Elsevier

Advanced Drug Delivery Reviews

Volume 60, Issue 2, 14 January 2008, Pages 277-285
Advanced Drug Delivery Reviews

Cell sheet engineering for heart tissue repair

https://doi.org/10.1016/j.addr.2007.08.031Get rights and content

Abstract

Recently, myocardial tissue engineering has emerged as one of the most promising therapies for patients suffering from severe heart failure. Nevertheless, conventional methods in tissue engineering involving the seeding of cells into biodegradable scaffolds have intrinsic shortcomings, such as inflammatory reactions and fibrous tissue formation caused by scaffold degradation. On the other hand, we have developed cell sheet engineering as scaffoldless tissue engineering, and applied it for myocardial tissue engineering. Using temperature-responsive culture surfaces, cells can be harvested as intact sheets and cell-dense thick tissues are constructed by layering these cell sheets. Myocardial cell sheets non-invasively harvested from temperature-responsive culture surfaces are successfully layered, resulting in electrically communicative 3-dimensional (3-D) cardiac constructs. Transplantation of cell sheets onto damaged hearts improved heart function in several animal models. In this review, we summarize the development of myocardial tissue engineering using cell sheets harvested from temperature-responsive culture surfaces and discuss about future views.

Introduction

Recently, cell-based therapies have emerged as alternative treatments to cardiac transplantation for the repair of damaged heart tissue, since the benefits of heart transplantation are restricted by donor shortages [1]. Although cell suspension transplantation is one of the promising treatments for impaired heart tissue, it is often difficult to control shape, size and location of the injected cells. Additionally, isolated cell transplantation may not be applicable in treating myocardial tissue defects. Therefore, research on methods of transplanting tissue-engineered functional heart grafts has been established over the past decade.

Tissue engineering has been developed as a basic technology for regenerative medicine. The popular components used in tissue engineering approaches have generally included isolated cells or cell substitutes, appropriate signaling molecules such as cytokines or growth factors, and extracellular matrix (ECM) proteins [2]. As alternatives for the extracellular matrix, 3-dimensional (3-D) biodegradable scaffolds have been used for the reconstruction of various tissues and organs including cartilage, bone, skin, blood vessels and heart valves.

By using the methods based on biodegradable polymers, the spaces occupied by the biodegradable polymers often become filled with large amounts of deposited ECM, with the number of cell-to-cell connections becoming reduced in the resultant tissues. In addition, scaffold biodegradation can result in inflammatory responses and pathological fibrotic states. To overcome these problems, we have developed a novel tissue engineering methodology termed “cell sheet engineering”, that constructs 3-D functional tissues by layering two-dimensional (2-D) confluent cell sheets without the use of any biodegradable ECM alternatives.

Section snippets

Cell sheet harvest using temperature-responsive culture dishes

Cell sheets are obtained by using specialized cell culture surfaces that are covalently grafted with the temperature-responsive polymer, poly (N-isopropylacrylamide) (PIPAAm) [3], [4]. The surfaces are slightly hydrophobic and cells adhere and proliferate under normal culture conditions at 37 °C. By lowering the temperature below 32 °C, the surfaces become highly hydrophilic and therefore non-adhesive to cells due to rapid hydration and swelling of the grafted PIPAAm. This unique surface change

Myocardial tissue engineering by layering cell sheets

In myocardial tissue engineering, various biomaterials such as poly (glycolic acid) (PGA), gelatin, alginate and collagen have been used as prefabricated biodegradable scaffolds [21]. For the repair of damaged cardiac muscle, two strategies have been applied to incorporate cells into the scaffolding materials. One method is to seed cells into prefabricated, highly porous scaffolds (Fig. 2A). The group of Papadaki and Vunjak-Novakovic reported the cultivation of neonatal rat cardiomyocytes on

Cell sources

Although it has been possible to reconstruct myocardial tissues using tissue engineering methods, several crucial problems remain unresolved for future clinical applications. One of the critical problems is the potential source of cardiac cells. Thus far, primary cells derived from fetal or neonatal hearts have been applied to regenerate myocardial tissues in animal studies, it is difficult to obtain human fetal or neonatal cardiomyocytes with regard to ethical and moral concepts. From these

Conclusions

Myocardial tissue engineering based on cell sheet engineering can provide new in vitro heart models and might be useful for cardiovascular tissue repair.

Acknowledgements

We would like to thank Joseph Yang for his helpful assistance. The present work was supported by grants for the High-Tech Research Center Program and the Center of Excellence Program for 21st Century from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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