TY - JOUR
T1 - Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes
AU - Kempen, Diederik H.R.
AU - Yaszemski, Michael J.
AU - Heijink, Andras
AU - Hefferan, Theresa E.
AU - Creemers, Laura B.
AU - Britson, Jason
AU - Maran, Avudaiappan
AU - Classic, Kelly L.
AU - Dhert, Wouter J.A.
AU - Lu, Lichun
N1 - Funding Information:
The authors thank Dr. Shanfeng Wang and Mr. James A. Greutzmacher from the Tissue Engineering and Biomaterials laboratory, Mrs. Teresa Decklever and Dr. Bradley Kemp from the Department of Nuclear Medicine, Dr. Erik Ritman, Mrs. Patricia Beighley and Mr. Andrew Vercnocke from the Physiological Imaging Research Laboratory and Mrs. Julie Burges and Mr. Jim Herrick from the Bone Histomorphometry Laboratory for their contributions to this work. The authors gratefully acknowledge the National Institutes of Health (R01 AR45871 and R01 EB03060) and The Netherlands Organization for Health Research and Development ZonMW (Agiko 920-03-325) for financial support.
PY - 2009/3/19
Y1 - 2009/3/19
N2 - 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 μg/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 125I and the local retention of 125I-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 (μCT). 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 125I within the body. Ectopic bone formation was induced in the scaffolds and the femur defects healed completely. In vivo μCT 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.
AB - 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 μg/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 125I and the local retention of 125I-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 (μCT). 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 125I within the body. Ectopic bone formation was induced in the scaffolds and the femur defects healed completely. In vivo μCT 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.
KW - Bone morphogenetic protein-2
KW - Controlled release
KW - Drug delivery
KW - Micro-computed tomography
KW - Scintillation probes
KW - Single photon emission computed tomography
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UR - http://www.scopus.com/inward/citedby.url?scp=61349098782&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2008.11.023
DO - 10.1016/j.jconrel.2008.11.023
M3 - Article
C2 - 19105972
AN - SCOPUS:61349098782
SN - 0168-3659
VL - 134
SP - 169
EP - 176
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -