title: Customized biomaterials to augment chondrocyte gene therapy.
abstract: A persistent challenge in enhancing gene therapy is the transient availability of the target gene product. This is particularly true in tissue engineering applications. The transient exposure of cells to the product could be insufficient to promote tissue regeneration. Here we report the development of a new material engineered to have a high affinity for a therapeutic gene product. We focus on insulin-like growth factor-I (IGF-I) for its highly anabolic effects on many tissues such as spinal cord, heart, brain and cartilage. One of the ways that tissues store IGF-I is through a group of insulin like growth factor binding proteins (IGFBPs), such as IGFBP-5. We grafted the IGF-I binding peptide sequence from IGFBP-5 onto alginate in order to retain the endogenous IGF-I produced by transfected chondrocytes. This novel material bound IGF-I and released the growth factor for at least 30days in culture. We found that this binding enhanced the biosynthesis of transfected cells up to 19-fold. These data demonstrate the coordinated engineering of cell behavior and material chemistry to greatly enhance extracellular matrix synthesis and tissue assembly, and can serve as a template for the enhanced performance of other therapeutic proteins.
  
  
  
  The present manuscript focuses on the enhancement of chondrocyte gene therapy through the modification of scaffold materials to enhance the retention of targeted gene products. This study combined tissue engineering and gene therapy, where customized biomaterials augmented the action of IGF-I by enhancing the retention of protein produced by transfection of the IGF-I gene. This approach enabled tuning of binding of IGF-I to alginate, which increased GAG and HYPRO production by transfected chondrocytes. To our knowledge, peptide-based modification of materials to augment growth factor-targeted gene therapy has not been reported previously.
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Izath Nizeet
authors.initials: IN
authors.lastname: Aguilar
authors.affiliation: Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Trippel
authors.affiliation: Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Shi
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States; Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, United States. Electronic address: lb244@cornell.edu.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Bonassar
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000502:physiology*; D004343:Drug Implants / Q000008:administration & dosage*; D015316:Genetic Therapy / Q000295:instrumentation / Q000379:methods*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000737:chemistry; D054457:Tissue Scaffolds; D014162:Transfection / Q000379:methods*
chemical_list: D001672:Biocompatible Materials; D004343:Drug Implants; D007334:Insulin-Like Growth Factor I
keywords: Binding peptide; Growth factor; IGF-I; Osteoarthritis