Host cell recruitment patterns by bone morphogenetic protein-2 releasing hyaluronic acid hydrogels in a mouse subcutaneous environment.

AIM This study aimed to identify host cell recruitment patterns in a mouse model in response to rhBMP-2 releasing hyaluronic acid hydrogels and influence of added nano-hydroxyapatite particles on rhBMP-2 release and pattern of bone formation. MATERIALS & METHODS Implanted gels were retrieved after implantation and cells were enzymatically dissociated for flow cytometric analysis. Percentages of macrophages, progenitor endothelial cells and putative mesenchymal stem cells were measured. Implants were evaluated for BMP-2 release by ELISA and by histology to monitor tissue formation. RESULTS & CONCLUSION Hyaluronic acid+BMP-2 gels influenced the inflammatory response in the bone healing microenvironment. Host-derived putative mesenchymal stem cells were major contributors. Addition of hydroxyapatite nanoparticles modified the release pattern of rhBMP-2, resulting in enhanced bone formation.

[1]  Vicki Rosen,et al.  BMP2 signaling in bone development and repair. , 2009, Cytokine & growth factor reviews.

[2]  G. Prestwich,et al.  The influence of collagen and hyaluronan matrices on the delivery and bioactivity of bone morphogenetic protein-2 and ectopic bone formation. , 2013, Acta biomaterialia.

[3]  R. Pignolo,et al.  Circulating osteogenic cells: Implications for injury, repair, and regeneration , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  M. Marcacci,et al.  New trends for knee cartilage regeneration: from cell-free scaffolds to mesenchymal stem cells , 2012, Current Reviews in Musculoskeletal Medicine.

[5]  E. Hunziker,et al.  Cell-mediated BMP-2 liberation promotes bone formation in a mechanically unstable implant environment. , 2010, Bone.

[6]  Hongji Yan,et al.  Mild and efficient strategy for site-selective aldehyde modification of glycosaminoglycans: tailoring hydrogels with tunable release of growth factor. , 2013, Biomacromolecules.

[7]  Antonios G Mikos,et al.  Injectable matrices and scaffolds for drug delivery in tissue engineering. , 2007, Advanced drug delivery reviews.

[8]  J. Hilborn,et al.  Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering , 2013 .

[9]  Thomas A Einhorn,et al.  Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation , 2003, Journal of cellular biochemistry.

[10]  Andrew D. A. Maidment,et al.  Identification of progenitor cells that contribute to heterotopic skeletogenesis. , 2009, The Journal of bone and joint surgery. American volume.

[11]  N. Kawazoe,et al.  Spatial immobilization of bone morphogenetic protein-4 in a collagen-PLGA hybrid scaffold for enhanced osteoinductivity. , 2012, Biomaterials.

[12]  Benjamin M Wu,et al.  High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. , 2011, Tissue engineering. Part A.

[13]  J. Hilborn,et al.  Injection and adhesion palatoplasty: a preliminary study in a canine model. , 2013, The Journal of surgical research.

[14]  M. Dickinson,et al.  Vessel Formation Is Induced Prior to the Appearance of Cartilage in BMP-2-Mediated Heterotopic Ossification , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  Mikaël M. Martino,et al.  Evaluation of Injectable Constructs for Bone Repair with a Subperiosteal Cranial Model in the Rat , 2013, PloS one.

[16]  M. Longaker,et al.  Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. , 2002, Plastic and reconstructive surgery.

[17]  B. Sacchetti,et al.  Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment , 2007, Cell.

[18]  Byung-Soo Kim,et al.  Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(L-lactic-co-glycolic acid) scaffold. , 2007, Biomaterials.

[19]  Shyni Varghese,et al.  Multifunctional chondroitin sulphate for cartilage tissue-biomaterial integration. , 2007, Nature materials.

[20]  Andrew W. Ritting,et al.  Exaggerated inflammatory response and bony resorption from BMP-2 use in a pediatric forearm nonunion. , 2012, The Journal of hand surgery.

[21]  S. Raiden,et al.  Mouse Bone Marrow-Derived Mesenchymal Stromal Cells Turn Activated Macrophages into a Regulatory-Like Profile , 2010, PloS one.

[22]  C. Colnot,et al.  Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair. , 2010, Bone.

[23]  R. Cecere,et al.  Hyaluronic acid-based hydrogel induces neovascularization and improves cardiac function in a rat model of myocardial infarction. , 2013, Interactive cardiovascular and thoracic surgery.

[24]  Maurilio Marcacci,et al.  Scaffold-based repair for cartilage healing: a systematic review and technical note. , 2013, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[25]  David L. Kaplan,et al.  BMP-silk composite matrices heal critically sized femoral defects. , 2007, Bone.

[26]  J. Hilborn,et al.  Minimally invasive mandibular bone augmentation using injectable hydrogels , 2012, Journal of tissue engineering and regenerative medicine.

[27]  A. Weiland,et al.  Immunolocalization and expression of bone morphogenetic proteins 2 and 4 in fracture healing , 1995, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[28]  A. Ghazanfari,et al.  Bone union rate with recombinant human bone morphogenic protein-2 versus autologous iliac bone in PEEK cages for anterior lumbar interbody fusion , 2014, International Orthopaedics.

[29]  Hideki Yoshikawa,et al.  Bone marrow-derived osteoblast progenitor cells in circulating blood contribute to ectopic bone formation in mice. , 2007, Biochemical and biophysical research communications.

[30]  K. Weinberg,et al.  The Role of the Hyaluronan Receptor CD44 in Mesenchymal Stem Cell Migration in the Extracellular Matrix , 2006, Stem cells.

[31]  E. Woo Adverse Events After Recombinant Human BMP2 in Nonspinal Orthopaedic Procedures , 2013, Clinical orthopaedics and related research.

[32]  D. Niederwieser,et al.  Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. , 2006, International journal of molecular medicine.

[33]  B. Brown,et al.  Expanded applications, shifting paradigms and an improved understanding of host-biomaterial interactions. , 2013, Acta biomaterialia.

[34]  Mikaël M. Martino,et al.  Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment. , 2013, Biomaterials.

[35]  T. Einhorn,et al.  Skeletal trauma generates systemic BMP2 activation that is temporally related to the mobilization of CD73+ cells , 2013, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[36]  Y. Chai,et al.  Bone Morphogenetic Protein for the Healing of Tibial Fracture: A Meta-Analysis of Randomized Controlled Trials , 2015, PloS one.

[37]  Jeffrey C. Wang,et al.  BMP induced inflammation: A comparison of rhBMP‐7 and rhBMP‐2 , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  James M. Anderson,et al.  Giant cell formation and function , 2009, Current opinion in hematology.

[39]  D. Aeschlimann,et al.  New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. , 1999, Journal of biomedical materials research.

[40]  D. Graves,et al.  BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells. , 2009, Bone.

[41]  Kai-Ming G. Fu,et al.  Does Bone Morphogenetic Protein Increasethe Incidence of Perioperative Complicationsin Spinal Fusion?: A Comparison of 55,862 Cases of Spinal Fusion With and Without Bone Morphogenetic Protein , 2011, Spine.

[42]  J. Hilborn,et al.  Complexation and Sequestration of BMP-2 from an ECM Mimetic Hyaluronan Gel for Improved Bone Formation , 2013, PloS one.

[43]  J. Hilborn,et al.  Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates , 2013, Journal of Materials Science: Materials in Medicine.

[44]  M C Sogayar,et al.  Bone Morphogenetic Proteins , 2014, Journal of dental research.

[45]  James M. Anderson,et al.  Foreign body reaction to biomaterials. , 2008, Seminars in immunology.

[46]  Yasuhiko Tabata,et al.  Controlled release of bone morphogenetic protein-2 enhances recruitment of osteogenic progenitor cells for de novo generation of bone tissue. , 2010, Tissue engineering. Part A.

[47]  H. Uludaǧ,et al.  Carrier systems for bone morphogenetic proteins. , 1999, Clinical orthopaedics and related research.

[48]  J. Hilborn,et al.  Pre-incubation of chemically crosslinked hyaluronan-based hydrogels, loaded with BMP-2 and hydroxyapatite, and its effect on ectopic bone formation , 2014, Journal of Materials Science: Materials in Medicine.

[49]  J. Hilborn,et al.  Critical assessment of rhBMP-2 mediated bone induction: an in vitro and in vivo evaluation. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[50]  J. Hilborn,et al.  Bone reservoir: Injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[51]  UliviValentina,et al.  In Vivo Implanted Bone Marrow-Derived Mesenchymal Stem Cells Trigger a Cascade of Cellular Events Leading to the Formation of an Ectopic Bone Regenerative Niche , 2013 .

[52]  Chulhee Choi,et al.  Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ , 2012, Molecules and cells.

[53]  F. Szoka,et al.  Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. , 2008, Molecular pharmaceutics.

[54]  F. Gao,et al.  Hyaluronan oligosaccharides promote excisional wound healing through enhanced angiogenesis. , 2010, Matrix biology : journal of the International Society for Matrix Biology.

[55]  B. Min,et al.  Changes in surface markers of human mesenchymal stem cells during the chondrogenic differentiation and dedifferentiation processes in vitro. , 2009, Arthritis and rheumatism.