title: Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes.
abstract: Non-invasive imaging can provide essential information for the optimization of new drug delivery-based bone regeneration strategies to repair damaged or impaired bone tissue. This study investigates the applicability of nuclear medicine and radiological techniques to monitor growth factor retention profiles and subsequent effects on bone formation. Recombinant human bone morphogenetic protein-2 (BMP-2, 6.5 microg/scaffold) was incorporated into a sustained release vehicle consisting of poly(lactic-co-glycolic acid) microspheres embedded in a poly(propylene fumarate) scaffold surrounded by a gelatin hydrogel and implanted subcutaneously and in 5-mm segmental femoral defects in 9 rats for a period of 56 days. To determine the pharmacokinetic profile, BMP-2 was radiolabeled with (125)I and the local retention of (125)I-BMP-2 was measured by single photon emission computed tomography (SPECT), scintillation probes and ex vivo scintillation analysis. Bone formation was monitored by micro-computed tomography (microCT). The scaffolds released BMP-2 in a sustained fashion over the 56-day implantation period. A good correlation between the SPECT and scintillation probe measurements was found and there were no significant differences between the non-invasive and ex-vivo counting method after 8 weeks of follow up. SPECT analysis of the total body and thyroid counts showed a limited accumulation of (125)I within the body. Ectopic bone formation was induced in the scaffolds and the femur defects healed completely. In vivo microCT imaging detected the first signs of bone formation at days 14 and 28 for the orthotopic and ectopic implants, respectively, and provided a detailed profile of the bone formation rate. Overall, this study clearly demonstrates the benefit of applying non-invasive techniques in drug delivery-based bone regeneration strategies by providing detailed and reliable profiles of the growth factor retention and bone formation at different implantation sites in a limited number of animals.
authors.affiliation: Tissue Engineering and Biomaterials Laboratory, Departments of Orthopedic Surgery and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Diederik H R
authors.initials: DH
authors.lastname: Kempen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yaszemski
authors.forename: Andras
authors.initials: A
authors.lastname: Heijink
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hefferan
authors.forename: Laura B
authors.initials: LB
authors.lastname: Creemers
authors.forename: Jason
authors.initials: J
authors.lastname: Britson
authors.forename: Avudaiappan
authors.initials: A
authors.lastname: Maran
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Classic
authors.forename: Wouter J A
authors.initials: WJ
authors.lastname: Dhert
authors.forename: Lichun
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001861:Bone Regeneration / Q000502:physiology*; D005269:Femur / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005650:Fumarates / Q000737:chemistry; D005780:Gelatin / Q000737:chemistry; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D007457:Iodine Radioisotopes; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011126:Polypropylenes / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D005650:Fumarates; D020100:Hydrogels; D007457:Iodine Radioisotopes; D011126:Polypropylenes; D011994:Recombinant Proteins; C097850:poly(propylene fumarate); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005780:Gelatin