Re-engineering development to instruct tissue regeneration

With few exceptions, tissue regeneration strategies based on the conventional combination of cells, scaffolding materials, and soluble factors (tissue engineering) have introduced a rather limited clinical impact. While it is being recognized that the non-convincing benefits of engineered grafts require more fundamental knowledge on mechanisms of action and potency factors, the attempt to mimic and recapitulate developmental events has inspired an evolution of the paradigm. In the context of skeletal regeneration, a "developmental engineering" approach has been advocated to generate intermediate grafts (i.e., hypertrophic cartilage templates) which, as suggested by limb developmental biology, are capable of autonomous spatial and temporal evolution into fully functional bone organs. However, limited consideration has been given to the fact that the recipient site within adult organisms may not be compatible with well-established developmental processes. This can be due to the possibly restricted function of resident progenitors, to the critical mechanical and physical boundary conditions of mature organs, or to the strong role of inflammatory signals and immune cells at repair sites. We thus propose that predictable, orderly, and durable tissue regeneration should be based on a "developmental RE-engineering" paradigm, with the challenge to instruct the execution of developmental programs in the context of an adult system.