As medicine therapy advances, we can now realistically set goals for fully functional living replacement of nearly every diseased organ or tissue. In the past several decades, the limitations of nonliving mechanical solutions to organ and tissue dysfunction are now recognized and include dialysis, mechanical heart valves, metallic orthopedic implants, and nonresorbable hernia mesh. Tissue engineering has broad goals including organ development, the elimination of the waiting time for transplants such as the liver and kidney, the creation of living tissue replacements for soft tissue, bone, cartilage, fascia, and virtually every structure in the body.
The principal mechanical supporting structure of any engineered tissue is the scaffold. These three-dimensional constructs are often composed of several materials and support the living cells required to generate a functional tissue (Fig. 69-1). The mechanical properties of the scaffolds, such as strength and elasticity, must correspond to the mechanical properties of the target tissue. Moreover, cells respond to environmental cues such that the scaffold should mimic the target tissue to achieve the desired cell alignment and the three-dimensional arrangement of the cells.
Schematic of basic principles of tissue engineering. (From R Langer, J Vacanti: Science 260:1993; with permission.)
The ideal scaffold materials for engineered tissues are resorbable materials that break down over time. During resorption, the engineered tissue is remodeled by normal healing processes, leaving only living cellular tissue with natural supporting connective tissue. Many implants or organ assist devices are under development utilizing the principles of tissue engineering with nonresorbable materials. These technologies such as lung assist devices, liver assist devices, and even composite implants with resorbable and nonresorbable components for orthopedic and hernia repair represent an important step toward developing fully resorbable scaffolds for all tissues. Current research is focused on resorbable synthetic polymers (e.g., polyglycolic acid, resorbable polyurethanes, polyglycerol sebacic acid); naturally occurring polymers (e.g., collagens, fibrin); and minerals (e.g., calcium triphosphate). Scaffold materials can be supplemented with growth factors or other cytokines to improve cellular incorporation and differentiation. Other surface modifications including surface texturing and protein or antibody coatings may improve cellular adhesion and migration.
Decellularized connective tissue, or organs, represents a rapidly developing area of materials for engineered tissues. Decellularized hearts reseeded with myocardial cells have been demonstrated to function in vitro, and research is focused on expanding this approach to other organs such as the lung and liver as well as soft tissues using material such as decellularized dermis.
The cellular components of engineered tissues must achieve organ functionality (e.g., hepatocytes), maintain organ structure (e.g., fibroblasts and stromal cells), and deliver blood to the tissue (e.g., endothelial cells and pericytes). The three-dimensional arrangement of the cells is critical for proper function; therefore, coordination of scaffold design and cellular components is essential. Maintenance of appropriate cell-to-cell interactions and cell-to-extracellular matrix interactions establishes the microenvironment that drives the differentiation, proliferation potential, and function of many cell types.
Using autologous cells is a principal goal when developing any engineered tissue. This avoids the tremendous burden of immunosuppression. Induced pluripotent stem cells and adult mesenchymal stem cells (e.g., bone marrow or adipose derived) are two promising autologous progenitor cells sources. Differentiation cues including soluble signals and incorporating genes can drive the progenitor cells into cell lineages and end-organ cells (Chaps. 67 and 68). Finally, achieving an adequate number of cells is important. For example, there are approximately 5 × 1010 hepatocytes in a normal adult liver. Therefore, any cellular differentiation strategy must take into account the number of cells needed to seed the scaffold for appropriate tissue function.
Allogenic cells remain an option for many tissues and have been the principal source of clinically successful engineered tissues to date. Embryonic stem cells continue to hold great promise as an allogenic cell option. Xenogenic cells are important to consider as they are available in large numbers, but their use has been mostly limited to organ support devices (i.e., liver devices) and they are not directly implanted into a patient.
Nearly all tissues have baseline mechanical requirements and many tissues such as heart valves, blood vessels, bone, and tendons must have adequate mechanical properties to achieve function. Mechanical forces are important to induce cell alignment and in the production of an extracellular matrix. Bioreactors have been developed to impart the needed mechanical forces to engineered tissues, including shear stress, pusatile flow, and pressure for valves and blood vessels, and axial tension and compression for bone, cartilage, and tendons.
Engineered skin substitutes were the first true clinical success of the principles of tissue engineering (Table 69–1). These clinically available products use autologous fibroblasts grown on a resorbable polymer scaffold for a single-layer product or fibroblasts covered with keratinocytes for a two-layer product. Recent products for promoting the healing of skin and dermal wounds also incorporate autologous fibroblasts delivered into the wound. Autologous chondrocytes are being used to heal damaged joints, and they have shown excellent results. Acellular collagen-based materials derived from human or animal dermis are being implanted for soft tissue reconstruction or hernia repair and become cellularized in vivo with autologous cells. Many engineered tissues are in clinical trials (Table 69–2) or under development, including those for bone, cartilage, nerve, skeletal muscle, small-diameter blood vessels, heart valves, and vital organs, including heart, liver, lung, and kidney.
Table 69–1 Examples of FDA-Approved Tissue Engineering Products
| Save Table
Table 69–1 Examples of FDA-Approved Tissue Engineering Products
|Alloderm (LifeCell)||Acellular dermal matrix for tissue repair|
|Apligraf (Organogenesis)||Living skin equivalent approved for the treatment of venous leg ulcers and diabetic foot ulcers|
|Carticel (Genzyme Biosurgery)||Autologous chondrocytes approved for cartilage repair|
|Dermagraft (Smith and Nephew)||Living skin equivalent approved ...|
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