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Ana Rey-Rico,1 Jagadeesh K Venkatesan,1 Gertrud Schmitt,1 Angel Concheiro,2 Henning Madry,1,3 Carmen Alvarez-Lorenzo,2 Magali Cucchiarini1 1Center of Experimental Orthopedics, Saarland University Medical Center, Homburg, Germany; 2Department of Pharmacology, Pharmacy and Pharmaceutical Technology, R+DPharma Group (GI-1645), Facultad de Farmacia and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain; 3Department of Orthopedics and Orthopedic Surgery, Saarland University Medical Center, Homburg, Germany Abstract: Recombinant adeno-associated virus (rAAV) vectors are clinically adapted vectors to durably treat human osteoarthritis (OA). Controlled delivery of rAAV vectors via polymeric micelles was reported to enhance the temporal and spatial presentation of the vectors into their targets. Here, we tested the feasibility of delivering rAAV vectors via poly (ethylene oxide) (PEO) and poly (propylene oxide) (PPO) (poloxamer and poloxamine) polymeric micelles as a means to overexpress the therapeutic factor transforming growth factor-beta (TGF-β) in human OA chondrocytes and in experimental human osteochondral defects. Application of rAAV-human transforming growth factor-beta using such micelles increased the levels of TGF-β transgene expression compared with free vector treatment. Overexpression of TGF-β with these systems resulted in higher proteoglycan deposition and increased cell numbers in OA chondrocytes. In osteochondral defect cultures, a higher deposition of type-II collagen and reduced hypertrophic events were noted. Delivery of therapeutic rAAV vectors via PEO-PPO-PEO micelles may provide potential tools to remodel human OA cartilage. Keywords: controlled delivery, human articular cartilage, rAAV gene transfer, TGF-β, poloxamer, poloxamine

Objectives: Gene therapy is an attractive strategy for the durable treatment of human osteoarthritis (OA), a gradual, irreversible joint disease. Gene carriers based on the small human adeno-associated virus (AAV) exhibit major efficacy in modifying damaged human articular cartilage in situ over extended[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Objectives: Articular cartilage supports joint loading and motion but has a limited ability for self-healing. Gene transfer using the clinically relevant recombinant adeno-associated viral (rAAV) vectors is a powerful tool to enhance cartilage repair. Here, we tested the ability of poly(sodium styrene[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Objectives: Adult articular cartilage has a restricted capability for self-repair. A highly established method is the transfer of genetically modified human bone marrow-derived mesenchymal stem cells (hMSCs) as progenitor cells to improve the natural healing of the damaged articular cartilage. In this[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)

The treatment of painful chronic tendinopathy is challenging. Multiple non-invasive and tendon-invasive methods are used. When traditional non-invasive treatments fail, the injections of platelet-rich plasma autologous blood or cortisone have become increasingly favored. However, there is little scientific evidence from human studies supporting injection treatment. As the last resort, intra- or peritendinous open or endoscopic surgery are employed even though these also show varying results. This ESSKA basic science committee current concepts review follows the first part on the biology, biomechanics and anatomy of tendinopathies, to provide a comprehensive overview of the latest treatment options for tendinopathy as reported in the literature.

Fragestellung: Die subchondrale Anbohrung ist eine etablierte Technik zur Behandlung kleinflächiger Knorpeldefekte [Pridie, 1959]. Trotz langjähriger Anwendung ist bislang weder im klinischen Kontext noch im translationalen Tiermodell untersucht, ob die subchondrale Anbohrung gegenüber[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Objectives: Adult articular cartilage has a restricted capability for self-repair. Direct gene based modification of bone marrow aspirates is a stunning tool to treat cartilage defects. In these studies, we investigated application of rAAV-FLAG-hsox9 in minipig bone marrow aspirates seeded in woven [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Objectives: Genetic modification of chondrocytes is a powerful approach to enhance the remodeling of osteoarthritic cartilage. Recombinant adeno-associated viral (rAAV) vectors are strong candidates to achieve this goal as these gene vehicles are highly safe and effective tools for clinical application.[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Objectives: Microfracture (MFX) is the most clinically used marrow stimulation technique for treatment of symptomatic focal articular cartilage defects. Recent data suggest that enhanced MFX by autologous bone marrow aspirate offers a promising one-step approach to overcome the shortcomings of the standard[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Objectives: Repairing articular cartilage remain an illusive goal and is the subject of many investigations using tissue engineering platforms and biologics. Cartilage tissue analogs (CTAs) provide attractive high cell density, scaffold-free system to engineer articular cartilage with unique features[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Patrick Orth,1 Ana Rey-Rico,2 Jagadeesh K Venkatesan,2 Henning Madry,1,2 Magali Cucchiarini2 1Department of Orthopaedic Surgery, 2Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany Abstract: Protocols based on the delivery of stem cells are currently applied in patients, showing encouraging results for the treatment of articular cartilage lesions (focal defects, osteoarthritis). Yet, restoration of a fully functional cartilage surface (native structural organization and mechanical functions) especially in the knee joint has not been reported to date, showing the need for improved designs of clinical trials. Various sources of progenitor cells are now available, originating from adult tissues but also from embryonic or reprogrammed tissues, most of which have already been evaluated for their chondrogenic potential in culture and for their reparative properties in vivo upon implantation in relevant animal models of cartilage lesions. Nevertheless, particular attention will be needed regarding their safe clinical use and their potential to form a cartilaginous repair tissue of proper quality and functionality in the patient. Possible improvements may reside in the use of biological supplements in accordance with regulations, while some challenges remain in establishing standardized, effective procedures in the clinics. Keywords: cartilage repair, knee, focal defects, osteoarthritis, stem cells, clinical trials

Objectives: Subchondral bone alterations are emerging as a considerable clinical problem associated with articular cartilage repair. Their analysis exposes a pattern of variable changes, including intra-lesional osteophytes, residual holes originating from marrow stimulation procedures, bone bridges[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

Objectives: Implantation of genetically modified bone marrow aspirates is a promising approach to treat cartilage defects. Here, we tested the benefits of applying an rAAV sox9 vector to human bone marrow aspirates in 3D woven poly(ε-caprolactone) (PCL) scaffolds to stimulate the chondrogenic [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

Objectives: rAAV are clinically adapted gene vectors for human regenerative medicine yet their use is still associated with a moderate cellular uptake due to host humoral immune responses and in the presence of inhibitory clinical compounds like heparin. Here, we tested the possibility of delivering[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

In view of cartilage tissue engineering, the possibility to prepare porous scaffolds releasing transforming growth factor-beta(1) (TGF-beta(1)) in a well controlled fashion was investigated by means of an emulsion-coating method. Poly(ether-ester) multiblock copolymers were used to prepare emulsions containing TGF-beta(1) which were subsequently applied onto prefabricated scaffolds. This approach resulted in defined porous structures (66%) with interconnected porosity, suitable to allow tissue ingrowth. The scaffolds were effectively associated with TGF-beta(1) and allowed to tailor precisely the release of the growth factor from 12 days to more than 50 days by varying the copolymer composition of the coating. An incomplete release was measured by ELISA, possibly linked to the rapid concentration decrease of the protein in solution. The released growth factor retained its biological activity as was assessed by a cell proliferation assay and by the ability of the released protein to induce chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. However, exact bioactivity quantification was rendered difficult by the protein concentration decrease during storage. Therefore, this study confirms the interest of poly(ether-ester) multiblock copolymers for controlled release of growth factors, and indicates that emulsion-coated scaffolds are promising candidates for cartilage tissue engineering applications requiring precise TGF-beta(1) release rates.

Objectives: Inclusion of viral vectors in polymeric systems is an attractive approach to enhance their stability and efficacy and decrease potential neutralizing immune responses. We developed different alginate-poloxamer hydrogel structures to entrap and release rAAV vectors for the genetic modification[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

Fragestellung: Markraumeröffnende Verfahren wie die Mikrofrakturierung sind etablierte Techniken zur Behandlung kleinflächiger Knorpeldefekte. Hierbei wird mittels Ahlen die subchondrale Knochenlamelle perforiert, um pluripotenten Stammzellen aus dem Knochenmarkraum das Einwandern in den Knorpeldefekt[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

Objectives: Controlling the release of gene transfer vectors from biocompatible materials is an attractive strategy to improve the processes of cartilage repair. Here, we examined the ability of the self-assembling peptide hydrogel RAD-16-I in a pure (M0) or combined form using hyaluronic acid (HA) [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

Objectives: Implantation of genetically modified MSCs with polyurethane (PU) scaffolds is an attractive tool to treat articular cartilage defects. Here we evaluated whether rAAV sox9 gene transfer in hMSCs seeded onto PU scaffolds enhances the chondrogenic differentiation processes in dynamic culture[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

Fragestellung: Knochenmarkaspirate können genetisch verändert werden und als Plattformen die Knorpelreparatur verbessern. Wir haben die Hypothese überprüft, dass rAAV-Vektoren humane Knochenmarkaspirate modifizieren können, um optimale Bedingungen für die Chondrogenese [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2014)

Fragestellung: Parathormon (PTH [1-34]) wird klinisch zur Osteoporosebehandlung eingesetzt und verbessert die experimentelle Frakturheilung. Die Wirkung von PTH [1-34] auf den subchondralen Knochen ist jedoch bislang nur unzureichend erforscht. Wir untersuchten die Hypothese, dass[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2014)

Fragestellung: Humane mesenchymale Stammzellen (hMSZ) könnten Kandidatengene zur Verbesserung der Knorpelreparatur überexprimieren. Wir untersuchten die Hypothese, daß eine rAAV-vermittelte Überexpression des humanen Wachstumsfaktors TGF-ß die Chondrogenese von hMSZ stimuliert.[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2013)

Fragestellung: Die Tibiakopfosteotomie (HTO) ist eine wichtige Behandlungsoption im Rahmen der rekonstruktiven Knorpelchirurgie von fokalen Gelenkknorpeldefekten bei gleichzeitiger Achsfehlstellung. Wir untersuchten die Hypothese, dass eine Achskorrektur bei bestehendem medialen femoralen Knorpeldefekt[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2012)

Fragestellung: Gentransfer therapeutischer Faktoren ist eine vielversprechende Methode, reparative Prozesse bei Gelenkknorpeldefekten zu verbessern. Wir testeten die Hypothese, daß nach Konstruktion eines rAAV-hTGF-ß-Vektors und Überexpression von humanem transformierenden Wachstumsfaktor[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2012)

Fragestellung: Therapeutischer Gentransfer kann potentiell die Reparatur von Gelenkknorpeldefekten verbessern. Wir testeten die Hypothese, daß die direkte Applikation eines neu klonierten rAAV-IGF-I-Vektors die Heilung osteochondraler Defekte im Kniegelenk von Kaninchen verbessert. Methodik:[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: Gentransfer therapeutischer Faktoren verbessert die Reparatur von Gelenkknorpeldefekten im Tiermodell. Ex-vivo-Gentransfer von insulinartigem Wachstumsfaktor I (IGF-I) mittels transfizierter und transplantierter Chondrozyten stimuliert die Knorpelreparatur in vivo. Obwohl rAAV-Vektoren[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: Der Fibroblastenwachstumsfaktor-2 (FGF-2) ist ein Polypeptid, welches unter anderem auch myoblastenproliferative Eigenschaften aufweist. Ziel der hier vorgestellten Studie war es, die Regenerationskapazität der traumatisierten peripheren Skelettmuskulatur, nach Transplantation von[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Fragestellung: Humane mesenchymale Stammzellen (hMSC) sind eine wichtige Zielzellpopulation für genbasierte Ansätze zur Knorpelreparatur. Wir untersuchten 15 verschiedene nichtvirale Transfektionssysteme auf ihre Fähigkeit zum Gentransfer in hMSC. Methodik: MSC wurden aus Knochenmarkaspiraten[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 73. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 95. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 50. Tagung des Berufsverbandes der Fachärzte für Orthopädie

Secretome and extracellular vesicles (EVs) are considered a promising option to exploit mesenchymal stem cells’ (MSCs) properties to address knee osteoarthritis (OA). The aim of this systematic review was to analyze both the in vitro and in vivo literature, in order to understand the potential of secretome and EVs as a minimally invasive injective biological approach. A systematic review of the literature was performed on PubMed, Embase, and Web of Science databases up to 31 August 2019. Twenty studies were analyzed; nine in vitro, nine in vitro and in vivo, and two in vivo. The analysis showed an increasing interest in this emerging field, with overall positive findings. Promising in vitro results were documented in terms of enhanced cell proliferation, reduction of inflammation, and down-regulation of catabolic pathways while promoting anabolic processes. The positive in vitro findings were confirmed in vivo, with studies showing positive effects on cartilage, subchondral bone, and synovial tissues in both OA and osteochondral models. However, several aspects remain to be clarified, such as the different effects induced by EVs and secretome, which is the most suitable cell source and production protocol, and the identification of patients who may benefit more from this new biological approach for knee OA treatment.