Consideration of mechanical factors.

The basic elements required for tissue engineering include an extracellular matrix scaffold, cells, and tissue-specific bioactive factors. Whether these elements are provided by the host or must be implanted in some combination within a construct depends critically on the in vivo biochemical, vascular, and mechanical environments. Using bone tissue engineering as an example, the initial repair response to a construct will vary substantially according to the local availability of osteoprogenitor cells, the vascularity of the wound bed, and the mechanical stability of the defect site. In vivo remodeling will subsequently reinforce, maintain, or degrade the tissue formed during repair. Thus, the initial and long-term biological responses to tissueengineered constructs are strongly influenced by interactions between construct design parameters and the in vivo environment. The variability of these interactions among different species, patients, and anatomic sites represents a key challenge in tissue engineering. Successful tissue regeneration must go beyond reproducing shape and structure to restore biological and mechanical function and long-term integration with surrounding native tissues. Initially, an implanted construct should be immune-acceptable and biocompatible and, in many cases, promote angiogenesis and the recruitment of progenitor cells. If these early response criteria are met, then an ordered repair sequence culminating in matrix synthesis and deposition may proceed. However, successful tissue formation during the repair phase does not alone guarantee long-term functional regeneration. The retention of newly-formed repair tissue and its integration with surrounding tissues depends on the subsequent remodeling response. For example, bone contains an intricate cellular communication network of osteocytes and is subject to local remodeling by bone-resorbing osteoclasts and bone-forming osteoblasts, serving under normal conditions to maintain skeletal structural integrity. In the absence of adequate mechanical stimuli, however, bone remodeling will also rapidly remove bone mass. This outcome is illustrated by a common model to test for bone-induction properties involving subcutaneous or intramuscular implantation of constructs into athymic rats and other animal species. Constructs that recruit local undifferentiated cells, induce differentiation along an