Tissue-engineered cartilage with inducible and tunable immunomodulatory properties.
The pathogenesis of osteoarthritis is mediated in part by inflammatory cytokines including interleukin-1 (IL-1), which promote degradation of articular cartilage and prevent human mesenchymal stem cell (MSC) chondrogenesis. In this study, we combined gene therapy and functional tissue engineering to develop engineered cartilage with immunomodulatory properties that allow chondrogenesis in the presence of pathologic levels of IL-1 by inducing overexpression of IL-1 receptor antagonist (IL-1Ra) in MSCs via scaffold-mediated lentiviral gene delivery. A doxycycline-inducible vector was used to transduce MSCs in monolayer or within 3D woven PCL scaffolds to enable tunable IL-1Ra production. In the presence of IL-1, IL-1Ra-expressing engineered cartilage produced cartilage-specific extracellular matrix, while resisting IL-1-induced upregulation of matrix metalloproteinases and maintaining mechanical properties similar to native articular cartilage. The ability of functional engineered cartilage to deliver tunable anti-inflammatory cytokines to the joint may enhance the long-term success of therapies for cartilage injuries or osteoarthritis.
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Katherine A
KA
Glass
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Jarrett M
JM
Link
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Jonathan M
JM
Brunger
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Franklin T
FT
Moutos
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address: charles.gersbach@duke.edu.
Charles A
CA
Gersbach
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: guilak@duke.edu.
Farshid
F
Guilak
D002356:Cartilage / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D020219:Chondrogenesis; D015316:Genetic Therapy; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D010003:Osteoarthritis / Q000628:therapy; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry; D015854:Up-Regulation
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1
Bioactive biomaterial; Cartilage repair; Immunoengineering; Lentivirus; Mesenchymal stem cell; Osteoarthritis