title: Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing.
abstract: Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ε-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra-expressing constructs produced nearly 1 µg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra-expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.
authors.affiliation: Cytex Therapeutics, Durham, NC 27705;
authors.forename: Franklin T
authors.initials: FT
authors.lastname: Moutos
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, MO 63110; Shriners Hospitals for Children, St. Louis, MO 63110; Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Glass
authors.affiliation: Cytex Therapeutics, Durham, NC 27705;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Compton
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, MO 63110; Shriners Hospitals for Children, St. Louis, MO 63110;
authors.forename: Alison K
authors.initials: AK
authors.lastname: Ross
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Gersbach
authors.affiliation: Cytex Therapeutics, Durham, NC 27705; Department of Orthopedic Surgery, Washington University, St. Louis, MO 63110; Shriners Hospitals for Children, St. Louis, MO 63110; Department of Biomedical Engineering, Duke University, Durham, NC 27708 guilakf@wudosis.wustl.edu bradley.estes@cytextherapeutics.com.
authors.forename: Farshid
authors.identifier: 0000-0001-7380-0330
authors.initials: F
authors.lastname: Guilak
authors.affiliation: Cytex Therapeutics, Durham, NC 27705; guilakf@wudosis.wustl.edu bradley.estes@cytextherapeutics.com.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Estes
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D015203:Reproducibility of Results; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein
keywords: cartilage repair; gene therapy; mesenchymal stem cell; osteoarthritis; tissue engineering