Despite significant technological and medical advances, tissue loss and/or organ failure remains one of the most devastating and costly problems in health care. Since 1989, the number of patients has more than quadrupled in the United States alone. Currently, there are more than 80,000 patients on the national waiting list for organ transplants. In addition to this rapid increase, demand for donor organs continues to exceed supply by a substantial margin [1].

Currently, the most common treatment modalities include artificial devices, surgical reconstruction, and transplantation. In some instances, drug therapy is sufficient to replace the formation of metabolic products of a diseased or malfunctioning organ. This approach is common in endocrinology, and perhaps the best-known example is insulin injections for the treatment of diabetes. Improved delivery devices have resulted in better patient compliance, but the lack of normal feedback mechanisms may lead to an imbalance of hormonal levels and cause either acute or long-term complications [2, 3].

Artificial devices made of nonbiological materials, such as metals and plastics, are now routinely used in a variety of applications, ranging from joint replacements to mechanical heart valves and vascular grafts. These devices are also used in various extracorporeal applications such as dialysis. Due to the interface between the host tissue and the foreign material, artificial devices are prone to infection, thromboembolism, and frequently subject to limited materials durability [4]. The increased life expectancy of the aging population and the need for surgical treatments in increasing numbers of younger patients are placing greater demands on the durability and expected clinical lifetime of artificial prostheses. At present, well-designed prostheses have excellent clinical success rates for the first decade in most patients. However, in the second decade of the prosthesis' life, the failure rate and need for revision operations increase significantly [5, 6]. To alleviate these problems, research efforts are being undertaken to develop a better understanding of the behavior of materials in the physiological environment and thereby create more biocompatible and biomi-metic materials [7-9]. While these research efforts are expected to lead to improved performance of artificial devices, the most important drawback of implantable artificial devices is the lack of growth potential, which is particularly relevant for pediatric patients.

Surgical reconstruction relies on using either different organs or unaffected tissue to replace damaged tissue or organs. Saphenous veins have been successfully used as bypass grafts. Myocutaneous flaps, either as pedicled flaps or as free tissue transfers, have also been effectively used for a variety of soft tissue defects [1013]. However, since the replacement tissues are of a different tissue type, they are usually unable to restore full function. Furthermore, donor site morbidity and the scarcity of harvest sites remain critical issues [14].

Since the first successful transplant of the cornea in 1906, transplantation surgery has made significant advances [15]. The first successful human organ transplant was performed by Murray and colleagues in 1954, and the success with the kidney led to attempts with other organs [16-18]. Today, survival times ranging from 12 years (intestine) to more than 38 years (kidney) have been reported [19]. This success has been made possible by advances in transplantation biology and immunology, e.g., the introduction of tissue typing and the development of immunosuppressants to prevent allograft rejection. In particular, the discovery of cyclosporine brought transplants from research surgery to live-saving treatment [20, 21]. Despite these significant advances, organ and tissue transplantation remain imperfect solutions. Transplant recipients must follow lifelong immunosuppression regimes that are associated with increased risks of infection, potential for tumor development, and side effects. Most importantly, the aforementioned donor organ shortage limits the widespread availability.

To overcome these shortcomings, tissue engineering has been proposed as an alternative approach. The term tissue engineering was initially coined at a meeting sponsored by the National Science Foundation (NSF) in 1987. Formally, tissue engineering can be de-

fined as "the application of the principles and methods of engineering and the life sciences toward the development of biological substitutes that restore, maintain or improve tissue function" [22]. Tissue engineering is an interdisciplinary approach that relies on the synergy of developmental biology, materials engineering, and surgery to achieve the goal of developing living substitutes that restore function and become fully integrated into the patient. Two principal approaches have been studied, the direct injections of selected cells, and combined transplantation of cells and biodegradable scaffolds to provide temporal structural support and guide tissue regeneration. The fundamental hypothesis underlying both approaches is that dissociated, healthy cells will reorganize into functional tissue when given the proper structural support and signaling cues.

Studies of direct cell injections have been carried out in animals and humans using a variety of cell types and organs [23-25]. This approach allows the use of selected cell populations to carry out a specific function and has attracted particular interest as a treatment option for infarcted myocardium [26, 27]. In addition, it is possible to manipulate cells prior to injection [24, 28, 29]. The injected cells rely on the stroma of the host organs for cell attachment and reorganization, and it is difficult to avoid migration of the injected cells.

The combination of temporary scaffolds and cells has become a key approach in tissue engineering (Fig. 16.1). Using this approach, tissue engineering requires three key components: (1) an appropriate cell source, (2) biodegradable scaffolds with suitable biological and mechanical properties, and (3) the proper environment to deliver the cells to the scaffold and promote attachment and proliferation.

Cells for tissue engineering may be drawn from a variety of sources. Primary cells may be autologous, syngeneic, allogeneic, or xenogeneic. The use of autol-ogous or syngeneic cells is generally preferred to avoid immune reactions, but donor site morbidity or limited proliferative capability can be important limitations. At present, the use of allogeneic and xenogeneic cells is limited due to the need for host immunosuppression. Cell lines, i.e., cells that have been modified genetically to proliferate indefinitely, are attractive since they have the potential for rapid in vitro expansion and may be appropriate candidates for gene therapy. However, the tendency for cell lines to lose differentiated function and potential tumor formation are important con

Fig. 16.1 Overview of the tissue engineering approach. Dissociated cells are harvested from an appropriate cell source and combined with a biodegradable, porous polymer scaffold that serves as a temporary extracellular matrix. Following an in vitro culturing period to increase cell attachment and proliferation, the constructs are implanted to replace or restore the function of missing tissue. (Reprinted with permission from [22])

cerns, and this requires further investigation. Recent advances in stem cell discovery have demonstrated the successful differentiation into various tissues like bone, cartilage, and muscle [30]. These discoveries have substantial potential for tissue engineering. Nonetheless, a more detailed understanding and control over differentiation is required to bring stem cells to clinical relevance.

The scaffold, typically in the form of a biodegradable polymer, serves several important functions. First, it acts as temporary filler for the defect site and prevents the formation of nonfunctional scar tissue. It also provides a temporary extracellular matrix (ECM) for the transplanted cells and guides tissue regeneration. Ideally, it also facilitates integration with the host tissue. The use of a scaffold provides better spatial control and permits the use of a higher cell number compared to injections alone. To this end, both natural and synthetic polymers have been investigated. Natural polymers, e.g., collagen, are appealing because they consist of ECM components and therefore mimic the native environment more closely. Since they are obtained from biological tissues, they are subject to batch-to-batch variations. Furthermore, there is concern about potential transmission of diseases. Synthetic polymers are very versatile materials because their chemical and physical properties can be tailored with a high degree of precision. The biocompatibility and degradation rate can be controlled during the polymer synthesis, and defined structures with appropriate mechanical properties can be fabricated reproducibly using a variety of polymer processing operations.

To obtain viable and functional tissue constructs from cells and biodegradable polymers, it is often necessary to culture the constructs in vitro for short period prior to implantation. Static culture conditions are usually sufficient to expand cells. However, to achieve optimal distribution, attachment, and proliferation of cells within the scaffold, a dynamic environment with appropriate mechanical forces, nutrient transfer, and gas exchange is required. The development of biore-actors in tissue engineering remains an active field of research. Various bioreactors have been developed to optimize the culture conditions through mixing, pulsatile flow and other mechanical stresses [31-33].

The remaining sections are organized as follows. Section 16.2 provides an overview of representative tissues and organs that have been investigated in tissue engineering. As representative examples, tissue-engineering approaches of skin, cartilage, bone, intestine, cardiovascular tissue, and liver are reviewed. The order of discussion reflects the increased complexity and challenges of regenerating quasi-two-dimensional and avascular tissues with low metabolic requirements to the regeneration of complex, vital organs. Section 16.3 describes the current shortcomings and the additional developments that are required to bring tissue engineering to widespread clinical reality. Future directions are also indicated. Section 16.4 addresses the relevance of tissue engineering for the practicing surgeon and concludes.

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