Cartilage is an avascular mesenchymal connective tissue that can be classified into three histological types-hyaline, elastic, and fibrous cartilage—that differ in contents and types of collagens, elastin, and proteogly-can matrix. Cartilage itself contains no blood vessels and obtains its blood supply from the overlying peri-chondrium. Due to the lack of blood supply and nervous innervation, it has a limited capacity for self-repair. In cases of small defects, cartilage is able to repair itself. However, in instances of partial or full-thickness defects, damaged cartilage cannot be repaired. Due to this limited self-repair potential and the low metabolic needs, cartilage is an attractive candidate for tissue engineering.

Initial studies demonstrated that primary chon-drocytes that had been isolated from bovine cartilage could be seeded onto synthetic, biodegradable polymer scaffolds and produce neocartilage after transplantation into athymic mice [41]. Subsequent studies followed this pioneering approach by relying on FDA-approved poly(a-hydroxyesters) like polyglycolic acid (PGA), polylactic acid (PLA), and their copolymers (PLGA) as the scaffold. It was shown that cartilage could be generated in predetermined shapes using specially configured synthetic biodegradable polymer scaffolds (Fig. 16.2). The cartilage showed no signs of resorption or overgrowth throughout the entire experimental period. Histological examination confirmed the presence of normal mature hyaline cartilage [42]. Tissue-engineered cartilage was also successful in the treatment of surgically created cranial bone defects in a rat model [43]. Articular cartilage is of particular interest because full-thickness defects may progress to osteoarthritis. Using a rabbit model, new hyaline cartilage was created for resurfacing distal femoral joint surfaces that had been surgically denuded of articular cartilage. Evidence of new cartilage growth was found after 7 weeks, while animals in control groups showed virtually no new cartilage formation [44].

In addition to scaffold-based approaches, autolo-gous chondrocyte transplantation without scaffolds has been used in a clinical study to repair deep cartilage defects in the femorotibial articular surface of the knee joint [45]. This has led to the development of Car-ticel®, consisting of autologous cultured chondrocytes, for the repair of symptomatic cartilage defects of the femoral condyle caused by acute or repetitive trauma in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure. It should be mentioned that Carticel® is not indicated as a treatment for osteoarthritis. Here, a small biopsy of healthy knee cartilage is obtained and expanded in vitro. The cells are subsequently implanted under the periosteum in the defect and covered with a small piece of the periosteum to hold the cells in place. About 4,000 patients have been treated, and the results to date are promising.

In addition to creating cartilage in flat shapes, there have been significant efforts in creating complex, three-dimensional cartilage by using a variety of synthetic biodegradable polymers. Polymer templates in the form of nasoseptal implants were successfully used to guide the reorganization of bovine chondrocytes into neocartilage. All constructs showed evidence of formation of histologically organized hyaline cartilage [46]. A similar strategy was employed to create temporo-mandibular joint discs. The scaffolds maintained their specific shape, and histologically resembled hyaline cartilage. The mechanical properties were found to be similar to that of the native donor cartilage [47]. Cartilage formation was also successful in even more complex, three-dimensional architectures like the human

Fig. 16.2 Tissue-engineered cartilage in specific shapes. Top row Porous, nonwoven sheets of polyglycolic acid, an FDA-approved biodegradable polymer for biomedical applications. The polymer scaffolds were seeded with freshly isolated bovine articular chondrocytes and implanted subcutaneously into athymic mice. Bottom row Gross examination of the excised specimens 12 weeks after implantation revealed the presence of new hyaline cartilage of approximately the same dimensions as the original construct. (Reprinted with permission from [42])

ear [48, 49]. Significant efforts have also been undertaken to create a tissue-engineered trachea [50, 51]. A study using a sheep model demonstrated the feasibility of recreating the cartilage and fibrous portions of the trachea with autologous tissue harvested from a single procedure [52]. In addition, a methodology for creating a composite tracheal equivalent composed of cylindrical cartilaginous structures with lumens lined with nasal epithelial cells was developed [53]. These studies demonstrate the validity of the tissue-engineering approach, but important additional variables remain to be determined. The foremost question concerns the cell source. Since cartilage is found in various parts of the body, it is preferable to use a site for cell harvest that is easily accessible and requires less invasive methods. To this end, various cell sources have been assessed [54]. In addition, the effect of the cell age on proliferation and neocartilage formation was also investigated [55, 56].

In general, tissue-engineered cartilage has the his-tological appearance and biochemical composition of native cartilage. However, the mechanical strength of engineered cartilage is quite low. It has been shown that the aggregate modulus of tissue-engineered cartilage increases during the culture period, but the native tissue is still much stronger. Much of the mechanical properties of cartilage result from the interactions of negatively charged glycosaminoglycans and water. It is argued that without proper loading, chondrocytes may not produce sufficient amounts of proteoglycans, and the resulting cartilage lacks the impressive com-pressive strength of normal cartilage. Current efforts are underway to develop bioreactors that improve the structure, function, and molecular properties of tissue-engineered cartilage [57, 58]. These efforts are likely to improve the long-term stability of tissue-engineered cartilage.

With the emergence of minimally invasive surgical techniques and improved diagnostic techniques, congenital malformations may be treated earlier. Several pilot studies in fetal tissue engineering have been undertaken, and the results are promising [59, 60]. In concert with these efforts, new scaffold materials are developed that allow delivery through small incisions and can fill irregularly shaped sites [61-63].

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