Polymers to direct cell fate by controlling the microenvironment

Abstract

Enhanced understanding of the signals within the microenvironment that regulate cell fate has led to the development of increasingly sophisticated polymeric biomaterials for tissue engineering and regenerative medicine applications. This advancement is exemplified by biomaterials with precisely controlled scaffold architecture that regulate the spatio-temporal release of growth factors and morphogens, and respond dynamically to microenvironmental cues. Further understanding of the biology, qualitatively and quantitatively, of cells within their microenvironments and at the tissue-material interface will expand the design space of future biomaterials.

Figure 1. 4D Pseudo-Phase Diagram of Cell Fate

The cellular microenvironment is composed of signals from neighboring cells, physical stimuli, soluble factors including growth factors, and insoluble molecules such as the extracellular matrix. The effects of these variables are plotted as different axes on this 4D diagram of cell fate (e.g. differentiation) and are symbolized in this illustration by the different shapes and colors of the cells located at different positions in space. In advanced tissue engineering and regenerative medicine the biomaterial may direct cell fate through any of the variables. The signals from the biomaterial may change over time as a result of preprogrammed spatio-temporal control or in response to the microenvironment, allowing for the recapitulation of complex signaling pathways.

Figure 2. Tissue Engineering and Regenerative Medicine at Many Length Scales

Many techniques are available to design biomaterials from the nanometer to centimeter length scales, some of which are listed above (A). Examples of biomaterials mentioned in the review can be seen approximately beneath their respective length scale (B–F). An illustration of a heparin-nucleating self-assembled peptide amphiphile (B) [29]. The fatty acid tail segregates to the center of the nanofiber while the heparin binding sequence bonds to heparin leading to charge shielding and gel formation. The nanofibers have a diameter of 6–7.5 nm and further aggregate to higher order structures with diameters of 50 to 100 nm. Mesenchymal stem cells seeded on submicrometer electrospun poly (ε-caprolactone) meshes (C) [26]. Anisotropic skeletal myotube formation after 7 days of culture (7 d) on poly (dimethylsiloxane) substrates patterned using soft lithography (D) [15]. Hematoxylin and eosin staining of a micropatterned dermal analog composed of a collagen-glycosaminoglycan membrane laminated to a collagen sponge (E) [22]. Tissue engineered blood vessel produced by seeding smooth muscle cells onto a polyglycolic acid substrate and then culturing the substrate in a pulsatile bioreactor (F) [57]. The vessel is approximately 5.5 cm in length and 3 mm in diameter. The scale bar in C, D, and E is 50 μm. The scale bar in D added to scale from the control sample. W and D represent the width and depth of the invagination. The original image in F was cut to fit into the figure. Images in B and D reproduced with permission, copyright 2006, American Chemical Society. Image in C reproduced with permission, copyright 2007, Elsevier. Image in E reprinted with permission of John Wiley & Sons, Inc., Journal of Biomedical Materials Research Part A, 72A, 2005, 53; copyright 2004, John Wiley & Sons, Inc. Image in F reproduced with permission, copyright 2006, National Academy of Sciences, USA.

Figure 3. Spatial and Temporal Control of Morphogen and Growth Factor Delivery

Polymeric systems allow for independent regulation of the localization, duration, and availability of one or more soluble factors, exemplified above by the delivery of two factors, A and B, with different release kinetics. Factor A is released locally from the biomaterial (circle) within a short duration of time. In contrast, Factor B is released over a large volume for a long period of time.