title: Osteochondral tissue regeneration through polymeric delivery of DNA encoding for the SOX trio and RUNX2.
abstract: Native osteochondral repair is often inadequate owing to the inherent properties of the tissue, and current clinical repair strategies can result in healing with a limited lifespan and donor site morbidity. This work investigates the use of polymeric gene therapy to address this problem by delivering DNA encoding for transcription factors complexed with the branched poly(ethylenimine)-hyaluronic acid (bPEI-HA) delivery vector via a porous oligo[poly(ethylene glycol) fumarate] hydrogel scaffold. To evaluate the potential of this approach, a bilayered scaffold mimicking native osteochondral tissue organization was loaded with DNA/bPEI-HA complexes. Next, bilayered implants either unloaded or loaded in a spatial fashion with bPEI-HA and DNA encoding for either Runt-related transcription factor 2 (RUNX2) or SRY (sex determining region Y)-box 5, 6, and 9 (the SOX trio), to generate bone and cartilage tissues respectively, were fabricated and implanted in a rat osteochondral defect. At 6weeks post-implantation, micro-computed tomography analysis and histological scoring were performed on the explants to evaluate the quality and quantity of tissue repair in each group. The incorporation of DNA encoding for RUNX2 in the bone layer of these scaffolds significantly increased bone growth. Additionally, a spatially loaded combination of RUNX2 and SOX trio DNA loading significantly improved healing relative to empty hydrogels or either factor alone. Finally, the results of this study suggest that subchondral bone formation is necessary for correct cartilage healing.
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Clark J
authors.initials: CJ
authors.lastname: Needham
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Sarita R
authors.initials: SR
authors.lastname: Shah
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Dahlin
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Kinard
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Lam
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Watson
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA.
authors.forename: F Kurtis
authors.initials: FK
authors.lastname: Kasper
authors.affiliation: Department of Bioengineering, Rice University, MS-142, 6100 Main St, Houston, TX 77005-1892, USA. Electronic address: mikos@rice.edu.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Mikos
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000293:injuries / Q000378:metabolism; D002356:Cartilage / Q000000981:diagnostic imaging / Q000293:injuries / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011094:Polyethyleneimine / Q000737:chemistry / Q000493:pharmacokinetics; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D055747:SOX Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection / Q000379:methods*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D020100:Hydrogels; D011091:Polyesters; C493717:Runx2 protein, rat; D055747:SOX Transcription Factors; C469550:oligo(poly(ethylene glycol)fumarate); D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; D004247:DNA
keywords: OPF; Polymeric gene delivery; RUNX-2; SOX trio; bPEI–HA