title: Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps.
abstract: Poly-ɛ-caprolactone (PCL) is a biocompatible polymer that has mechanical properties suitable for bone tissue engineering; however, it must be integrated with biologics to stimulate bone formation. Bone morphogenetic protein-2 (BMP2) delivered from PCL produces bone when implanted subcutaneously, and erythropoietin (EPO) works synergistically with BMP2. In this study, EPO and BMP2 are adsorbed separately on two 3D-printed PCL scaffold modules that are assembled for codelivery on a single scaffold structure. This assembled modular PCL scaffold with dual BMP2 and EPO delivery was shown to increase bone growth in an ectopic location when compared with BMP2 delivery along a replicate scaffold structure. EPO (200 IU/mL) and BMP2 (65 μg/mL) were adsorbed onto the outer and inner portions of a modular scaffold, respectively. Protein binding and release studies were first quantified. Subsequently, EPO+BMP2 and BMP2 scaffolds were implanted subcutaneously in mice for 4 and 8 weeks, and the regenerated bone was analyzed with microcomputed tomography and histology; 8.6±1.4 μg BMP2 (22%) and 140±29 IU EPO (69.8%) bound to the scaffold and <1% BMP2 and 83% EPO was released in 7 days. Increased endothelial cell proliferation on EPO-adsorbed PCL discs indicated protein bioactivity. At 4 and 8 weeks, dual BMP2 and EPO delivery regenerated more bone (5.1±1.1 and 5.5±1.6 mm(3)) than BMP2 alone (3.8±1.1 and 4.3±1.7 mm(3)). BMP2 and EPO scaffolds had more ingrowth (1.4%±0.6%) in the outer module when compared with BMP2 (0.8%±0.3%) at 4 weeks. Dual delivery produced more dense cellular marrow, while BMP2 had more fatty marrow. Dual EPO and BMP2 delivery is a potential method to regenerate bone faster for prefabricated flaps.
authors: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors: Janki Jayesh
authors: JJ
authors: Patel
authors: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors: Jane E
authors: JE
authors: Modes
authors: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors: Colleen L
authors: CL
authors: Flanagan
authors: 2 School of Dentistry, University of Michigan , Ann Arbor, Michigan.
authors: Paul H
authors: PH
authors: Krebsbach
authors: 3 Department of Oral and Maxillofacial Surgery, University of Michigan , Ann Arbor, Michigan.
authors: Sean P
authors: SP
authors: Edwards
authors: 1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan.
authors: Scott J
authors: SJ
authors: Hollister
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D007700:Kinetics; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D011091:Polyesters / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D054457:Tissue Scaffolds / Q000737:chemistry*; D055114:X-Ray Microtomography
chemical_list: D055396:Bone Morphogenetic Protein 2; D011091:Polyesters; D004921:Erythropoietin; C016240:polycaprolactone