The treatment of bone defects remains a critical challenge in orthopedic surgery. Currently, bone grafts are used to treat defects caused by trauma, pathological degeneration, or congenital deformities. Bone grafting has become a common procedure in orthopedic surgery, and it is estimated that over 500,000 grafting procedures are performed each year in the United States [64]. Allografts are widely available and provide the defect site with structural stability. However, their use is limited by immunogenic response to foreign tissue, inflammation, and potential risk of disease transmission. Vascularized autografts show optimal skeletal incorporation and are currently considered the gold standard. However, important drawbacks are donor site mor bidity and limited availability of donor sites. To overcome these problems, synthetic or natural biomaterials have been developed to promote the migration, proliferation, and differentiation of bone cells. Currently, several bone replacement materials are commercially available. These materials vary in composition and include ceramics, polymers, and natural materials such as collagen and hydroxyapatite [65-67]. A common drawback of these materials is the lack of mechanical strength. Hence, their use is limited to bone void filling applications. Furthermore, their potential to repair large bone defects is limited since they lack the osteo-conductive and osteoinductive properties of bone au-tografts. To date, there is no clinically available implant that mimics the function of living bone.

Tissue engineering offers the potential to create living bone in specific forms and shapes by combining a resorbable scaffold and suitable cells, leading to improved integration with the native bone and improved function. To achieve this goal, a variety of cell sources and scaffold materials have been assessed. Bovine periosteum-derived cells and degradable PGA fiber constructs were successfully used to heal large segmental bone defects in the femurs of athymic rats. Histological evaluation revealed bone formation with islands of hy-pertrophying chondrocytes indicative of endochondral bone formation [68]. Phalanges and small joints were created by selective placement of bovine periosteum, chondrocytes, and tenocytes on biodegradable poly mer scaffolds and subsequent assembly into a composite tissue structure (Fig. 16.3). Following implantation into athymic mice, mature articular cartilage and sub-chondral bone with a tenocapsule that had a structure similar to that of human phalanges and joints was observed [69]. Bone formation in heterotropic sites was also observed by injecting a mixture of fibrin glue and cultured periosteal cells into the subcutaneous space on the dorsum of athymic mice [70]. In a seminal clinical report, an avulsed phalanx of a patient was replaced with tissue-engineered bone. The procedure resulted in functional restoration of a stable thumb, without the pains usually associated with an autologous bone graft harvest [71].

Advances in stem cell biology have shown that the bone marrow contains regeneration-competent cells that can differentiate into osteoblasts, chondrocytes, ad-ipocytes, and myoblasts. These cells have been termed marrow stromal cells and are commonly referred to as mesenchymal stem cells (MSCs) [72-74]. Autologous bone marrow can be obtained conveniently from the iliac crest or sternum of a patient, using minimally invasive techniques with less pain and lower risk of infection, hemorrhage, or nerve damage compared to bone graft harvests. Various studies have investigated bone formation from MSC-derived osteoblasts on biodegradable polymer foams [75-79]. Typically, mineralization is observed within 2 weeks, but cell penetration and bone formation is limited to the outer sections

Fig. 16.3 Tissue-engineered phalanges and small joints. a Schematic representation. Fresh bovine periosteum was wrapped around a copolymer of polyg-lycolic and poly-L-lactic acid. Separate sheets of polyglycolic acid polymer were seeded with bovine chondrocytes and tenocytes. The gross form of a composite tissue structure was constituted in vitro by assembling the parts and suturing them to create models of a distal phalanx, a middle phalanx, and a distal interphalangeal joint. The sutured composite tissues were implanted into athymic mice. b After 20 weeks, formation of new tissue with the shape and dimensions of human phalanges with joints was observed. Histological examination revealed mature articular cartilage and subchondral bone with a tenocapsule that had a structure similar to that of human phalanges and joints. There was continuous cell differentiation at the ectopic site even after extended periods. (Reprinted with permission from [69])

of the scaffold. To address this problem and improve cell engraftment and survival, several approaches are currently being pursued. Scaffold fabrication techniques to create scaffolds with improved and more biomimetic architectures are being developed [80-83]. Mechanical stresses are important in determining the architecture of bone, and bioreactors are under development to provide the proper mechanical loading [84, 85]. An improved understanding of stem cell biology and in combination with gene therapy offers exciting potential to treat genetic disorders of skeletal tissues [86, 87]. It is expected that research activities in these areas will lead to the ultimate goal of bone tissue engineering, namely the development of vascularized bone grafts with clinically relevant dimensions.

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