Preclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration

The extended life expectancy and the raise of accidental trauma call for an increase of osteoarticular surgical procedures. Arthroplasty, the main clinical option to treat osteoarticular lesions, has limitations and drawbacks. In this manuscript, we test the preclinical safety of the innovative implant ARTiCAR for the treatment of osteoarticular lesions. Thanks to the combination of two advanced therapy medicinal products, a polymeric nanofibrous bone wound dressing and bone marrow-derived mesenchymal stem cells, the ARTiCAR promotes both subchondral bone and cartilage regeneration. In this work, the ARTiCAR shows 1) the feasibility in treating osteochondral defects in a large animal model, 2) the possibility to monitor non-invasively the healing process and 3) the overall safety in two animal models under GLP preclinical standards. Our data indicate the preclinical safety of ARTiCAR according to the international regulatory guidelines; the ARTiCAR could therefore undergo phase I clinical trial.Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.

[1]  N. Benkirane-Jessel,et al.  Double compartmented and hybrid implant outfitted with well-organized 3D stem cells for osteochondral regenerative nanomedicine. , 2015, Nanomedicine.

[2]  S. Odum,et al.  Early Failures in Total Knee Arthroplasty , 2001, Clinical orthopaedics and related research.

[3]  S. Anders,et al.  A randomized controlled trial demonstrating sustained benefit of Autologous Matrix-Induced Chondrogenesis over microfracture at five years , 2017, International Orthopaedics.

[4]  H. Friess,et al.  VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma , 2008, British Journal of Cancer.

[5]  T. Piontek,et al.  Enhanced microfracture techniques in cartilage knee surgery: Fact or fiction? , 2014, World journal of orthopedics.

[6]  C. Mendoza-Palomares,et al.  Smart hybrid materials equipped by nanoreservoirs of therapeutics. , 2012, ACS nano.

[7]  Olivia S. Beane,et al.  Isolation, Characterization, and Differentiation of Stem Cells for Cartilage Regeneration , 2012, Annals of Biomedical Engineering.

[8]  L. Engebretsen,et al.  Microfracture technique versus osteochondral autologous transplantation mosaicplasty in patients with articular chondral lesions of the knee: a prospective randomized trial with long-term follow-up , 2014, Knee Surgery, Sports Traumatology, Arthroscopy.

[9]  F. O'Brien,et al.  Long-term controlled delivery of rhBMP-2 from collagen-hydroxyapatite scaffolds for superior bone tissue regeneration. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[10]  N. Benkirane-Jessel,et al.  Nanoengineered implant as a new platform for regenerative nanomedicine using 3D well-organized human cell spheroids , 2017, International journal of nanomedicine.

[11]  A. Hébraud,et al.  Electrospun nanofibrous 3D scaffold for bone tissue engineering. , 2012, Bio-medical materials and engineering.

[12]  H. Clevers,et al.  Reparative inflammation takes charge of tissue regeneration , 2016, Nature.

[13]  R. Narkbunnam,et al.  Causes of failure in total knee arthroplasty. , 2012, Journal of the Medical Association of Thailand = Chotmaihet thangphaet.

[14]  P. Müller,et al.  Matrix based autologous chondrocyte implantation in children and adolescents: a match paired analysis in a follow-up over three years post-operation , 2017, International Orthopaedics.

[15]  Mohamadreza Baghaban Eslaminejad,et al.  Mesenchymal stem cells as a potent cell source for articular cartilage regeneration , 2014 .

[16]  Jinxi Wang,et al.  Cell-based articular cartilage repair: the link between development and regeneration. , 2015, Osteoarthritis and cartilage.

[17]  Jens Kurth,et al.  Assessing the safety of stem cell therapeutics. , 2011, Cell stem cell.

[18]  F. Dubrana,et al.  Treatment of knee cartilage defect in 2010. , 2011, Orthopaedics & traumatology, surgery & research : OTSR.

[19]  S. Giannini,et al.  Osteochondral lesions of the knee: a new one-step repair technique with bone-marrow-derived cells. , 2010, The Journal of bone and joint surgery. American volume.

[20]  A. Goldberg,et al.  The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review , 2017, Journal of Orthopaedic Surgery and Research.

[21]  J. Cobb,et al.  The Global Economic Cost of Osteoarthritis: How the UK Compares , 2012, Arthritis.

[22]  L. Sensébé,et al.  Biodistribution of Mesenchymal Stem/Stromal Cells in a Preclinical Setting , 2013, Stem cells international.

[23]  J. Hui,et al.  Postoperative evaluation of the knee after autologous chondrocyte implantation: what radiologists need to know. , 2007, Radiographics : a review publication of the Radiological Society of North America, Inc.

[24]  R. Kandel,et al.  A New Histology Scoring System for the Assessment of the Quality of Human Cartilage Repair: ICRS II , 2010, The American journal of sports medicine.

[25]  Troy D. Bornes,et al.  Mesenchymal stem cells in the treatment of traumatic articular cartilage defects: a comprehensive review , 2014, Arthritis Research & Therapy.

[26]  A. U. Daniels,et al.  Engineering human cell-based, functionally integrated osteochondral grafts by biological bonding of engineered cartilage tissues to bony scaffolds. , 2010, Biomaterials.

[27]  J. M. Badura,et al.  A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE® Bone Graft) , 2007, International Orthopaedics.

[28]  N. Benkirane-Jessel,et al.  Bi-layered nano active implant with hybrid stem cell microtissues for tuned cartilage hypertrophy , 2015 .

[29]  Jaume Puig-Junoy,et al.  Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies. , 2015, Seminars in arthritis and rheumatism.

[30]  Jan Henkel,et al.  Bone Regeneration Based on Tissue Engineering Conceptions — A 21st Century Perspective , 2013, Bone Research.

[31]  S. Giannini,et al.  One-Step Repair in Talar Osteochondral Lesions , 2013, The American journal of sports medicine.

[32]  T. Aigner,et al.  Autologous Chondrocyte Implantation and Osteochondral Cylinder Transplantation in Cartilage Repair of the Knee Joint: A Prospective, Comparative Trial , 2003, The Journal of bone and joint surgery. American volume.

[33]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[34]  H. An,et al.  Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery. , 2014, The spine journal : official journal of the North American Spine Society.

[35]  C. Howie,et al.  Predicting dissatisfaction following total knee replacement: a prospective study of 1217 patients. , 2010, The Journal of bone and joint surgery. British volume.

[36]  D. Kalyon,et al.  Functionally graded electrospun polycaprolactone and beta-tricalcium phosphate nanocomposites for tissue engineering applications. , 2008, Biomaterials.

[37]  W. Dunn,et al.  Treatment of Focal Articular Cartilage Defects in the Knee , 2008, Clinical orthopaedics and related research.

[38]  K. Na,et al.  Mesenchymal Stem Cell-Based Tissue Engineering for Chondrogenesis , 2011, Journal of biomedicine & biotechnology.

[39]  Rui L. Reis,et al.  Orthopaedic regenerative tissue engineering en route to the holy grail: disequilibrium between the demand and the supply in the operating room , 2018, Journal of Experimental Orthopaedics.

[40]  H. Nejadnik,et al.  Autologous Bone Marrow–Derived Mesenchymal Stem Cells Versus Autologous Chondrocyte Implantation , 2010, The American journal of sports medicine.

[41]  A. Ferrand,et al.  Nanomechanical Properties of Active Nanofibrous Implants After In Vivo Bone Regeneration , 2014 .

[42]  M. Marcacci,et al.  Treatment of cartilage lesions: what works and why? , 2013, Injury.

[43]  A. Nixon,et al.  A chondrocyte infiltrated collagen type I/III membrane (MACI® implant) improves cartilage healing in the equine patellofemoral joint model. , 2015, Osteoarthritis and cartilage.

[44]  J. Somerson,et al.  Preclinical good laboratory practice-compliant safety study to evaluate biodistribution and tumorigenicity of a cartilage advanced therapy medicinal product (ATMP) , 2015, Journal of Translational Medicine.

[45]  Andrés J. García,et al.  Engineering graded tissue interfaces , 2008, Proceedings of the National Academy of Sciences.

[46]  K. Hjelle,et al.  Articular cartilage defects in 1,000 knee arthroscopies. , 2002, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[47]  Canary Wharf,et al.  Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted , 2013 .

[48]  D. Magne,et al.  Mesenchymal stem cell therapy to rebuild cartilage. , 2005, Trends in molecular medicine.

[49]  Laetitia Keller,et al.  A living thick nanofibrous implant bifunctionalized with active growth factor and stem cells for bone regeneration , 2015, International journal of nanomedicine.

[50]  N. Paschos,et al.  Update on mesenchymal stem cell therapies for cartilage disorders , 2017, World journal of orthopedics.

[51]  N. Faucheux,et al.  Biomimetic materials for controlling bone cell responses. , 2013, Frontiers in bioscience.

[52]  R. Xiang,et al.  Mesenchymal Stem Cells Engineered to Secrete Pigment Epithelium-Derived Factor Inhibit Tumor Metastasis and the Formation of Malignant Ascites in a Murine Colorectal Peritoneal Carcinomatosis Model. , 2016, Human gene therapy.

[53]  M. Axe,et al.  Knee pain and mobility impairments: meniscal and articular cartilage lesions. , 2010, The Journal of orthopaedic and sports physical therapy.

[54]  Frank P Barry,et al.  Mesenchymal stem cells avoid allogeneic rejection , 2005, Journal of Inflammation.