Cytomechanics and cell-level cues in tissue engineering

Summary form only given. Many of the most common targets for tissue engineering involve replacement of substantive connective tissue function. To achieve rational strategies for engineering of such mechanically active tissues it is essential to consider the importance and application of mechanical loads as cellular control cues. Inasmuch as our aim is to develop biomimetic systems for tissue growth and repair, it will not be possible to ignore the key mechanical signals, which govern function and form in tissues such as skin, cartilage, tendon, bone, muscle. Indeed, for most adult mammalian, connective tissues, the default repair pathway results in scar tissue and this may be, in large part, a result of inappropriate cell-level mechanical signalling. The key architectural cues in CTs are thought to be mechanical but as long as these regulatory mechanisms remain unclear they cannot be used predictably in tissue engineering. Importantly signals must act at the cell (cytomechanical), rather than the tissue level. We have developed model systems based on 3D cell-seeded collagen gel cultures and uniaxial tensile loading and measuring devices (the culture force monitors - CFMs) to help to identify and quantify key cytomechanic control mechanisms. This approach has emphasised that external loads can only be used to regulate cell function through the mediation of the material properties of their extracellular matrix. At the same time cells change shape and attachment during tissue remodelling and alter the structure of the very matrix, which propagates those mechanical cues. Consequently, cytomechanical control cues must be delivered in a dynamic and vectored manner, taking account of the progressive responses of resident fibroblastic cells. It is concluded that cell responses to external loads can be regulated through: loading patterns, relative to planes of maximum and minimum matrix compliance; cell-matrix interactions (substrate structure, ligand density, integrin modification); cell shape and cytoskeletal structure (regulating cell motility & contraction).