The field of tissue engineering has reached a critical junction. The fundamental principles of tissue engineering are based on cell transplantation, which has been studied for more than 60 years. The concept of tissue engineering is appealing and easily understood by clinicians, scientists, investors, and the general public. During the 1990s, tissue engineering received highly favorable media attention. Tissue engineering was hailed as one of the greatest scientific achievements of the twentieth century, and both scientific and general media endorsed the field's potential. In 2000, Time magazine predicted that a career in tissue engineering would become one of the "10 Hottest Jobs of the Future" . In 2002, Science magazine featured a special issue on the bionic human and the development of "off-the-shelf replacement parts for the human body" . During the economic boom of the 1990s, there was significant capital inflow into tissue engineering, and several tissue-engineering companies were founded.
Twenty years later, the future seems to look less promising. Although the concepts have been known for 20 years, and serious research activity has been conducted for 15 years, there are only a few clinical applications of tissue engineering. An ambitious plan to grow a fully functioning heart from a Petri dish of human cells within 10 years was proposed by the LIFE (Living Implants From Engineering) initiative, based at the University of Toronto, and ultimately collapsed. Furthermore, the financial performance of companies with tissue-engineered products has been rather dismal, and almost all tissue-engineering companies have disappeared. The financial collapse of Advanced Tissue Sciences and Organogenesis, two of the leading tissue-engineering companies, is related to the economic recession, but also indicates decreased investor confidence. Currently, four products have received FDA approval. Apligraf®, Dermagraft®, and OrCel® are living-skin equivalents for the diabetic and venous ulcers and burn patients, and Carticel® consists of autologous chondrocytes for cartilage repair. In addition, ten tissue-engineered products are engaged in clinical trials, while another six products failed to meet efficacy in phase III or were abandoned during phases I or II. To assess the past performance and future of tissue engineering, it is important to distinguish between the scientific and finance-related aspects. A detailed discussion about the past performance and the economic lessons is beyond the scope of this chapter, and the interested reader is referred elsewhere .
Despite the failure of tissue engineering to grow whole, complex organs in the laboratory, the field is adapting and continuing to move forward. It has become apparent that the task of growing a whole organ is too complex, and a recent shift in focus toward individual components has occurred. One of the largest efforts is the BEAT (BioEngineered Autologous Tissue) initiative, based at the University of Washington and supported by a $10 million, 5-year grant from the National Institutes of Health (NIH) to create patches of cardiac muscle to repair the damage caused by heart attacks. Should this approach be successful, the next goal is to create a ventricle. This approach could possibly lead to a complete tissue-engineered heart. Hence, the concept of whole organs has not been completely abandoned yet. To achieve this goal, an even more integrated and interdisciplinary approach combining the life sciences, engineering and clinical medicine will be required.
One of the key limitations to applying cell-based therapies toward organ replacement has been the inherent difficulty to grow specific cell types in sufficient quantities. Even organs like the liver that have high regenerative capabilities in vivo, show reduced cell growth and expansion in vitro. The arguably greatest contribution for tissue engineering is from cell biology. The completion of the Human Genome Project is providing a wealth of information that is expected to lead to a more complete understanding of cells and cell behavior. Another critical contribution is the understanding of cell phenotype. The discovery of nuclear
Fig. 16.6 a Vasculature of a human liver. Nature solves the mass transport problem by providing a convective network of blood vessels. The asterisks (*) denote the largest vessels, which subsequently branch into 10 generations of smaller vessels. (Reprinted with permission from Vonnahme FJ (1993). The human liver: a scanning electron microscopic atlas. Karger, Basel). b Silicon microfabrication offers enhanced resolution to create a network of channels with a topology reminiscent of a vasculature. The network design is created using a computational model that mimics blood flow and takes blood rheology into account. Silicon wafers with etched channels are created using standard microfabrication techniques. c Schematic representation of the microfabrication approach to create vascularized tissue-engineered organs. (Reprinted with permission from IEEE Spectrum Online, http://www.spectrum.ieee.org)
transfer has shown that reprogramming nuclear DNA to express many phenotypic programs is possible. It is anticipated that this will lead to a better understanding of differentiation pathways. Adult and embryonic stem cells have also become the focus of attention due to their inherent plasticity. Embryonic stem cells are of particular interest because they can be expanded in an undifferentiated state in vitro and subsequently induced to form many different cell types. This is particularly beneficial in applications where the source of cells is limited or not available. Stem cell research and gene therapy are still in the early stages, so their full biology and therapeutic potential remain to be discovered. Other areas of interest are wound healing and tissue assembly. While cell biology has traditionally focused on molecular events on a cellular level, efforts to move to the next hierarchical level and understand how molecules and cells form tissues will directly contribute to tissue engineering. Cancer research is another area that is likely to affect tissue engineering because the formation of blood vessels is central to both fields .
Another active area of research is biomaterials and scaffold development. Since the early days of using debrided surgical sutures as a scaffold, materials synthesis and processing have made significant advances. New fabrication methods for creating three-dimensional scaffolds with improved mechanical properties and surface chemistries have emerged. Integration with imaging and the development of patient-specific scaffolds is also actively investigated . New materials are being synthesized, e.g., biomimetic natural and synthetic polymers, and osteoconductive ceramics [164-166]. A detailed understanding of cell-material interactions is also crucial. The ultimate goal is to create scaffolds that encode specific instructions for controlling tissue formation, analogous to signals during embryological development. The biggest challenge is the creation of three-dimensional structures that contain more than several cell layers. To this end, several approaches have emerged. The incorporation of growth factors to induce angiogenesis is one strategy that is showing promise [167, 168]. However, angiogenesis takes 3 to 5 days, and this approach may be limited to specific applications. Another approach is to abandon the scaffold and stack individual cell layers. This versatile approach has been applied to many different tissues and has significant potential . Advances in active research areas such as nanotechnology, hydrogels, and self-assembled materials are also expected to find application in tissue engineering [170-172].
Despite the initial problems, tissue engineering has a bright future. The overall goal of tissue engineering of developing tissue equivalents for the repair, replacement, maintenance, or augmentation of tissue and organs is expected to have a significant impact on health care. However, the impact of tissue engineering is expected to be even more significant. In addition to therapeutic tissue engineering as discussed here, diagnostic tissue engineering is emerging as an approach to develop tissue equivalents for in vitro drug testing and the development of improved therapeutic agents. In particular, the development of human tissue equivalents would alleviate some of the problems associated with species-specific events. If the tissue is organized in its native configuration rather than in a two-dimensional Petri dish, such constructs are expected to be better models for the search of therapeutic treatments and improve the physiologic relevance of in vitro testing.
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