Tissue engineering is classified into two categories in terms of the site where tissue engineering is performed: in vitro and in vivo (Fig. 1). In vitro tissue engineering involves tissue reconstruction and organ substitution, otherwise known as bioartificial organs. Table 1 provides tissues and organs undergoing tissue engineering. The targeted tissues and organs have been extensively investigated based on combinations of cells, scaffolds, and growth factors (1).
If tissues can be reconstructed in vitro in factories or laboratories on a large scale, the tissue constructs can be supplied to patients when they are needed. This approach would be very attractive for commercialization once the feasibility is established. However, it is quite difficult to completely reconstruct the event in vitro using the cell culture technologies currently available. Another approach to in vitro tissue engineering is the substitution of organ functions by the use of allogenic or xenogenic cells. Such engineered organs have been called bioartificial organs because they are composed of heterogeneic cells and man-made membranes or porous constructs for immunoisolation to protect the cells from host attack and maintain cell function. This approach has been performed for the liver, pancreas, and kidney (2,3).
Distinct from in vitro tissue engineering, in vivo tissue engineering has the advantage of using the native environment for induction of tissue regeneration. Most of the materials necessary for tissue regeneration are automatically supplied by the host living body. Therefore, almost all the approaches to tissue engineering have been currently performed in vivo with or without biodegradable scaffolds. This approach is more realistic and clinically acceptable if it
Tissues and Organs Being Regenerated or Reconstructed by Tissue Engineering
Scaffold + growth factor Barrier membrane Barrier membrane
Skin (epidermis + dermis), articular cartilage, bone, artery, myocardium Dermis, dura mater, esophagus, trachea
Skin, cornea, retina, artery, cartilage
(fibrous and hyaline), bone (skull, jaw, long), myocardium, trachea, esophagus, small intestine, stomach, smooth muscle, bladder, ureter, central nerve
Bone (skull, jaw, long), hair, arteriole, smooth muscle, bladder, periodontal tissue Mamma, fat, hair, myocardium, liver, kidney
Liver, pancreas, kidney
Peripheral nerve, periodontal tissue, alveolar bone
Liver, pancreas, chromaffin cells (angiogenesis)
works well. If the healthy ECM is still available in the body, no artificial scaffold is needed. In addition to bone marrow transplantation, eye-related stem cells are being used for regeneration of defective cornea and retina (4), and the transplantation of myocardial cells has been experimentally tried for the treatment of myocardial infarction (5). For the regeneration of a large defect, it is absolutely necessary to use a biodegradable scaffold. The scaffold is implanted with or without cell seeding. For example, sponge form collagen is the most popular material (6), because a collagen scaffold is compatible with cells and is degraded in the body, hence preventing a physical hindrance to new tissue construction. In vivo tissue engineering using a collagen sponge or a biodegradable polymer sheet with no cell seeding has succeeded in inducing regeneration of the skin dermis (7), trachea (8), esophagus (9), and dura mater (10).
There are many body tissues that cannot be regenerated unless the scaffold used is seeded with the cells specifically needed for tissue regeneration. Regeneration of epidermis and cartilage necessitates seeding of the scaffold with keratinocytes and chondrocytes, respectively. Cells isolated from blood vessels and small intestines have been combined with biodegradable scaffolds to achieve in vivo regeneration of the respective organs (11,12). Bone marrow cells have also been widely used to this end; bone marrow cells contain mesen-chymal stem cells (MSCs) that can differentiate into the osteocytic lineage (13,14). It is possible to seed more than one type of cell for regeneration of tissue composed of several subtissues. For example, phalanges and small fingers could be reconstructed by using three different scaffolds combined with periosteum, chondrocytes, and tenocytes for reconstruction of bone, cartilage, and tendon (ligament), respectively (15).
Sometimes successful tissue regeneration cannot be achieved by merely combining cells and their scaffolds. In such cases, one practical, possible way to promote tissue generation is to use suitable growth factors as well. The type of growth factor depends not only on the target tissue under investigation but also the site where the tissue is expected to generate. Besides the single use of growth factor, sometimes a combination of multiple growth factors with the scaffold preseeded with cells is required to accelerate tissue regeneration.
When a body defect is incurred, the defect space is soon filled with fibrous tissue produced by fibroblasts, which are ubiquitously present in the body and can rapidly proliferate. Once this ingrowth of fibrous connective tissue takes place, further repair or regeneration of other tissues is effectively terminated. To prevent tissue ingrowth, additional biomaterials, known as barrier membranes, are needed. The objective is to make space for tissue regeneration and prevent the undesirable tissue ingrowth, thereby permitting repair of the defect by natural tissue. Some successful examples include guided channels for lost peripheral nerve fibers (16) and guided regeneration of lost periodontal tissues and alveolar bone (17). Barrier membranes should be prepared from biodegradable materials, because they are no longer needed after completion of tissue regeneration. This chapter presents an overview of several research trials on tissue regeneration based on the use of DDS growth factors with or without cells and/or the scaffolds.
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