Prefabricated 3D-Printed Tissue-Engineered Bone for Mandibular Reconstruction: A Preclinical Translational Study in Primate

The advent of three dimensionally (3D) printed customized bone grafts using different biomaterials has enabled repairs of complex bone defects in various in vivo models. However, studies related to their clinical translations are truly limited. Herein, 3D printed poly(lactic-co-glycolic acid)/β-tricalcium phosphate (PLGA/TCP) and TCP scaffolds with or without recombinant bone morphogenetic protein -2 (rhBMP-2) coating were utilized to repair primate's large-volume mandibular defects and compared efficacy of prefabricated tissue-engineered bone (PTEB) over direct implantation (without prefabrication). 18F-FDG PET/CT was explored for real-time monitoring of bone regeneration and vascularization. After 3-month's prefabrication, the original 3D-architecture of the PLGA/TCP-BMP scaffold was found to be completely lost, while it was properly maintained in TCP-BMP scaffolds. Besides, there was a remarkable decrease in the PLGA/TCP-BMP scaffold density and increase in TCP-BMP scaffolds density during ectopic (within latissimus dorsi muscle) and orthotopic (within mandibular defect) implantation, indicating regular bone formation with TCP-BMP scaffolds. Notably, PTEB based on TCP-BMP scaffold was successfully fabricated with pronounced effects on bone regeneration and vascularization based on radiographic, 18F-FDG PET/CT, and histological evaluation, suggesting a promising approach toward clinical translation.

[1]  P. Miranda,et al.  Bioinspired channeled, rhBMP-2-coated β-TCP scaffolds with embedded autologous vascular bundles for increased vascularization and osteogenesis of prefabricated tissue-engineered bone. , 2021, Materials science & engineering. C, Materials for biological applications.

[2]  Chunli Song,et al.  3D printed porous titanium cages filled with simvastatin hydrogel promotes bone ingrowth and spinal fusion in rhesus macaques. , 2020, Biomaterials science.

[3]  C. Zurla,et al.  Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging , 2019, Nature Biomedical Engineering.

[4]  Y. Açil,et al.  Man as a living bioreactor: Long-term histological aspects of a mandibular replacement engineered in the patient's own body. , 2018, International journal of oral and maxillofacial surgery.

[5]  L. Khachatryan,et al.  The Treatment of Lower Jaw Defects Using Vascularized Fibula Graft and Dental Implants , 2018, The Journal of craniofacial surgery.

[6]  E. Abel,et al.  Glucose metabolism induced by Bmp signaling is essential for murine skeletal development , 2018, Nature Communications.

[7]  M. Lubberink,et al.  Non‐invasive tri‐modal visualisation via PET/SPECT/&mgr;CT of recombinant human bone morphogenetic protein‐2 retention and associated bone regeneration: A proof of concept , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[8]  Derek M. Steinbacher,et al.  Journal of Oral and Maxillofacial Surgery , 2019, Journal of Oral and Maxillofacial Surgery.

[9]  J. Fricain,et al.  The periosteum-like effect of fresh human amniotic membrane on bone regeneration in a rabbit critical-sized defect model. , 2018, Bone.

[10]  Jiandong Ding,et al.  Degradation rate affords a dynamic cue to regulate stem cells beyond varied matrix stiffness. , 2018, Biomaterials.

[11]  Scott J Hollister,et al.  Design and Structure–Function Characterization of 3D Printed Synthetic Porous Biomaterials for Tissue Engineering , 2018, Advanced healthcare materials.

[12]  Christopher D Lopez,et al.  Three dimensionally printed bioactive ceramic scaffold osseoconduction across critical-sized mandibular defects. , 2018, The Journal of surgical research.

[13]  Yu Wang,et al.  Reconstruction of Mandibular Contour Using Individualized High-Density Porous Polyethylene (Medpor®) Implants Under the Guidance of Virtual Surgical Planning and 3D-Printed Surgical Templates , 2018, Aesthetic Plastic Surgery.

[14]  Hai-tao Huang,et al.  Electron beam melting in the fabrication of three-dimensional mesh titanium mandibular prosthesis scaffold , 2018, Scientific Reports.

[15]  R. O’Keefe,et al.  Distinct metabolic programs induced by TGF-β1 and BMP2 in human articular chondrocytes with osteoarthritis , 2018, Journal of orthopaedic translation.

[16]  S. Mundlos,et al.  BMPs as new insulin sensitizers: enhanced glucose uptake in mature 3T3-L1 adipocytes via PPARγ and GLUT4 upregulation , 2017, Scientific Reports.

[17]  T. Reichert,et al.  Bone Morphogenetic Protein-7 Enhances Degradation of Osteoinductive Bioceramic Implants in an Ectopic Model , 2017, Plastic and reconstructive surgery. Global open.

[18]  G. Hansmann,et al.  PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism. , 2017, Cell metabolism.

[19]  O. Emodi,et al.  Reconstruction of complex mandibular defects using integrated dental custom-made titanium implants. , 2017, The British journal of oral & maxillofacial surgery.

[20]  Y. Lai,et al.  [Biological evaluation of three-dimensional printed co-poly lactic acid/glycolic acid/tri-calcium phosphate scaffold for bone reconstruction]. , 2016, Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology.

[21]  J. Jansen,et al.  SPECT vs. PET monitoring of bone defect healing and biomaterial performance in vivo , 2016, Journal of tissue engineering and regenerative medicine.

[22]  Y. Açil,et al.  Man as a Living Bioreactor: Prefabrication of a Custom Vascularized Bone Graft in the Gastrocolic Omentum. , 2016 .

[23]  Dong Han,et al.  Guided Self-Generation of Vascularized Neo-Bone for Autologous Reconstruction of Large Mandibular Defects , 2016, The Journal of craniofacial surgery.

[24]  S. Berrone,et al.  Correction of a mandibular asymmetry after fibula reconstruction using a custom-made polyetheretherketone (PEEK) onlay after implant supported occlusal rehabilitation , 2015, Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale.

[25]  Guang-Yan Yu,et al.  The Value of SPECT/CT in Monitoring Prefabricated Tissue-Engineered Bone and Orthotopic rhBMP-2 Implants for Mandibular Reconstruction , 2015, PloS one.

[26]  Sophia P Pilipchuk,et al.  3D-printed Bioresorbable Scaffold for Periodontal Repair , 2015, Journal of dental research.

[27]  G. Pei,et al.  Efficacy of prevascularization for segmental bone defect repair using β-tricalcium phosphate scaffold in rhesus monkey. , 2014, Biomaterials.

[28]  J. Jansen,et al.  Monitoring the biological effect of BMP-2 release on bone healing by PET/CT. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[29]  H. Chuang,et al.  FDG PET/CT of primary bone tumors. , 2014, AJR. American journal of roentgenology.

[30]  James F. Griffith,et al.  Comparative study of poly (lactic-co-glycolic acid)/tricalcium phosphate scaffolds incorporated or coated with osteogenic growth factors for enhancement of bone regeneration , 2014 .

[31]  Eduardo Saiz,et al.  Toward Strong and Tough Glass and Ceramic Scaffolds for Bone Repair , 2013, Advanced functional materials.

[32]  A. James,et al.  BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1. , 2013, Tissue engineering. Part A.

[33]  L. Qin,et al.  PLGA/TCP composite scaffold incorporating bioactive phytomolecule icaritin for enhancement of bone defect repair in rabbits. , 2013, Acta biomaterialia.

[34]  Y. Leng,et al.  Comparative study of osteogenic potential of a composite scaffold incorporating either endogenous bone morphogenetic protein-2 or exogenous phytomolecule icaritin: an in vitro efficacy study. , 2012, Acta biomaterialia.

[35]  Ana Civantos,et al.  Biological Properties of Solid Free Form Designed Ceramic Scaffolds with BMP-2: In Vitro and In Vivo Evaluation , 2012, PloS one.

[36]  Jing Hu,et al.  Computer-Aided Design and Manufacturing and Rapid Prototyped Nanoscale Hydroxyapatite/Polyamide (n-HA/PA) Construction for Condylar Defect Caused by Mandibular Angle Ostectomy , 2011, Aesthetic Plastic Surgery.

[37]  S. Vallabhajosula,et al.  A broad overview of positron emission tomography radiopharmaceuticals and clinical applications: what is new? , 2011, Seminars in nuclear medicine.

[38]  Younan Xia,et al.  Three-dimensional scaffolds for tissue engineering: the importance of uniformity in pore size and structure. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[39]  Guang-Yan Yu,et al.  Primate mandibular reconstruction with prefabricated, vascularized tissue-engineered bone flaps and recombinant human bone morphogenetic protein-2 implanted in situ. , 2010, Biomaterials.

[40]  Gang Chai,et al.  Rapid prototyped PGA/PLA scaffolds in the reconstruction of mandibular condyle bone defects , 2010, The international journal of medical robotics + computer assisted surgery : MRCAS.

[41]  Torsten Kuwert,et al.  A review on the clinical uses of SPECT/CT , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[42]  T. Hefferan,et al.  Non-invasive screening method for simultaneous evaluation of in vivo growth factor release profiles from multiple ectopic bone tissue engineering implants. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[43]  Andreas Hess,et al.  Engineering of vascularized transplantable bone tissues: induction of axial vascularization in an osteoconductive matrix using an arteriovenous loop. , 2006, Tissue engineering.

[44]  Stefan Wolfart,et al.  Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. , 2006, Biomaterials.

[45]  D. Kaplan,et al.  Porosity of 3D biomaterial scaffolds and osteogenesis. , 2005, Biomaterials.

[46]  H. Eufinger,et al.  Growth and transplantation of a custom vascularised bone graft in a man , 2004, The Lancet.

[47]  Y. Tabata,et al.  Prefabrication of vascularized bone graft using guided bone regeneration. , 2004, Tissue engineering.

[48]  S. Boden,et al.  Demineralized bone matrix, bone morphogenetic proteins, and animal models of spine fusion: an overview , 2001, European Spine Journal.

[49]  M W Bidez,et al.  Mechanical properties of trabecular bone in the human mandible: implications for dental implant treatment planning and surgical placement. , 1999, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[50]  N. Kawazoe,et al.  Porous Scaffolds for Regeneration of Cartilage, Bone and Osteochondral Tissue. , 2018, Advances in experimental medicine and biology.

[51]  Z. Gou,et al.  Custom Repair of Mandibular Bone Defects with 3D Printed Bioceramic Scaffolds , 2018, Journal of dental research.

[52]  秦岭,et al.  Comparative study of osteogenic potential of a composite scaffold incorporating either endogenous bone morphogenetic protein-2 or exogenous phytomolecule icaritin: An in vitro efficacy study , 2012 .