I. Introduction II. Cell Technology III. Construct Technology IV. Integration into the Living System V. Concluding Discussion VI. Acknowledgments VII. References The Challenge of Imitating Nature Robert M. Nerem Principles of Tissue Engineering, 3 rd Edition ed. by Lanza, Langer, and Vacanti Copyright © 2007, Elsevier, Inc. All rights reserved. I. INTRODUCTION Tissue engineering, through the imitation of nature, has the potential to confront the transplantation crisis caused by the shortage of donor tissues and organs and also to address other important, but yet unmet, patient needs. If we are to be successful in this, a number of challenges need to be faced. In the area of cell technology, these include cell sourcing, the manipulation of cell function, and the effective use of stem cell technology. Next are those issues that are part of what is called here construct technology. These include the design and engineering of tissuelike con- structs and/or delivery vehicles and the manufacturing technology required to provide off-the-shelf availability to the clinician. Finally, there are those issues associated with the integration of cells or a construct into the living system, where the most critical issue may be the engineering of immune acceptance. Only if we can meet the challenges presented by these issues and only if we can ultimately address the tissue engineering of the most vital of organs will it be possible to achieve success in confronting the crisis in transplantation. An underlying premise of this is that the utilization of the natural biology of the system will allow for greater success in developing therapeutic strategies aimed at the replacement, maintenance, and/or repair of tissue and organ function. Another way of saying this is that, just maybe, the great creator, in whatever form one believes he or she exists, knows something that we mere mortals do not, and if we can only tap into a small part of this knowledge base, if we can only imitate nature in some small way, then we will be able to achieve greater success in our efforts to address patient needs in this area. It is this challenge of imitating nature that has been accepted by those who are providing leadership to this new area of technology called tissue engineering (Langer and Vacanti, 1993; Nerem and Sambanis, 1995). To imitate nature requires that we first understand the basic biology of the tissues and organs of interest, including developmental biology; with this we then can develop methods for the control of these biologic pro- cesses; and based on the ability to control, we finally can develop strategies either for the engineering of living tissue substitutes or for the fostering of tissue repair or regeneration. The initial successes have been for the most part sub- stitutes for skin, a relatively simple tissue, at least by com- parison with most other targets of opportunity. In the long term, however, tissue engineering has the potential for creating vital organs, such as the kidney, the liver, and the pancreas. Some even believe it will be possible to tissue engineer an entire heart. In addressing the repair, replace- ment, and/or regeneration of such vital organs, tissue engineering has the potential literally to confront the trans- plantation crisis, i.e., the shortage of donor tissues and organs available for transplantation. It also has the potential Chapter Two