Abstract
Advanced biomaterial-guided delivery of gene vectors is an emerging and highly attractive therapeutic solution for targeted articular cartilage repair, allowing for a controlled and minimally invasive delivery of gene vectors in a spatiotemporally precise manner, reducing intra-articular vector spread and possible loss of the therapeutic gene product. As far as it is known, the very first successful in vivo application of such a biomaterial-guided delivery of a potent gene vector in an orthotopic large animal model of cartilage damage is reported here. In detail, an injectable and thermosensitive hydrogel based on poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig model in vivo. These comprehensive analyses of the entire osteochondral unit with multiple standardized evaluation methods indicate that rAAV-FLAG-hsox9/PEO-PPO-PEO hydrogel-augmented microfracture significantly improves cartilage repair with a collagen fiber orientation more similar to the normal cartilage and protects the subchondral bone plate from early bone loss.
Highlights
PEO–PPO–PEO copolymers are nonionic on poly(ethylene oxide) (PEO)–poly(propylene oxide) (PPO)–PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig triblock copolymers based on hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) (Figure 1a)[5] in a linear and bifunctional form or X-shaped form linked by a dyamine cenmodel in vivo
Defects of the articular cartilage, the smooth white tissue cov- networks with high viscosity,[6] displaying a sol–gel transiering the ends of bones, do not regenerate and may induce tion around 37 °C, enabling a minimally invasive in vivo injection osteoarthritis (OA),[1] the number one cause of chronic dis, and becoming semiability in the USA, afflicting more than 67 million people by solid to solid gels capable of a sustained and controlled release of
We observed higher type-II collagen deposition in the sox9/hydrogel defects compared with the lacZ/hydrogel group or with free lacZ application (P ≤ 0.026) (Figure 2c,s; Table S4, Supporting Information), probably resulting from higher numbers of SOX9-positive cells in the sox9/hydrogel defects relative to all other groups (P ≤ 0.001) (Figure 2d,t; Table S4, Supporting Information), indicating improved transgene expression via PEO–PPO–PEO-guided recombinant adeno-associated virus (rAAV) controlled release
Summary
PEO–PPO–PEO copolymers are nonionic on poly(ethylene oxide) (PEO)–poly(propylene oxide) (PPO)–PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig triblock copolymers based on hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) (Figure 1a)[5] in a linear and bifunctional form (poloxamers) or X-shaped form linked by a dyamine cenmodel in vivo. We studied the effects of injecting a thermosensitive hydrogel based on PEO–PPO–PEO poloxamers for the in situ release of an rAAV encoding for the chondrogenic sox9 transcription factor on the repair of full-thickness chondral defects in a clinically relevant large animal model in vivo.
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