Enzyme responsive polymers polymer hydrogels

Thornton, P.D. McConnell, G. Ulijn, R.V. Enzyme responsive polymer hydrogel beads. Chem. Commun. 2005, 47 (47), 5913-5915. 

Thornton, P. D. Mart, R. J. Ulijn, R. V. Enzyme-responsive polymer hydrogel particles for controlled release. Maiei 2007,19, 1252-1256. 

Enzyme-responsive polymers can be classified in various ways, for example according to their structure, function or response type or mechanism. Here, we classify enzyme-responsive polymers, according to their structural elements, into polymer hydrogels, supramolecular polymers, polymer particles and self-immolative polymers. The general properties of these classes and their importance in biomaterial apphcations will be introduced. Using examples from the recent literature, we will demonstrate how enzyme responsiveness can be incorporated into these materials. 

Enzyme responsiveness in injectable hydrogels has also been used to render the material biodegradable such that it can be removed once it is no longer required. In this case, poly(N-isopropylacrylamide-co-acrylic acid) that included peptide-based cross-links was used as the stimuli-responsive polymer. Hydrogelation was triggered thermally, whereas the enzyme-responsive functionality is used to provide proteolytically degradable sites in the hydrogel (Kim and Healy,2003). 

Enzyme-responsive polymers can be developed as enzyme-responsive polymeric assemblies, micro- and nanoparticles and hydrogels because of their similar properties to the extracellular matrix. Thus, a wide variety of hydrogels that suffer degradation in the presence of proteases for the release of encapsulated contents have been designed and tested for therapeutic purposes (Roy et al., 2010 de la Rica et al., 2012). 

In summary, the steady state and transient performance of the poly(acrylamide) hydrogel with immobilized glucose oxidase and phenol red dye (pAAm/GO/PR) demonstrates phenomena common to all polymer-based sensors and drag delivery systems. The role of the polymer in these systems is to act as a barrier to control the transport of substrates/products and this in turn controls the ultimate signal and the response time. For systems which rely upon the reaction of a substrate for example via an immobilized enzyme, the polymer controls the relative importance of the rate of substrate/analyte delivery and the rate of the reaction. In membrane systems, the thicker the polymer membrane the longer the response time due to substrate diffusion limitations as demonstrated with our pAAm/GO/PR system. However a membrane must not be so thin as to allow convective removal of the substrates before undergoing reaction, or removal of the products before detection. The steady state as well as the transient response of the pAAm/GO/ PR system was used to demonstrate these considerations with the more complicated case in which two substrates are required for the reaction. 

Key words enzyme-responsive materials (ERMs), regenerative medicine and drug delivery applications, polymer hydrogels and scaffolds, supramolecular particles and self-assembly polymer particles. 

Polymer hydrogels consist of a cross-finked network of hydrophilic polymers with a very large water content (up to 99%) (Wichterle and Lim, 1960).They are structurally similar to the ECM and have therefore frequently been used as ECM mimics (Fedorovich et al., 2007 Shoichet, 2010). Other biological applications include the use as injectable scaffolds, (temporary) cell culture supports and drug delivery matrices (Mano, 2008). For all these applications, the introduction of enzyme-responsive functionalities into the polymer hydrogel is attractive because it would either more closely mimic the ECM (which is itself enzyme responsive) or allow drug delivery in response to the presence of a specific enzyme. 

The introduction of enzyme-sensitive cross-links in an otherwise nonenzyme-responsive polymer such as PEG is frequently used to prepare enzyme-responsive polymer hydrogels and polymer particles. Because of their versatility and natural predisposition as enzyme substrates, short peptide sequences are almost exclusively used as cross-linkers, although dex-tran has also been used (Klinger et al., 2012). They can be readily changed to respond to a variety of proteases such as matrix metalloproteinases,plasmin or trypsin (Lutolf et al., 2003a Yang et al, 2010). In most cases, the peptides have to be modified at the termini to introduce reactive groups that are able to react with the polymer. 

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