TY - JOUR
T1 - Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs
AU - Rowland, Christopher R.
AU - Glass, Katherine A.
AU - Ettyreddy, Adarsh R.
AU - Gloss, Catherine C.
AU - Matthews, Jared R.L.
AU - Huynh, Nguyen P.T.
AU - Guilak, Farshid
N1 - Funding Information:
The authors thank Sara Oswald for providing technical writing support for the manuscript, Matt Joens for assistance in SEM imaging, and Drs. Jonathan Brunger and Charles Gersbach for important discussions and advice in the early stages of the study. This study was supported in part by NIH grants AR50245 , AR48852 , AG15768 , AR48182 , AR067467 , AR065956 , the Nancy Taylor Foundation for Chronic Diseases , the Arthritis Foundation , and the Collaborative Research Center of the AO Foundation, Davos, Switzerland .
Funding Information:
The authors thank Sara Oswald for providing technical writing support for the manuscript, Matt Joens for assistance in SEM imaging, and Drs. Jonathan Brunger and Charles Gersbach for important discussions and advice in the early stages of the study. This study was supported in part by NIH grants AR50245, AR48852, AG15768, AR48182, AR067467, AR065956, the Nancy Taylor Foundation for Chronic Diseases, the Arthritis Foundation, and the Collaborative Research Center of the AO Foundation, Davos, Switzerland.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/9
Y1 - 2018/9
N2 - Cartilage-derived matrix (CDM) has emerged as a promising scaffold material for tissue engineering of cartilage and bone due to its native chondroinductive capacity and its ability to support endochondral ossification. Because it consists of native tissue, CDM can undergo cellular remodeling, which can promote integration with host tissue and enables it to be degraded and replaced by neotissue over time. However, enzymatic degradation of decellularized tissues can occur unpredictably and may not allow sufficient time for mechanically competent tissue to form, especially in the harsh inflammatory environment of a diseased joint. The goal of the current study was to engineer cartilage and bone constructs with the ability to inhibit aberrant inflammatory processes caused by the cytokine interleukin-1 (IL-1), through scaffold-mediated delivery of lentiviral particles containing a doxycycline-inducible IL-1 receptor antagonist (IL-1Ra) transgene on anatomically-shaped CDM constructs. Additionally, scaffold-mediated lentiviral gene delivery was used to facilitate spatial organization of simultaneous chondrogenic and osteogenic differentiation via site-specific transduction of a single mesenchymal stem cell (MSC) population to overexpress either chondrogenic, transforming growth factor-beta 3 (TGF-β3), or osteogenic, bone morphogenetic protein-2 (BMP-2), transgenes. Controlled induction of IL-1Ra expression protected CDM hemispheres from inflammation-mediated degradation, and supported robust bone and cartilage tissue formation even in the presence of IL-1. In the absence of inflammatory stimuli, controlled cellular remodeling was exploited as a mechanism for fusing concentric CDM hemispheres overexpressing BMP-2 and TGF-β3 into a single bi-layered osteochondral construct. Our findings demonstrate that site-specific delivery of inducible and tunable transgenes confers spatial and temporal control over both CDM scaffold remodeling and neotissue composition. Furthermore, these constructs provide a microphysiological in vitro joint organoid model with site-specific, tunable, and inducible protein delivery systems for examining the spatiotemporal response to pro-anabolic and/or inflammatory signaling across the osteochondral interface.
AB - Cartilage-derived matrix (CDM) has emerged as a promising scaffold material for tissue engineering of cartilage and bone due to its native chondroinductive capacity and its ability to support endochondral ossification. Because it consists of native tissue, CDM can undergo cellular remodeling, which can promote integration with host tissue and enables it to be degraded and replaced by neotissue over time. However, enzymatic degradation of decellularized tissues can occur unpredictably and may not allow sufficient time for mechanically competent tissue to form, especially in the harsh inflammatory environment of a diseased joint. The goal of the current study was to engineer cartilage and bone constructs with the ability to inhibit aberrant inflammatory processes caused by the cytokine interleukin-1 (IL-1), through scaffold-mediated delivery of lentiviral particles containing a doxycycline-inducible IL-1 receptor antagonist (IL-1Ra) transgene on anatomically-shaped CDM constructs. Additionally, scaffold-mediated lentiviral gene delivery was used to facilitate spatial organization of simultaneous chondrogenic and osteogenic differentiation via site-specific transduction of a single mesenchymal stem cell (MSC) population to overexpress either chondrogenic, transforming growth factor-beta 3 (TGF-β3), or osteogenic, bone morphogenetic protein-2 (BMP-2), transgenes. Controlled induction of IL-1Ra expression protected CDM hemispheres from inflammation-mediated degradation, and supported robust bone and cartilage tissue formation even in the presence of IL-1. In the absence of inflammatory stimuli, controlled cellular remodeling was exploited as a mechanism for fusing concentric CDM hemispheres overexpressing BMP-2 and TGF-β3 into a single bi-layered osteochondral construct. Our findings demonstrate that site-specific delivery of inducible and tunable transgenes confers spatial and temporal control over both CDM scaffold remodeling and neotissue composition. Furthermore, these constructs provide a microphysiological in vitro joint organoid model with site-specific, tunable, and inducible protein delivery systems for examining the spatiotemporal response to pro-anabolic and/or inflammatory signaling across the osteochondral interface.
KW - Cartilage repair
KW - Gene activated matrix
KW - Gene therapy
KW - Immunoengineering
KW - Osteoarthritis
KW - Regenerative medicine
UR - http://www.scopus.com/inward/record.url?scp=85049320781&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2018.04.049
DO - 10.1016/j.biomaterials.2018.04.049
M3 - Article
C2 - 29894913
AN - SCOPUS:85049320781
VL - 177
SP - 161
EP - 175
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
ER -