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Indian Journal of Cancer, Vol. 47, No. 3, July-September, 2010, pp. 274-279 Symposium The current role of tissue engineering in head and neck reconstruction Jallali N, James S, Elmiyeh B1, Searle A, Ghattaura A, Dwivedi RC1, Kazi R1, Harris P Department of Plastic Surgery and 1 Head and Neck Surgery, Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK Code Number: cn10068 PMID: 20587902 DOI: 10.4103/0019-509X.64722 Abstract Tissue engineering is an emerging field that has the potential to revolutionize the field of reconstructive surgery by providing off-the-shelf replacement products. The literature has become replete with tissue engineering studies, and the aim of this article is to review the contemporary application of tissue-engineered products. The use of tissue-engineered cartilage, bone and nerve in head and neck reconstruction is discussed.Keywords: Bone, cartilage, nerve, tissue engineering, trachea Introduction Tissue engineering is an emerging multidisciplinary field with the primary aim of producing replacement tissue that can be used for the reconstruction of diseased or damaged organs. Tissue engineering typically involves seeding dissociated cells on to a three-dimensional scaffold, [1] followed by a period of in vitro growth and maturation, to produce tissues and, ultimately, organs. The primary aim of tissue engineering is to restore function through the delivery of biological replacements that become integrated into the host. Therefore, it potentially offers the advantages of autologous tissue replacement but minimizes donor-site morbidity. Tissue engineering has the potential to revolutionize reconstructive surgery and, since the original report, [2] the literature has become replete with studies on tissue-engineered products. The aim of this article is to review the current use of this promising modality in head and neck reconstruction. Cartilage Tissue Engineering Unlike bone, which has great reparative potential, the cartilage possesses little innate ability for repair and regeneration. Consequently, injury to the cartilage often results in scar formation, leading to permanent loss of structure and function. Cartilage loss in the head and neck region through traumatic, degenerative or neoplastic processes is a common reconstructive problem. In the pediatric setting, there are a number of congenital cartilage abnormalities such as microtia that require complex reconstructive surgery. Reconstruction of cartilage defects, however, is challenging due to the lack of suitable donor sites and complications associated with prosthetic materials. This clinical dogma has been the catalyst for attempts at engineering cartilage in the laboratory. The cartilage has several characteristics that make it suitable for tissue engineering. Firstly, it is a relatively simple tissue consisting of one cell type, the chondrocyte. Secondly, in vivo, the cartilage relies on diffusion rather than on a vascular network for its nutrition and excretion of waste products, which means that neovascularization of constructs will probably be unnecessary. The fabrication of the cartilage is one of the most successful areas of tissue engineering, [3] and tissue-engineered cartilage (TEC) has been produced using bovine, ovine and human sources. [4] The technique involves the in vitro seeding of dissociated chondrocytes on to an absorbable scaffold that is then placed into a subcutaneous pocket on the back of nude mouse for further growth and differentiation. Constructs in the shape of auricle, [5] temporomandibular joint [6] and trachea [7] have been produced. Using human septal chondrocytes grown on to polylactide-polyglycolide (PGLA) scaffolds, [8] it has also been possible to manufacture neocartilage with similar properties as hyaline cartilage, which will have significant application for joint resurfacing. One of the major problems with TEC has been its brittle nature and susceptibility to fracture if the perichondrium is missing. Recently, composite TEC has been manufactured with the use of expanded polytetrafluoroethylene (PTFE) membrane as pseudoperichondrium. [9] Histological analysis revealed that the chondrocytes bonded to the expanded PTFE, while failure testing revealed that the pseudoperichondrium conferred elastic properties to the constructs. In a further refinement, lyophilized swine perichondrium was used as a pseudoperichondrium and it was found that the constructs had similar mechanical and histological properties as native swine ear. [10] These studies demonstrate that it is feasible to manufacture constructs that resemble an auricle not only in shape but also in mechanical properties. However, while these results are encouraging, it must be borne in mind that all these constructs were implanted subcutaneously into athymic (nude) mice. Thus, the effects of inflammation and resorption on the constructs following implantation could not be elucidated. The strong inflammatory response to tissue-engineered constructs has been the major obstacle in using these products in head and neck surgery. [11] There has been a report on the clinical use of TEC for auricle reconstruction. [11] Although the construct remained stable for 3 weeks, it was then strongly reabsorbed. The mechanism behind resorption of the construct remains unclear, although autoantibodies directed against collagen may be responsible. [11] One proposed strategy to prevent resorption of constructs is encapsulation. Haisch et al. investigated the use of polyelectrolyte complex (PEC) membranes for the prevention of TEC resorption and rejection. [12] With protection by PEC encapsulation, the implanted TEC showed no signs of degeneration and had a significantly weaker cellular immune response at 12 weeks. Thus, PEC membrane encapsulation may be a suitable method for protecting cartilage implants from host immune response after autologous transplantation. A further concern regarding TEC grown in the laboratory is that most investigators have used young animal donors. However, the majority of the demand for these products will be in the elderly population in whom there are important age-related changes. It has been shown that aging induces significant loss of chondrocytes in the cartilage as a result of free radical damage secondary to loss of oxidative homeostasis. [13] Furthermore, aged chondrocytes appear to be more susceptible to reactive oxygen species-induced cell death in culture. Growth factors may prove to be important in reducing the deleterious effects of these harmful species in culture. [14] A further method of circumnavigating the problems of age-related senescence is the use of stem cells, which retain the capacity to multiply and differentiate into a number of cell types and tissues. There is considerable interest in stem cells as they have a significant potential to regenerate diseased or damaged tissues and organs. Stem cells are classified according to their capacity to differentiate. Totipotent stem cells can differentiate into any cell type and can be derived from early embryos. Pluripotent stem cells can almost form any cell type and are also derived from a more mature embryo. Multipotent stem cells can only differentiate into particular cell types, and examples include peripheral blood stem cells. Adult stem cells are undifferentiated cells found in fully differentiated tissue that have limited capacity to differentiate into other cells. The most common source of adult stem cells is the bone marrow, which contains hemopoeitic and stromal mesenchymal stem cells (MSC). The former can differentiate into mature blood cells while the latter can differentiate into a number of adult tissues such as bone and cartilage. MSCs have been isolated not only from bone marrow but also from many other tissues such as adipose tissue, skeletal muscle, liver, brain and pancreas, and the multilineage differentiation potential of adult MSCs coupled to their immunoprivileged properties is being exploited for autologous cell replacement strategies. [15] MSCs are ideal candidates for use in tissue engineering as they can be harvested from the host and be manipulated into different tissue types. The major advantage of using adult MSC is the reduced possibility of immune responses and, thus, rejection. However, the major disadvantage is difficulties in their isolation and limited availability of cells. Human umbilical cord-derived MSCs (hUCMSCs) are fetus-derived stem cells collected from discarded tissue (Wharton′s jelly) after birth and may be a suitable alternative source of stem cells. Compared with human bone marrow-derived MSCs (hBMSCs), hUCMSCs have the advantages of abundant supply and no donor site morbidity and have been used successfully for fibrocartilage tissue engineering. [16] Clearly, significant progress has been made in the field of tissue engineering cartilage. However, resorption remains a significant obstacle and much further work is necessary before the application of TEC in head and neck reconstruction becomes a clinical reality. Tracheal Tissue Engineering Tracheal reconstruction poses a significant surgical challenge. Reconstruction is most commonly necessary after tumor resection but may also be required for benign conditions such as strictures. A number of surgical methods, including autologous tissue, allografts and prosthetic material have been described in the literature. [17],[18],[19] None of the methods described thus far are ideal, particularly in children in whom the reconstruction must have the ability to grow. Kojima et al. have engineered a composite trachea from sheep nasal chondrocytes and epithelial cells. [7] They found that the morphology of constructs following implantation into subcutaneous pockets on the back of nude mice was similar to native sheep trachea with presence of mature cartilage and pseudostratified columnar epithelium. It was also found that the constructs had satisfactory patency, rigidity and shape. To date, there are no reports of the use of tissue-engineered trachea clinically, but this may become an important tool in the reconstructive armamentarium. Bone Tissue Engineering Bone is a highly specialized and vascular tissue that possesses the ability to remodel and heal without scarring. It has a number of important functions such as protection of internal organs and load bearing and is a dynamic source of minerals such as calcium. The bone has a remarkable capacity to heal; however, extensive bony defects following tumor extirpation, trauma and, occasionally, non-union of fractures require more sophisticated surgical treatments. In general, small defects can be reconstructed with non-vascularized grafts. However, large defects or defects in an unsuitable environment, e.g. post-radiotherapy, require the use of vascularized tissue and complex microsurgery. The utilization of free tissue transfer is associated with donor site morbidity and the quantity and, sometimes, the quality of bone is limited. Allografts have been touted as an alternative in order to reduce the morbidity associated with the use of autografts. However, allografts have higher resorption and lower revascularization rates and may potentially transmit harmful viruses to the recipient. Thus, there is a real clinical demand for the application of tissue-engineering techniques to bone. Broadly speaking, two approaches have emerged for the fabrication of tissue-engineered bone, referred to as cell-based or growth factor-based technologies. Both techniques use a three-dimensional scaffold as a carrier, but the former technique utilizes progenitor cells while the latter relies solely on the use of growth factors. There has been considerable work carried on the use of growth factors to promote healing and development of new bone, since their inception. [20] Bone morphogenetic proteins (BMPs) are the most important growth factors for formation and differentiation of bone and are part of the transforming growth factor-beta (TGF-ί) super family. Bone formation can be induced by the application of BMPs in orthotopic or heterotopic sites, a process referred to as osseoinduction. Khouri et al. induced the in vivo transformation of muscle in to bone in an animal model with the use of osseoinductive factor, osteogenin, and by its parent substratum, demineralized bone matrix. [21] They were able to generate well-perfused autologous bone in the shape of femoral heads and mandibles. This raises the possibility of converting readily available muscle flaps into vascularized bone grafts that could be used as skeletal replacement parts. However, the clinical application of this method remains to be investigated further. Similarly, other investigators have also attempted to engineer bone with the use of growth factors and, based on Phase III trials, the FDA has now approved the use of BMP-7 (also known as osteogenic protein 1) for long bone non-union. [22] BMP-7 has also been used to promote bone formation and avoid non-unions following Le Fort I osteotomies. [23] BMPs appear to retain their osseoinductive effect even in wounds contaminated with bacteria. [24] The opponents of the growth factor-based approach have argued that the employment of factors alone is costly and requires the use of supraphysiological concentrations with potential detrimental side-effects. Furthermore, it is difficult to achieve a sustained and coordinated release of the growth factors that may limit the applicability of this approach. This has lead to the development and increased interest in cell-based approaches, which has been a success story in rats. [25],[26],[27],[28],[29],[30] The clinical application of this approach however has not been so successful. The first clinical report described the treatment of three patients with segmental bony defects using an ex vivo expanded human MSC loaded on a three-dimensional scaffold in the shape of the missing bone fragment. [31] In all three patients, the fracture healed with abundant callus formation and the implant showed good integration. However, it is difficult to ascertain whether the callus formation was due to implants alone as there was no control group. The second published clinical study describes the augmentation of the posterior maxilla in 27 patients using a bone matrix derived from mandibular periosteum cells on an Ethisorb (Ethicon, Germany) fleece. [32] However, only 15 patients had bone biopsies carried out in advance of dental implant placement and, in over 50%, there was failure of new bone formation. Thus, the clinical application of tissue-engineered bone has had variable and unpredictable outcome. In order to fabricate tissue-engineered bone, there are a number of conditions that need to be satisfied.
Significant advances have been made in the field of tissue engineering bone. However, the major hurdle is neovascularization of the constructs and new research must be directed toward resolving the problem of inadequate diffusion and insufficient oxygen supply for the cell-based approach.Nerve Tissue Engineering Nerve injury poses significant morbidity through loss of motor function or reduced sensibility. The gold standard treatment of peripheral nerve injuries currently is primary neurorrhaphy or the use of autografts, e.g. the sural nerve. However, the harvest of autografts is associated with donor-site morbidity and less-than-optimal recovery. Allografts and xenografts have also not been so successful principally because of the host′s immune response that leads to rejection. Acellular grafts lead to inflammatory response probably as a result of failure to fully extract cellular remnants. Recent approaches with the use of chemical detergents appear to be more successful in rendering the allografts non-immunogenic, creating a nerve graft devoid of cells but with a well-preserved extracellular matrix. [45] In an animal model, it has been shown that this chemical decellularization process produces axonal density similar to isografts. [46] An alternative approach has been the use of biodegradable synthetic material such as PLGA as nerve conduits. In an animal model, polyglycolic acid (PGA) tube coated with collagen was used to bridge a gap in the recurrent laryngeal nerve, and was found to lead to superior recovery compared to autologous tissue. [47] Similarly, it has been demonstrated that PLGA-microbraided conduits can be effective aids for nerve regeneration and repair and may potentially have clinical applications. [48] Other novel biodegradable elastomers, such as polyglycerol sebacate (PGS) have also been developed and shown to be less toxic to Schwann cells when compared to PLGA. [49] Innovations such as electrical poling have also been applied to bioengineered conduits and appear to increase the ability of injured nerves to reach their target organs through enhanced axonal regeneration and improved conduction rates. [50] However, the efficacy of these scaffolds in humans remains to be examined in a clinical setting. It is likely that successful nerve regeneration will require the use of growth factors. A number of growth factors such as insulin-like growth factor and fibroblast growth factor are thought to be neurotropic and neurotrophic. Nerve growth factor appears to be the principal growth factor involved in nerve differentiation and survival. [51] The main obstacle is the delivery of these growth factors in a sustained and coordinated manner and much more needs to be learnt about the interplay of these factors in nerve regeneration. Tissue-engineered nerve constructs are an attractive alternative to current treatment of nerve gaps with autografts. Significant advances have been made in the manufacture of these constructs and in the physiology of nerve healing. It remains to be seen whether the use of tissue-engineered nerve will become routine in clinical practice. Conclusions Tissue engineering is an exciting new multidisciplinary field in science that has the potential to revolutionize reconstructive surgery. Great advances have been made in tissue engineering simple structures such as bone and cartilage. A number of obstacles remain to be surmounted but the progress made in the laboratory is gradually being applied to resolve clinical problems. Better understanding of vascular processes will lead to more sophisticated constructs fulfilling the ultimate goal of off-the-shelf replacement tissue. References
Copyright 2010 - Indian Journal of Cancer |
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