title: In vitro, in vivo, and in silico evaluation of the bioresponsive behavior of an intelligent intraocular implant.
abstract: OBJECTIVE
  An autofeedback complex polymeric platform was used in the design of an intelligent intraocular implant-the I(3)-using stimuli-responsive polymers, producing a smart release system capable of delivering therapeutic levels of an anti-inflammatory agent (indomethacin) and antibiotic (ciprofloxacin) for posterior segment disorders of the eye in response to inflammation.
  
  
  METHODS
  Physicochemical and physicomechanical analysis of the I(3) was undertaken to explicate the highly crosslinked make-up and 'on-off' inflammation-responsive performance of the I(3). In addition, energetic profiles for important complexation reactions were generated using Molecular Mechanics Energy Relationships by exploring the spatial disposition of energy minimized molecular structures. Furthermore, preliminary in vivo determination of the inflammation-responsiveness of the I(3) was ascertained following implantation in the normal and inflamed rabbit eye.
  
  
  RESULTS
  In silico modeling simulating a pathological inflammatory intraocular state highlighted the interaction potential of hydroxyl radicals with the selected polysaccharides comprising the I(3). The intricately crosslinked polymeric system forming the I(3) thus responded at an innate level predicted by its molecular make-up to inflammatory conditions as indicated by the results of the drug release studies, rheological analysis, magnetic resonance imaging and scanning electron microscopic imaging. In vivo drug release analysis demonstrated indomethacin levels of 0.749 ± 0.126 μg/mL and 1.168 ± 0.186 μg/mL, and ciprofloxacin levels of 1.181 ± 0.150 μg/mL and 6.653 ± 0.605 μg/mL in the normal and inflamed eye, respectively.
  
  
  CONCLUSIONS
  Extensive in vitro, molecular, and in vivo characterization therefore highlighted successful inflammation-responsiveness of the I(3). The I(3) is a proposed step forward from other described ocular systems owing to its combined bioresponsive, nano-enabled architecture.
authors.affiliation: Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road Parktown, 2193, Johannesburg, South Africa.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: du Toit
authors.forename: Trevor
authors.initials: T
authors.lastname: Carmichael
authors.forename: Thirumala
authors.initials: T
authors.lastname: Govender
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Yahya E
authors.initials: YE
authors.lastname: Choonara
authors.forename: Viness
authors.initials: V
authors.lastname: Pillay
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002939:Ciprofloxacin / Q000008:administration & dosage*; D003198:Computer Simulation; D016503:Drug Delivery Systems; D005123:Eye / Q000187:drug effects / Q000473:pathology; D005137:Eye, Artificial / Q000009:adverse effects; D007213:Indomethacin / Q000008:administration & dosage*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011108:Polymers / Q000009:adverse effects / Q000737:chemistry*; D011134:Polysaccharides / Q000009:adverse effects / Q000737:chemistry; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D011108:Polymers; D011134:Polysaccharides; D002939:Ciprofloxacin; D007213:Indomethacin