Cartilage Repair Using Hydrogels: A Critical Review of in Vivo Experimental Designs.

This review analyzes the outcomes and technical aspects of in vivo studies published in the past decade using gels and hydrogels for cartilage repair. Using PubMed search engine, original research publications during the period of 2002/01/01 to 2015/04/30 identified 115 published papers. Of these, 3 studies failed to find a statistically significant improvement of treatment group as compared to control and 18 studies did not clearly identify hyaline-like cartilage formation in the treated groups. The most frequent repaired lesion was the rabbit acute full thickness trochlear defect, using a scaffold combining a gel or hydrogel and other material. One third of the scaffolds were cell-free (35%) and the majority of the studies did not use growth factors (71%). The present review may constitute a useful tool in design of future studies, as limitations of study designs are pointed and results in terms of translation to human application is discussed.

[1]  Liu Yang,et al.  Bone marrow-derived mesenchymal stem cells versus bone marrow nucleated cells in the treatment of chondral defects , 2012, International Orthopaedics.

[2]  Bernhard Schmidt-Rohlfing,et al.  A comparative study of 3 different cartilage repair techniques , 2011, Knee Surgery, Sports Traumatology, Arthroscopy.

[3]  Glenn D Prestwich,et al.  Osteochondral defect repair with autologous bone marrow-derived mesenchymal stem cells in an injectable, in situ, cross-linked synthetic extracellular matrix. , 2006, Tissue engineering.

[4]  Frank Witte,et al.  Simultaneous regeneration of articular cartilage and subchondral bone induced by spatially presented TGF-beta and BMP-4 in a bilayer affinity binding system. , 2012, Acta biomaterialia.

[5]  J. S. Park,et al.  Chondrogenesis of human mesenchymal stem cells encapsulated in a hydrogel construct: neocartilage formation in animal models as both mice and rabbits. , 2009, Journal of biomedical materials research. Part A.

[6]  J H Brekke,et al.  Regeneration of articular cartilage--evaluation of osteochondral defect repair in the rabbit using multiphasic implants. , 2005, Osteoarthritis and cartilage.

[7]  M. Shokrgozar,et al.  Biological evaluation of polyvinyl alcohol hydrogel crosslinked by polyurethane chain for cartilage tissue engineering in rabbit model , 2013, Journal of Materials Science: Materials in Medicine.

[8]  J. Jansen,et al.  Degradable hydrogel scaffolds for in vivo delivery of single and dual growth factors in cartilage repair. , 2007, Osteoarthritis and cartilage.

[9]  Antonios G Mikos,et al.  Osteochondral repair in the rabbit model utilizing bilayered, degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds. , 2005, Journal of biomedical materials research. Part A.

[10]  R. Shah,et al.  Supramolecular design of self-assembling nanofibers for cartilage regeneration , 2010, Proceedings of the National Academy of Sciences.

[11]  T. Kurokawa,et al.  Influence of the gel thickness on in vivo hyaline cartilage regeneration induced by double-network gel implanted at the bottom of a large osteochondral defect: Short-term results , 2013, BMC Musculoskeletal Disorders.

[12]  T. Kurokawa,et al.  A novel double-network hydrogel induces spontaneous articular cartilage regeneration in vivo in a large osteochondral defect. , 2009, Macromolecular bioscience.

[13]  S. Dong,et al.  Scaffolding biomaterials for cartilage regeneration , 2014 .

[14]  S. Lee,et al.  Synovial membrane-derived mesenchymal stem cells supported by platelet-rich plasma can repair osteochondral defects in a rabbit model. , 2013, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[15]  R. Bohle,et al.  In vitro and in vivo characterization of nonbiomedical- and biomedical-grade alginates for articular chondrocyte transplantation. , 2011, Tissue engineering. Part C, Methods.

[16]  馬﨑 哲朗 A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering , 2014 .

[17]  C. Han,et al.  Chondrocyte apoptosis in the regenerated articular cartilage after allogenic chondrocyte transplantation in the rabbit knee. , 2007, The Journal of bone and joint surgery. British volume.

[18]  Johan Vanlauwe,et al.  Tissue engineering approaches for osteoarthritis. , 2012, Bone.

[19]  C. Yeow,et al.  Cartilage repair using hyaluronan hydrogel-encapsulated human embryonic stem cell-derived chondrogenic cells. , 2010, Biomaterials.

[20]  A. Mikos,et al.  Oligo[poly(ethylene glycol)fumarate] Hydrogel Enhances Osteochondral Repair in Porcine Femoral Condyle Defects , 2013, Clinical orthopaedics and related research.

[21]  Hai-bin Wang,et al.  The support of matrix accumulation and the promotion of sheep articular cartilage defects repair in vivo by chitosan hydrogels. , 2010, Osteoarthritis and cartilage.

[22]  J. Werkmeister,et al.  Repair of porcine articular cartilage defect with autologous chondrocyte transplantation , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[23]  Hai Yao,et al.  Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study , 2010, The Lancet.

[24]  M. Lind,et al.  Cartilage repair with chondrocytes in fibrin hydrogel and MPEG polylactide scaffold: an in vivo study in goats , 2008, Knee Surgery, Sports Traumatology, Arthroscopy.

[25]  I. Kiviranta,et al.  Repair of osteochondral defects with recombinant human type II collagen gel and autologous chondrocytes in rabbit. , 2013, Osteoarthritis and cartilage.

[26]  A. Nixon,et al.  Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[27]  M. Fujimiya,et al.  Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair , 2007, Acta orthopaedica.

[28]  R. Wittenauer,et al.  Background Paper 6.12 Osteoarthritis , 2013 .

[29]  Young Ha Kim,et al.  The use of de-differentiated chondrocytes delivered by a heparin-based hydrogel to regenerate cartilage in partial-thickness defects. , 2011, Biomaterials.

[30]  T. Aigner,et al.  Histopathology atlas of animal model systems - overview of guiding principles. , 2010, Osteoarthritis and cartilage.

[31]  Freddie H Fu,et al.  Muscle derived, cell based ex vivo gene therapy for treatment of full thickness articular cartilage defects. , 2002, The Journal of rheumatology.

[32]  D Mainard,et al.  Cartilage repair using new polysaccharidic biomaterials: macroscopic, histological and biochemical approaches in a rat model of cartilage defect. , 2003, Osteoarthritis and cartilage.

[33]  H. Kijima,et al.  Potential of exogenous cartilage proteoglycan as a new material for cartilage regeneration , 2012, International Orthopaedics.

[34]  T. Xi,et al.  Performance of novel bioactive hybrid hydrogels in vitro and in vivo used for artificial cartilage , 2009, Biomedical materials.

[35]  A. Mikos,et al.  Articular chondrocytes and mesenchymal stem cells seeded on biodegradable scaffolds for the repair of cartilage in a rat osteochondral defect model. , 2014, Biomaterials.

[36]  B. Cogliati,et al.  Evaluation of chitosan-GP hydrogel biocompatibility in osteochondral defects: an experimental approach , 2014, BMC Veterinary Research.

[37]  D. Betts,et al.  Stem cell therapy for joint problems using the horse as a clinically relevant animal model , 2007, Expert opinion on biological therapy.

[38]  I. Sekiya,et al.  Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit , 2008, Cell and Tissue Research.

[39]  M. Handl,et al.  Composite hyaluronate-type I collagen-fibrin scaffold in the therapy of osteochondral defects in miniature pigs. , 2007, Physiological research.

[40]  J. Goh,et al.  Intra-articular delivery of chondroitin sulfate for the treatment of joint defects in rabbit model , 2007, Journal of Molecular Histology.

[41]  T. Ishii,et al.  Repair of large full-thickness articular cartilage defects in the rabbit: the effects of joint distraction and autologous bone-marrow-derived mesenchymal cell transplantation. , 2005, The Journal of bone and joint surgery. British volume.

[42]  T. Kurokawa,et al.  Gene expression profile of the cartilage tissue spontaneously regenerated in vivo by using a novel double-network gel: Comparisons with the normal articular cartilage , 2011, BMC musculoskeletal disorders.

[43]  Ali Khademhosseini,et al.  Hydrogels and microtechnologies for engineering the cellular microenvironment. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[44]  M Kubo,et al.  A novel exogenous concentration-gradient collagen scaffold augments full-thickness articular cartilage repair. , 2007, Osteoarthritis and cartilage.

[45]  Freddie H. Fu,et al.  Analysis of rabbit articular cartilage repair after chondrocyte implantation using optical coherence tomography. , 2003, Osteoarthritis and cartilage.

[46]  M. Gomes,et al.  Injectable gellan gum hydrogels with autologous cells for the treatment of rabbit articular cartilage defects , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[47]  Wei Wang,et al.  In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes. , 2010, Biomaterials.

[48]  A. Grodzinsky,et al.  Effect of self-assembling peptide, chondrogenic factors, and bone marrow-derived stromal cells on osteochondral repair. , 2010, Osteoarthritis and cartilage.

[49]  H. Kurz,et al.  Cell-laden and cell-free biopolymer hydrogel for the treatment of osteochondral defects in a sheep model. , 2009, Tissue engineering. Part A.

[50]  J. Hilborn,et al.  In situ cross‐linkable hyaluronan hydrogel enhances chondrogenesis , 2011, Journal of tissue engineering and regenerative medicine.

[51]  Young Ha Kim,et al.  Composite system of PLCL scaffold and heparin-based hydrogel for regeneration of partial-thickness cartilage defects. , 2012, Biomacromolecules.

[52]  D. W. Jackson,et al.  Symptomatic articular cartilage degeneration: the impact in the new millennium. , 2001, Clinical orthopaedics and related research.

[53]  Zhongmin Jin,et al.  Cartilage Repair and Subchondral Bone Migration Using 3D Printing Osteochondral Composites: A One-Year-Period Study in Rabbit Trochlea , 2014, BioMed research international.

[54]  達弥 五十嵐 A cellular implantation system using an injectable ultra-purified alginate gel for repair of osteochondral defects in a rabbit model , 2010 .

[55]  Y. Kuang,et al.  Mosaicplasty associated with gene enhanced tissue engineering for the treatment of acute osteochondral defects in a goat model , 2009, Archives of Orthopaedic and Trauma Surgery.

[56]  J T Oliveira,et al.  Polysaccharide‐based materials for cartilage tissue engineering applications , 2011, Journal of tissue engineering and regenerative medicine.

[57]  Benjamin M. Wu,et al.  NELL-1 promotes cartilage regeneration in an in vivo rabbit model. , 2012, Tissue engineering. Part A.

[58]  R. Katayama,et al.  Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow. , 2004, Rheumatology.

[59]  Antonios G Mikos,et al.  Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair. , 2014, Biomaterials.

[60]  H. Fischer,et al.  Supporting Biomaterials for Articular Cartilage Repair , 2012, Cartilage.

[61]  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.

[62]  Milan Držík,et al.  A cell-free nanofiber composite scaffold regenerated osteochondral defects in miniature pigs. , 2013, International journal of pharmaceutics.

[63]  James L Cook,et al.  In vivo outcomes of tissue-engineered osteochondral grafts. , 2010, Journal of biomedical materials research. Part B, Applied biomaterials.

[64]  Eva Prosecká,et al.  Fibrin/Hyaluronic Acid Composite Hydrogels as Appropriate Scaffolds for In Vivo Artificial Cartilage Implantation , 2010, ASAIO journal.

[65]  T. Taguchi,et al.  Repair of full-thickness articular cartilage defects using injectable type II collagen gel embedded with cultured chondrocytes in a rabbit model , 2008, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[66]  J. Hirose,et al.  Healing of full-thickness defects of the articular cartilage in rabbits using fibroblast growth factor-2 and a fibrin sealant. , 2007, The Journal of bone and joint surgery. British volume.

[67]  T. Kurokawa,et al.  Spontaneous hyaline cartilage regeneration can be induced in an osteochondral defect created in the femoral condyle using a novel double-network hydrogel , 2011, BMC musculoskeletal disorders.

[68]  W. Akeson,et al.  The Repair of Large Osteochondral Defects An Experimental Study in Horses , 1972, Clinical orthopaedics and related research.

[69]  D. Saris,et al.  Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage. , 2010, Osteoarthritis and cartilage.

[70]  伊藤 洋平 Repair of osteochondral defect with tissue-engineered chondral plug in a rabbit model , 2006 .

[71]  Y. Kato,et al.  Transplantation of autologous rabbit BM-derived mesenchymal stromal cells embedded in hyaluronic acid gel sponge into osteochondral defects of the knee. , 2006, Cytotherapy.

[72]  E B Hunziker,et al.  Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. , 2002, Osteoarthritis and cartilage.

[73]  W. Chan,et al.  Implantation of platelet-rich fibrin and cartilage granules facilitates cartilage repair in the injured rabbit knee: preliminary report , 2011, Clinics.

[74]  K. Nishizawa,et al.  Improved quality of cartilage repair by bone marrow mesenchymal stem cells for treatment of an osteochondral defect in a cynomolgus macaque model , 2015, Acta orthopaedica.

[75]  A. Mikos,et al.  Repair of osteochondral defects with rehydrated freeze-dried oligo[poly(ethylene glycol) fumarate] hydrogels seeded with bone marrow mesenchymal stem cells in a porcine model. , 2013, Tissue engineering. Part A.

[76]  O. Gauthier,et al.  Effects of In Vitro Low Oxygen Tension Preconditioning of Adipose Stromal Cells on Their In Vivo Chondrogenic Potential: Application in Cartilage Tissue Repair , 2013, PloS one.

[77]  K. Messner,et al.  Regional variations of indentation stiffness and thickness of normal rabbit knee articular cartilage. , 1996, Journal of biomedical materials research.

[78]  A. Khademhosseini,et al.  Microscale technologies for tissue engineering and biology. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[79]  J. Jansen,et al.  Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[80]  Young Ha Kim,et al.  Cartilage regeneration with highly-elastic three-dimensional scaffolds prepared from biodegradable poly(L-lactide-co-epsilon-caprolactone). , 2008, Biomaterials.

[81]  L. Kaplan,et al.  Development of partial thickness articular cartilage injury in an ovine model , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[82]  T. Ishii,et al.  Repair of large full‐thickness articular cartilage defects by transplantation of autologous uncultured bone‐marrow‐derived mononuclear cells , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[83]  T. Kurokawa,et al.  Intra-articular administration of hyaluronic acid increases the volume of the hyaline cartilage regenerated in a large osteochondral defect by implantation of a double-network gel , 2014, Journal of Materials Science: Materials in Medicine.

[84]  G. Osterhoff,et al.  Perilesional changes of focal osteochondral defects in an ovine model and their relevance to human osteochondral injuries. , 2009, The Journal of bone and joint surgery. British volume.

[85]  J. Dragoo,et al.  Healing full-thickness cartilage defects using adipose-derived stem cells. , 2007, Tissue engineering.

[86]  M. Menger,et al.  Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid‐mediated gene transfer in a gel suspension delivery system , 2003, The journal of gene medicine.

[87]  Konrad Malinowski,et al.  Treatment of full thickness chondral lesions of the knee with microfracture in a group of athletes , 2005, Knee Surgery, Sports Traumatology, Arthroscopy.

[88]  B. Baroli,et al.  Hydrogels for tissue engineering and delivery of tissue-inducing substances. , 2007, Journal of pharmaceutical sciences.

[89]  J. Buckwalter Articular cartilage: injuries and potential for healing. , 1998, The Journal of orthopaedic and sports physical therapy.

[90]  Dietmar W Hutmacher,et al.  Evaluation of a hybrid scaffold/cell construct in repair of high-load-bearing osteochondral defects in rabbits. , 2006, Biomaterials.

[91]  V. Kish,et al.  Repair of full-thickness femoral condyle cartilage defects using allogeneic synovial cell-engineered tissue constructs. , 2009, Osteoarthritis and cartilage.

[92]  S. Lee,et al.  Synovium-derived mesenchymal stem cells encapsulated in a novel injectable gel can repair osteochondral defects in a rabbit model. , 2012, Tissue engineering. Part A.

[93]  G. Balian,et al.  Chondrocyte transplantation into articular cartilage defects with use of calcium alginate: the fate of the cells. , 2003, The Journal of bone and joint surgery. American volume.

[94]  C. Sledge,et al.  Healing of chondral and osteochondral defects in a canine model: the role of cultured chondrocytes in regeneration of articular cartilage. , 1996, Biomaterials.

[95]  J. S. Park,et al.  Chondrogenesis of human mesenchymal stem cells in fibrin constructs evaluated in vitro and in nude mouse and rabbit defects models. , 2011, Biomaterials.

[96]  T. Kurokawa,et al.  Poly(2-acrylamido-2-methylpropanesulfonic acid) gel induces articular cartilage regeneration in vivo: comparisons of the induction ability between single- and double-network gels. , 2012, Journal of biomedical materials research. Part A.

[97]  J. L. Aguiar,et al.  Comparative study of the areas of osteochondral defects produced in the femoral condyles of rabbits treated with gel of sugarcane biopolymer. , 2011, Acta cirurgica brasileira.

[98]  M. Handl,et al.  Novel composite hyaluronan/type I collagen/fibrin scaffold enhances repair of osteochondral defect in rabbit knee. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[99]  V. Goldberg,et al.  Repair of osteochondral defects with hyaluronan- and polyester-based scaffolds. , 2005, Osteoarthritis and cartilage.

[100]  Liu Yang,et al.  In Vivo Tracking of Superparamagnetic Iron Oxide Nanoparticle Labeled Chondrocytes in Large Animal Model , 2012, Annals of Biomedical Engineering.

[101]  E B Hunziker,et al.  Articular cartilage repair: are the intrinsic biological constraints undermining this process insuperable? , 1999, Osteoarthritis and cartilage.

[102]  C. Ohlsson,et al.  Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. , 1994, The New England journal of medicine.

[103]  Zhengyuan Tu,et al.  Fabrication of poly(lactide-co-glycolide) scaffold filled with fibrin gel, mesenchymal stem cells, and poly(ethylene oxide)-b-poly(L-lysine)/TGF-β1 plasmid DNA complexes for cartilage restoration in vivo. , 2013, Journal of biomedical materials research. Part A.

[104]  Wei Wang,et al.  The restoration of full-thickness cartilage defects with BMSCs and TGF-beta 1 loaded PLGA/fibrin gel constructs. , 2010, Biomaterials.

[105]  J. Hui,et al.  Injectable Mesenchymal Stem Cell Therapy for Large Cartilage Defects—A Porcine Model , 2007, Stem cells.

[106]  J. Somerson,et al.  A novel MSC‐seeded triphasic construct for the repair of osteochondral defects , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[107]  D. Steinberg,et al.  Cartilage repair and subchondral bone remodeling in response to focal lesions in a mini-pig model: implications for tissue engineering. , 2015, Tissue engineering. Part A.

[108]  G. Im,et al.  SOX trio-co-transduced adipose stem cells in fibrin gel to enhance cartilage repair and delay the progression of osteoarthritis in the rat. , 2012, Biomaterials.

[109]  H. Sakai,et al.  Effects of atelocollagen gel containing bone marrow-derived stromal cells on repair of osteochondral defect in a dog. , 2007, Journal of Veterinary Medical Science.

[110]  R. Barbucci,et al.  An amidated carboxymethylcellulose hydrogel for cartilage regeneration , 2008, Journal of materials science. Materials in medicine.

[111]  Sun-Woong Kang,et al.  Articular cartilage regeneration with microfracture and hyaluronic acid , 2008, Biotechnology Letters.