Thermosensitive Hydrogel Based on PEO–PPO–PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno‐Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects

• Published in: Advanced materials (Weinheim) Vol. 32; no. 2; pp. e1906508 - n/a
• Main Authors: Madry, Henning, Gao, Liang, Rey‐Rico, Ana, Venkatesan, Jagadeesh K., Müller‐Brandt, Kathrin, Cai, Xiaoyu, Goebel, Lars, Schmitt, Gertrud, Speicher‐Mentges, Susanne, Zurakowski, David, Menger, Michael D., Laschke, Matthias W., Cucchiarini, Magali
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2020
• Subjects: biomaterial‐guided therapy; Biomedical materials; Cartilage; cartilage defects; Controlled release; Defects; Ethylene oxide; Fiber orientation; Gene therapy; Hydrogels; Materials science; Microfracture; Poloxamers; Polyethylene oxide; Propylene oxide; rAAV; Repair; tissue engineering; Viruses; rAAV; gene therapy; tissue engineering; biomaterial-guided therapy; cartilage defects
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.201906508

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. An injectable thermosensitive hydrogel based on PEO–PPO–PEO poloxamers is shown to be able to control the release of an rAAV vector overexpressing the chondrogenic sox9 transcription factor to treat full‐thickness knee chondral defects in minipigs in vivo. Such therapeutic biomaterial‐guided gene transfer with augmented microfracture can enhance cartilage repair and protect from early postoperative bone loss.