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Circulation Research. 2002;90:120-122

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(Circulation Research. 2002;90:120.)
© 2002 American Heart Association, Inc.

Editorials

Can Tissue Engineering Mend Broken Hearts?

Robert E. Akins

From the Department of Biomedical Research, A.I. duPont Hospital for Children, Wilmington, Del.

Correspondence to Robert E. Akins, PhD, Head of Tissue Engineering and Regenerative Medicine Research, Dept of Biomedical Research, A.I. duPont Hospital for Children, PO Box 269, Wilmington, DE 19899. E-mail rakins{at}nemours.org


Key Words: heart disease • tissue engineering • congenital heart defects • cell biology • surgery

Cardiac tissue engineering is an emerging field that may hold great promise for advancing the treatment of heart diseases. Cardiac tissue engineering is in its infancy, and the overall field of tissue engineering, which was formalized in the late 1980s at conferences and workshops sponsored by the National Science Foundation, is still new enough to warrant some description. By broad definition, tissue engineering involves the construction of tissue equivalents through the manipulation and combination of living cells and biomaterials. It is a multidisciplinary field combining diverse aspects of the life sciences, engineering, and clinical medicine. The overall goal of tissue engineering is to develop tissue equivalents for use in the repair, replacement, maintenance, or augmentation of tissues or organs. Although some aspects of cardiac tissue engineering research have been ongoing for generations, albeit without being known as such, directed efforts in the field are only beginning.

The main justification for cardiac tissue engineering initiatives is straightforward: congenital and acquired heart diseases are substantial health problems, and there is a limited amount of donor tissue for use in surgical repairs. Heart defects are the most common congenital defect and are the leading cause of death in the first year of life.1,2 Congenital heart defects may occur in as many as 14 of every 1000 live births,3 and approximately 25 000 surgical procedures are performed each year to correct them. Acquired heart diseases also have a profound effect on the population, and despite tremendous advances in medical and surgical treatments, it is estimated that each year 20 000 to 40 000 Americans could benefit from a heart transplant.4 Unfortunately, fewer than 2500 heart transplants are performed each year.4,5 One of the principal reasons for the disparity between patient need and procedures performed is the lack of donor material for implantation. Furthermore, current treatments short of transplantation are essentially restricted to medical and surgical approaches that address the sequelae of the primary defect, and current approaches do not always restore lost structure and/or function. A large number of patients who are not necessarily candidates for transplant may benefit from smaller structures like pieces of muscle, valves, or vessels. There is a need for new approaches to treat profound heart disease, and the possibility that diminished cardiac function may be recovered through the implantation of tissue-engineered, biosynthetic constructs is compelling.

The need for advanced surgical implant materials is not the only justification for cardiac tissue engineering research, however. The development of tissue equivalents for use in vitro could improve the testing of drugs and potential therapeutic agents and could expand our understanding of cardiac cell biology. Large numbers of animals are used each year in research, drug testing, drug development, pharmacological testing, and education (more than 1.2 million in 1998, excluding rats and mice, according to the USDA). Cell culture alternatives are also routinely used in research and testing; however, typical cell culture models confine cells to a 2-dimensional configuration that does not resemble the organization of cells within the intact tissue. With evidence that cellular activities and responses are affected by organization and mechanical activities,6,7 there is an increasing need to perform studies within the context of the intact cardiac tissue. In addition, the numerous species differences between humans and the animal models used for the research, development, and testing often preclude the use of data derived from animal models to draw specific conclusions about what may happen in humans. The development of human cardiac tissue equivalents would alleviate some of the serious problems associated with species-specific effects. By virtue of being of human origin and organized like tissue, such constructs would provide superior cell culture models for research, reduce the number of animals required for testing, and improve the physiological relevance of in vitro testing.

Clearly, the development of either implantable materials or tissue equivalents for use in vitro will require a large amount of concerted effort. Fortunately, substantial groundwork for this effort has been established over the past decades. The first demonstration of in vitro cardiac cell culture was provided by Burrows in the early 1900s.8,9 Ensuing generations of researchers have performed an enormous amount of research using in vitro culture models. Examples of the many contributions in this area include work on extracellular matrix,10,11 studies of 3-dimensional models from suspension culture,12 and details of mechanical force transduction affecting cardiomyocytes.13,14 Each of these may be especially significant to tissue engineers. The application of the wealth of information to potential regenerative therapies has only recently begun.

Three general tissue-engineering approaches have been attempted thus far. The first approach involves the implantation of cell suspensions directly into the heart. A number of cell-implantation studies have been performed in animals15–19 and humans20,21 using a variety of cell types. Results from these and related studies demonstrate that implanted cells can incorporate into existing cardiac structures. This approach, however, may be of little clinical benefit when the local cardiac structure cannot support cell seeding because it is missing or seriously damaged. The second approach is primarily materials-based and involves culturing cardiac cells within pre-formed 3-dimensional mesh, foam, or ceramic scaffolds.22–24 Some of the most promising studies have used this approach. Shinoka et al25 demonstrated the use of a biosynthetic pulmonary valve in sheep, and Sodian et al have constructed trileaflet valves using biodegradable polyhydroxyalkanoate scaffolds.26,27 Li and coworkers28–30 have grown small 3-dimensional cardiac grafts and implanted them into host myocardia and the right ventricular outflow tract. Two critical observations from this work were the survival of grafted material and the apparent vascularization of the implants by the host circulation. Highly engineered scaffolds could, in theory, direct the gross conformation of a construct, influence the phenotype of cellular components, or direct particular cells to specific sites within a construct. This approach may prove immensely powerful in the eventual production of large tissue equivalents. The third approach involves the culture of cells in suspension with31–34 or without12 orienting surfaces, matrix, or cell adhesion molecules. The establishment of structure through this last approach is apparently directed by the cell population or by the mechanical and fluid environments of the culture. One observation from these studies is that tissue architecture can be formed without extensive 3-dimensional cues form the matrix. For now, methods of this third type may be best suited for studying tissue-engineering concepts or for producing small implants or devices, but in the long-run the technologies will likely converge with the materials-based methods.

In an article in this issue of Circulation Research,35 Eschenhagen’s group uses the third type of approach to provide one of the most advanced examples of engineered cardiac tissue to date. The group used a modification of a previous procedure in which cells were suspended in a mixture of collagen, basement membrane, and serum then cast in circular molds. After the mixture coalesced, the constructs were subjected to unidirectional cyclic stretch. The application of cyclic stretch resulted in orientation of myocyte contractile activity in a manner previously elaborated by their group and similar to that described by Vandenburgh’s group.14 The resulting constructs were characterized in terms of similarity to tissue, and the investigators report that oriented bundles of myocytes exhibiting electrical and mechanical coupling were prevalent. The contractile activity of the constructs was superb, and the method appears to be highly reproducible. This and related reports by the same group establish a method for generating engineered heart tissue (EHT). By virtue of the method’s reproducibility and the characteristics of the constructs described so far, EHTs should represent an excellent source of material for in vitro testing. With some modifications to the procedure, EHTs may also provide suitable material for implantation studies.

Clearly, there are many further characterizations required to establish EHTs as true tissue equivalents. Some of these characterizations are straightforward. For example, do EHTs exhibit the Frank-Starling effect or do inotropic and chronotropic agents affect the muscle as predicted? These assessments are likely underway. Several issues regarding EHTs, however, may prove more difficult to address. Some of these may be crucial in future tissue engineering efforts. Elucidation of the mechanism by which EHTs achieve tissue- or organ-level functionality would be key to allowing tissue engineers to manipulate and control the process to produce desired constructs. A host of comparisons between EHTs and intact tissue, especially those related to the responsiveness of EHTs to hormones, cytokines, pharmaceutical compounds, etc, might be needed. Detailed assessments of the genomic, proteomic, and/or metabolic profiles of the EHTs will be needed to establish firmly that EHTs are tissue equivalents. The applicability of the current method to human heart cells will be critical. Controlling automaticity, which was apparent in the rat EHTs described in the paper, may be critical, and the arrhythmogenic potential of the EHTs in general will need to be evaluated. Eschenhagen’s group has made a clear step forward in cardiac tissue engineering, but numerous more steps need to be taken to realize the potential of cardiac tissue engineering.

There are also fundamental questions surrounding cardiac tissue engineering as a field. The recent success of the AbioCor artificial heart36,37 must be taken into account, and though it will take some time to evaluate, tissue engineering a complete heart replacement may not be necessary. The true value of cardiac tissue engineering in the surgical setting may be in the provision of implantable constructs short of complete hearts or in small biological interfaces for mechanical hearts. The development of such small implants has been emphasized by the NIH. Developing smaller pieces of heart as waypoints in developing an entire organ is also the approach being used by the LIFE tissue engineering initiative.38 The development of the AbioCor will be unlikely to affect tissue-engineering initiatives in the near future but may factor heavily in the future.

In the nonsurgical setting of the lab, the need for tissue-engineered constructs is not affected by the development of mechanical devices or even by the refinement of xenografting techniques. In fact, the need for human tissue equivalents may grow as more effort is placed into verifying the safety and the arrhythmogenic potential of test drugs. Recent experience has shown that even drugs that are not targeted to the cardiovascular system may adversely affect the heart, and tissue engineering may be a desirable approach to assuring drug actions.

If, as suggested by Zimmermann et al35 and others, researchers can culture functional constructs with the biological, mechanical, and electrical properties of cardiac tissue, it may be possible to specifically tissue engineer constructs for clinical and laboratory use. Autologous or heterologous cells collected from a variety of sources including biopsies, reductive surgeries, donor organs, or stem cells of some type may have practical use in the construction of biosynthetic implants. The eventual application of tissue engineering to the heart will require a profound understanding of varied and complex topics. Eschenhagen’s group has taken a big first step toward developing tissue equivalents, and the development of first-generation human tissue equivalents may soon follow. With concerted effort within the scientific community, it may be possible to treat diverse diseases of the heart using tissue engineering sometime in the future.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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