We hope readers will appreciate that the term tissue engineering represents a spectrum of novel approaches to managing significant clinical problems. As a new field that is developing rapidly, it must surmount many challenges before any widespread clinical use can result. Most of these challenges are not unique to tissue-engineering approaches, but rather are variants of issues faced by previous (and now established) advances in biomedicine. It is beyond the scope of this review to address these concerns in detail. However, we wish to call attention to two areas of particular importance, one practical and the other philosophical. Interested readers can find additional information in several sources.2,3,8,9
Manufacturing concerns. For tissue engineering to help alleviate clinical problems, it is necessary for tissue-engineered products to be manufactured reliably.26,27 This need is almost self-evident, but worthy of emphasis. The goals of successful tissue-engineering research are all commercially applicable (that is, to develop products for patient use). This health-related use raises numerous concerns, including the following:
- – feasibility of scaling up from research levels to industrial output;
- – batch-to-batch repeatability in production;
- – methods to achieve and maintain sterility;
- – tissue procurement for cell preparations;
- – optimal handling and storage methods.
THE TERM TISSUE ENGINEERING REPRESENTS A SPECTRUM OF NOVEL APPROACHES TO MANAGING SIGNIFICANT CLINICAL PROBLEMS.
These challenges already have been met for some tissue-engineered skin,26,27 as well as for conventional pharmaceuticals. Although new tissue-engineered products likely will be similarly successful, these concerns must be addressed for each product individually.
An additional and important consideration in the application of these new technologies is the cost associated with each device. It is likely that the cost of producing inductive factors (that is, purified proteins) and cells will be high, and will contribute significantly to the end cost for the patient. For example, a commercially available autologous chondrocyte transplantation system for orthopedic use has a cost of about $10,000 per patient. Although it is likely that fewer cells would be required for localized dental applications of this or an analogous cellular therapy, the cost, without doubt, will be in this range.
This economic issue is one of several concerns leading many companies to develop cellular allograft products. Large-scale production of allogeneic cells (that is, cells not targeted to a specific person), in contrast to a relatively small-scale production of each patient’s cells for an autograft device, will greatly decrease cell production costs. While the cost of inductive proteins is likely to be less than that of cell-based products, the first product commercially available, a bone growth-factor therapy, is likely to add several thousand dollars to the cost of bone fracture treatments.
Ethical concerns. There is significant debate among researchers in the biomedical community about at least two major ethical concerns related to tissue-engineered products. The first, tissue procurement, also is a manufacturing concern (see "Manufacturing Concerns" above). For many tissue-engineered products (such as skin equivalents and bioartificial organs), viable cells are an essential component. Unless a patient’s own cells can be amplified in an adequate and timely manner, enabling them to be used in the tissue-engineered device (that is, a cell autograft), then cells must be derived from another tissue.
This situation raises a number of significant ethical issues. For example, should the tissue source be other people or can an animal tissue (that is, a xenograft) be used? If the source is to be other people (that is, a cell allograft), should they be paid for their tissue samples (such as skin, liver)? This may induce people in financial distress to "donate" their tissues. Since fetal tissues often have more growth potential than adult tissues, should fetal tissues be used as a cell source? If, as with organs for transplantation, there are not enough cellular sources to meet the demand for any particular tissue-engineered device, how does one decide who will get the products (on the basis of need, ability to pay)?
For several cell-based tissue-engineering products, the use of animal cells has been explored. Perhaps the most significant effort has been in the development of an artificial pancreas and the use of porcine cells. Recently, researchers have called for a moratorium on research using cellular xenografts, in large part because of a hypothetical risk.58–60 This risk is that an animal (in this case, porcine) virus might successfully overcome the human species barrier, perhaps mutate, and result in a serious human disease. Although this circumstance, with respect to a porcine virus, is hypothetical, and there is no evidence that such an event could occur, there is recognition in the research community that the AIDS virus apparently had its origin in primates and "jumped species" through the human consumption of infected animals. A moratorium on xenograft research would recognize such potential societal implications and permit public and legislative discussion of xenograft use. Not surprisingly, there is no uniform agreement on this issue, although the dialogue has generally heightened awareness of ethical considerations in tissue engineering.59–61
THE IMPACT OF TISSUE ENGINEERING LIKELY WILL BE MOST SIGNIFICANT WITH MINERALIZED TISSUES, ALREADY THE FOCUS OF SUBSTANTIAL RESEARCH EFFORTS.