduced adverse LV remodeling [19].

5.3CLINICAL TRIALS

In the MAGNUM (Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium) phase 1 clinical trial, bone marrow cells seeded in collagen type 1 patch were implanted onto 10 patients who had coronary artery bypass grafts and were intramyocardially injected with suspensions of autologous bone marrow cells. In 10 other patients, the treatment was only cell suspension injection

60 BIBLIOGRAPHY

into the infarcted myocardium. The results of this investigation revealed that the combined strategy of cell suspension injection and implantation of the cardiac patch on the infarct resulted in greater LV ED volume and scar thickness compared to cell suspension injection alone, at a 10±3.5 months follow-up. Both treatments improved ejection fraction in those patients compared with the baseline measurements performed one week before coronary artery bypass [20, 21]. Clearly, the implantation of biomaterial scaffolds onto the infarct zone significantly contributed to the maintenance of LV wall thickness, probably by increasing the retention of transplanted cells as well as by providing space and support for penetrating host cells. Together, this resulted in thicker scars and reduced stress on LV wall, eventually attenuating remodeling of the heart.

5.4SUMMARY AND CONCLUSIONS

This chapter presented a handful of studies aimed to investigate the applications of biomaterials as stem cell delivery vehicles. Only a few of these studies directly measured the extent of cell retention and engraftment. These studies show increased percentage of cells surviving in the infarct, when delivered as a biomaterial patch. However, the long-term engraftment (several months) is still low ( 10-20%), emphasizing the need for continuous refinement and engineering of the biomaterial schemes, and the possible introduction of pro-survival factors. In parallel, the feasibility and efficacy of biomaterial-based cell delivery awaits confirmation in large and randomized clinical trials.

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