Functional integration of tissue-engineered bone constructs.

Tissue engineering has immense potential to provide significantly improved therapies to patients for the functional restoration of damaged or degenerated bone 1 . The overall goal of these efforts is to develop bone graft substitutes that combine the availability and structural integrity of allograft bone with the osteogenic properties of autograft bone. The strategies being developed are numerous and diverse, reflecting the broad range of potential clinical applications, including, for example, fracture healing, repair of large bone defects, spine fusion, implant fixation, and osteoporosis. Tissue-engineered bone constructs typically start with a porous biomaterial scaffold that provides a template for repair and may serve as a delivery vehicle for bioactive factors such as cells or growth factors. Bone repair scaffolds may be composed of natural or synthetic materials and must have adequate mechanical properties to withstand site-dependent levels of load-bearing following implantation in vivo 2 . Cells capable of osteogenesis may be included to enhance the limited endogenous supply of osteoprogenitor cells 3 . Osteoinductive factors, such as bone morphogenetic proteins or genes, may also be combined directly with scaffolds or delivered via genetically engineered cells. Clearly, interactions among tissue-engineered construct design parameters and the local physiologic environment in vivo are critical to whether or not functional integration is successfully achieved. As tissue-engineered constructs become more sophisticated, critical design trade-offs must be made in the selection and integration of cell and scaffold parameters. The scaffold material and architecture that provide optimal mechanical properties, for example, may not be ideally suited for delivering cells and proteins or facilitating the invasion of host cells and vascularity from the surrounding tissue bed in vivo. Clinically relevant in vivo models are needed to address these challenging construct design decisions. Although preliminary in vitro studies are appropriate for demonstrating initial proof of concept, bone regenerative technologies must ultimately be tested in vivo. Bone defect models should be critically-sized, such that they will not heal if left empty 4 . For example, a stabilized 5 mm femoral defect in the rat will heal in some cases when left empty, whereas a 7.5 mm femoral defect will consistently fail to bridge without treatment. Particularly in small animals, in vivo test beds should be made as challenging as possible to allow discrimination of the effects of different construct designs. The rat calvarial defect model, for example, can be made critically-sized and is commonly used to test bone repair materials. However, it can not be considered a challenging or discriminatory test bed model since most porous scaffolds easily facilitate complete repair of the defect. In addition to discriminatory in vivo models, quantitative