(8c) Modeling Bioresponsive Hydrogels for Targeted Homeostasis in Drug Delivery

                                                                                                     Modeling Bioresponsive Hydrogels for Targeted Homeostasis in Drug Delivery

A. Nolan Wilson and Anthony Guiseppi-Elie

Center for Bioelectronics, Biosensors and Biochips (C3B), Clemson University Advanced Materials Center, 100 Technology Drive, Anderson, South Carolina 29625, USA

Department of Chemical and Biomolecular Engineering, Department of Bioengineering,  Department of Electrical and Computer Engineering, Clemson University, Clemson, South Carolina 29634, USA

ABTECH Scientific, Inc., Biotechnology Research Park, 800 East Leigh Street, Richmond, Virginia 23219, USA.

The use of bioresponsive hydrogels as drug delivery platforms has enabled functionality and versatility far beyond what is achievable by classical tablet formulations or bolus injection.  Key features of these materials leading too much of their success are high biocompatibility, adaptability, tuneability, and relative ease of manufacturing.  Bioresponsive hydrogels have proliferated into a wide range of applications including drug delivery, biosensing, and tissue engineering.  Initially, hydrogels began as passive materials with an objective to remain invisible to the host tissue; however, as engineering capabilities grew, intrinsic stimuli responsiveness of hydrogels were coupled with the biospecificity of biological moieties to create a new class of materials, bioresponsive hydrogels, who actively interact with the surrounding environment[1].  These materials have distinct advantages over their predecessors as they can sense and respond to a specific metabolic stimuli.  Further advancement of bioresponsive hydrogels, in the realm of drug delivery, has been to engineer self-regulating control loops into the materials such that metabolic activity dictates the release rate and establishes a pseudo-steady state, or homeostatic conditions, over the delivery period.  Homeostatic drug delivery is akin to the intrinsic controls existing in natural metabolic pathways as they both exert spatiotemporal control to dampen dynamic inputs from the environment to maintain target metabolic activities[2].

Here we have performed an in silico investigation into a bioresponsive hydrogel which controls the relative activity of the bathing matrix metalleoprotease (MMP). The goal is to regulate MMP-9 activity to levels associated with normal wound repair over a delivery period that is time consistent with wound remodeling. Immobilized to the hydrogel is a peptide-drug conjugate which upon exposure to the specific enzyme matrix metalleoprotease-9 (MMP-9), a protease involved in tissue remodeling, is cleaved and the pendant inhibitor (drug) released. After release, the drug, an inhibitor of MMP-9, is able to modulate the activity of the very protease which cleaved it from the hydrogel matrix. Key engineering factors were illuminated by perturbing system constants such as component diffusion coefficients, co-polymer content, and enzyme kinetic parameters; it was determined that transport path length (i.e. microsphere radius) and pendant inhibitor concentration (i.e. drug loading) offered two key design parameters for engineering the control set point, from 99% to 7% relative activity (R = 5 – 200 µm) , and performance time, from 3 to 24 hours ([I]_loaded = 0.050 – 0.300 mM ), respectively.  The model was used to demonstrate enzyme activity could be modulated to normal, <1ng/mL, levels under static and dynamic conditions.  By calculation of the Thiele modulus, it was determined the system operated under reaction limited conditions for short length scales and that the material could reduce metabolic activity to a desired set point under dynamic enzyme activities in the surrounding environment.  Additionally, the relation between radii (R = 300 – 2500 µm) and effective diffusivity (D_eff = 7.71×10^-10 – 4.90×10^-8 cm²s^-1) was interrogated to show operation in diffusion limited and reaction limited domains.  Self-regulated delivery offers advanced functionality and increases the range of applications of bioresponsive hydrogels as the focus turns toward integrating the material’s response into native biochemical pathways and away from drug release rates.

1.            Wilson, A.N., R. Salas, and A. Guiseppi-Elie, Bioactive hydrogels demonstrate mediated release of a chromophore by chymotrypsin.Journal of Controlled Release, 2012.

2.            Wilson, A.N. and A. Guiseppi‐Elie, Bioresponsive Hydrogels. Advanced healthcare materials, 2012.