Biofunctional Hydrogels - Biomaterials - page 179

rendered as coatings to biomedical devices or body tissues. In addition, this polymer, which is bioinert
in its unmodified form, is easily functionalized to allow for an abundance of bioactivity. For this reason,
PEG is discussed as an exemplary system in many of the sections that follow.
8.2.2 In Situ Gelation
The ability of some hydrogels to be formed in situ is a notable advantage since it provides an alternative
to invasive biomaterial implantation strategies. In these methods, prepolymer solutions are delivered
directly to the site of action (e.g., via syringe and needle) prior to initiation of the polymerization reac-
tion. Many hydrogel synthesis protocols are amenable to in situ applications; however, those that require
nonbiocompatible chemical activators or that are significantly exothermic are obviously ill-suited for
such purposes. Synthetic elastin-mimetic hydrogels were employed in this manner to fill cartilage tissue
defects in an osteochondral goat model (Nettles et al. 2008). Injection of the aqueous prepolymer solution
proved a facile delivery method, while crosslinking in situ is believed to have enhanced tissue integration
with the synthetic matrix, leading to increased cell and tissue infiltration. Though this example makes
use of a chemically crosslinked polymer, even photoreactive polymerization strategies can thus be under-
taken since fiber-optic devices now make delivering light to locations within the body almost trivial.
8.3 Hydrogel Biofunctionality
As mentioned, the hydrophilic nature of synthetic hydrogels results in materials that are resistant to
protein adsorption and cell adhesion. This means that if the hydrogel function necessitates the capacity
to interact with or respond to cells or tissues, additional modification must be made. For these purposes,
the three most common types of engineered biofunctionality are (1) adhesion, (2) protein/growth factor
presentation to control cell signaling, and (3) enzymatic degradation.
8.3.1 Engineering Cellular Adhesion
To engineer adhesion into the inert matrices formed by synthetic hydrogels, researchers aim to recapitu-
late the binding events that occur between cells and the ECM. The majority of cell-ECM interactions
are mediated through a class of cell surface receptors called integrins. These transmembrane proteins
bind to specific sites on matrix proteins allowing the cell to sense and interact with its environment. In
addition, integrin binding can induce intracellular signaling that affects processes including migration,
proliferation, and protein synthesis (Mann and West 2002). Though creating a heterogeneous synthetic
scaffold that incorporates whole proteins such as collagen or fibronectin would accomplish the goal of
creating a cell-adhesive matrix, this methodology is rarely preferred. For one reason, whole proteins
would prove unstable in the cellular environment due to their susceptibility to enzymatic digestion.
Furthermore, large proteins have many functional domains, only a few of which are needed for cell
attachment. The inclusion of superfluous functionality could confound or even hinder the efficacy of
synthetic matrices, which are often hailed as materials with “specifically designed” bioactivity.
Seminal work in this area over two decades ago used systematic studies of the amino acid sequences
of various ECM proteins to determine that a minimal peptide unit is all that is required for recognition
by cell surface receptors (Pierschbacher and Ruoslahti 1984). The most well studied of these peptides is
the Arg-Gly-Asp (RGD) sequence which is ubiquitously distributed in proteins, including fibronectin,
collagen, laminin, and vitronectin. RGD binds to many members of the integrin family, and as such
serves as a ligand for a wide variety of cell surface receptors. The addition of this short peptide sequence
has been shown to confer adhesive properties to otherwise inert synthetic hydrogels in a concentration-
dependent manner (Figure 8.1).
An even greater level of specificity can be introduced by incorporating adhesion sequences derived
from other ECM proteins (Table 8.2). These additional sequences permit the design of materials that