title: Targeting homeostasis in drug delivery using bioresponsive hydrogel microforms.
abstract: A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-drug conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating protease. The delivery platform contains a peptide-drug conjugate covalently tethered to the hydrogel matrix, which in the presence of the appropriate protease, was cleaved and the drug released into the bathing environment. This platform was developed and investigated in silico using a finite element modeling (FEM) approach. Firstly, the primary governing phenomena guiding drug release profiles were investigated, and it was confirmed that under transport-limited conditions, the diffusion of the enzyme within the hydrogel and the coupled enzyme kinetics accurately model the system and are in agreement with published results. Secondly, the FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP9 in order to achieve targeted homeostasis of MMP-9 activity, such as in the pathophysiology of chronic wounds, via closed-loop feedback control. The key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate. Homeostatic drug delivery, where the focus turns away from the drug release rate and turns toward achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized.
authors: Center for Bioelectronics, Biosensors and Biochips (C3B), Clemson University Advanced Materials Center, 100 Technology Drive, Anderson, SC 29625, USA; Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC 29634, USA.
authors: A Nolan
authors: AN
authors: Wilson
authors: Center for Bioelectronics, Biosensors and Biochips (C3B), Clemson University Advanced Materials Center, 100 Technology Drive, Anderson, SC 29625, USA; Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC 29634, USA; Department of Bioengineering, Clemson University, Clemson, SC 29634, USA; Department of Electrical and Computer Engineering, Clemson University, Clemson, SC 29634, USA; ABTECH Scientific Inc., Biotechnology Research Park, 800 East Leigh Street, Richmond, VA 23219, USA. Electronic address: guiseppi@clemson.edu.
authors: Anthony
authors: A
authors: Guiseppi-Elie
mesh_terms: D000577:Amides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004058:Diffusion; D016503:Drug Delivery Systems; D020342:Finite Element Analysis; D006706:Homeostasis; D020100:Hydrogels; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008863:Microspheres; D008962:Models, Theoretical; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D020100:Hydrogels; C413045:MAG 283; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D020780:Matrix Metalloproteinase 9
keywords: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (PubChem CID: 2723939); 4-Nitroaniline (PubChem CID: 7475); Bioresponsive hydrogel; Chronic wound; Closed-loop control; Drug delivery; Homeostasis; Hydroxy-2,5-dioxopyrrolidine-3-sulfonicacid sodium salt (PubChem CID: 23697313); Hydroxyethyl methacrylate (PubChem CID: 13360); Succinyl-alanyl-alanyl-prolyl-phenylalanine-4-nitroanilide (PubChem CID: 5496888); Tetraethyleneglycol diacrylate (PubChem CID: 28803)