FIG. 4.

Strategies to promote the release of multiple bioactive factors from a matrix. Molecules can be physically dispersed inside the matrix by dispersion of the factor before the carrier processing or by impregnation postcarrier preparation (A). Typically, this leads to uncontrolled and fast drug delivery kinetics. One strategy to incorporate multiple bioactive signaling molecules into a matrix is developing hierarchical multiscale systems by the incorporation of nano- and microscale carriers into the constructs. The entrapment of the drugs in these carriers might offer an enhanced protection for degradation and high control over the delivery kinetics. These particulate carriers can be tailored to release bioactive factors in specific kinetics, allowing either a simultaneous (B) or sequential (C) presentation of signaling molecules. The spatiotemporal controlled release profiles can also be achieved through the conjugation of the drugs with ligands. Bioactive factors or particulate carriers can be covalently bound to the matrix, resulting in a more controlled mechanism of incorporation (D). Affinity-bound systems such as binding through heparin domains are a common approach. These mechanisms can be combined to design even more complex systems. Moreover, the development of multiscale systems is highly promising as nanoparticles can be incorporated inside microparticles within the constructs (E), promoting dual or multiple release systems with distinct delivery rates. The development of gradients of bioactive factors (F) is also an increasingly used approach. Besides promoting cell migration and inducing specific cell responses according to the concentration gradients, these systems allow a precise tailoring over the availability of the desired factor, following a biomimetic approach. Color images available online at www.liebertpub.com/teb