Francesca Gunnella1, Elke Kunisch1, Matthias Bungartz2, Stefan Maenz3, Victoria Horbert1, Long Xin1, Joerg Mika1, Juliane Borowski1, Sabine Bischoff4, Harald Schubert4, Peter Hortschansky5, Andre Sachse6, Bernhard Illerhaus4, Jens Günster7, Jörg Bossert8, Klaus D Jandt9, Frank Plöger10, Raimund W Kinne11, Olaf Brinkmann2. 1. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany. 2. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany; Chair of Orthopedics, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany. 3. Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany. 4. Institute of Laboratory Animal Sciences and Welfare, Jena University Hospital, Dornburger Straße 23, 07743 Jena, Germany. 5. Leibniz-Institute for Natural Products Research and Infection Biology - Hans-Knoell-Institute, Beutenbergstr. 11a, 07745 Jena, Germany. 6. Chair of Orthopedics, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany. 7. BAM Bundesanstalt für Materialforschung und -prüfung (BAM), Unter den Eichen 44-46, 12203 Berlin; Germany. 8. Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743 Jena, Germany. 9. Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany; Jena School for Microbial Communication (JSMC), Friedrich Schiller University Jena, Neugasse 23, 07743 Jena, Germany. 10. BIOPHARM GmbH, Handelsstrasse 15, 69214 Eppelheim, Germany. 11. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany. Electronic address: raimund.w.kinne@med.uni-jena.de.
Abstract
BACKGROUND CONTEXT: Bioresorbable calcium phosphate cement (CPC) may be suitable for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures. However, additional targeted delivery of osteoinductive bone morphogenetic proteins (BMPs) in the CPC may be required to counteract the augmented local bone catabolism and support complete bone regeneration. PURPOSE: This study aimed at testing an injectable, poly (l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement (CPC) containing low-dose bone morphogenetic protein BMP-2 in a sheep lumbar osteopenia model. STUDY DESIGN/ SETTING: This is a prospective experimental animal study. METHODS: Bone defects (diameter 5 mm) were generated in aged, osteopenic female sheep and filled with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of BMP-2 (L5; CPC+fibers+BMP-2; 1, 5, 100, and 500 µg BMP-2; n=5 or 6 each). The results were compared with those of untouched controls (L1). Three and 9 months after the operation, structural and functional effects of the CPC (±BMP-2) were analyzed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (assessed by micro-computed tomography [micro-CT] and histomorphometry), trabecular thickness, and trabecular number; (3) bone formation, that is, osteoid volume/bone volume, osteoid surface/bone surface, osteoid thickness, mineralizing surface/bone surface, mineral apposition rate, and bone formation rate/bone surface; (4) bone resorption, that is, eroded surface/bone surface; and (5) compressive strength. RESULTS: Compared with untouched controls (L1), CPC+fibers (L4) and/or CPC+fibers+BMP-2 (L5) significantly improved all parameters of bone formation, bone resorption, and bone structure. These effects were observed at 3 and 9 months, but were less pronounced for some parameters at 9 months. Compared with CPC without BMP-2, additional significant effects of BMP-2 were demonstrated for bone structure (bone volume/total volume, trabecular thickness, trabecular number) and formation (osteoid surface/bone surface and mineralizing surface/bone surface), as well as for the compressive strength. The BMP-2 effects on bone formation at 3 and 9 months were dose-dependent, with 5-100 µg as the optimal dosage. CONCLUSIONS: BMP-2 significantly enhanced the bone formation induced by a PLGA fiber-reinforced CPC in sheep lumbar osteopenia. A single local dose as low as ≤100 µg BMP-2 was sufficient to augment middle to long-term bone formation. The novel CPC+BMP-2 may thus represent an alternative to the bioinert, supraphysiologically stiff polymethylmethacrylate cement presently used to treat osteoporotic vertebral fractures by vertebroplasty/kyphoplasty.
BACKGROUND CONTEXT: Bioresorbable calcium phosphate cement (CPC) may be suitable for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures. However, additional targeted delivery of osteoinductive bone morphogenetic proteins (BMPs) in the CPC may be required to counteract the augmented local bone catabolism and support complete bone regeneration. PURPOSE: This study aimed at testing an injectable, poly (l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement (CPC) containing low-dose bone morphogenetic protein BMP-2 in a sheep lumbar osteopenia model. STUDY DESIGN/ SETTING: This is a prospective experimental animal study. METHODS: Bone defects (diameter 5 mm) were generated in aged, osteopenic female sheep and filled with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of BMP-2 (L5; CPC+fibers+BMP-2; 1, 5, 100, and 500 µg BMP-2; n=5 or 6 each). The results were compared with those of untouched controls (L1). Three and 9 months after the operation, structural and functional effects of the CPC (±BMP-2) were analyzed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (assessed by micro-computed tomography [micro-CT] and histomorphometry), trabecular thickness, and trabecular number; (3) bone formation, that is, osteoid volume/bone volume, osteoid surface/bone surface, osteoid thickness, mineralizing surface/bone surface, mineral apposition rate, and bone formation rate/bone surface; (4) bone resorption, that is, eroded surface/bone surface; and (5) compressive strength. RESULTS: Compared with untouched controls (L1), CPC+fibers (L4) and/or CPC+fibers+BMP-2 (L5) significantly improved all parameters of bone formation, bone resorption, and bone structure. These effects were observed at 3 and 9 months, but were less pronounced for some parameters at 9 months. Compared with CPC without BMP-2, additional significant effects of BMP-2 were demonstrated for bone structure (bone volume/total volume, trabecular thickness, trabecular number) and formation (osteoid surface/bone surface and mineralizing surface/bone surface), as well as for the compressive strength. The BMP-2 effects on bone formation at 3 and 9 months were dose-dependent, with 5-100 µg as the optimal dosage. CONCLUSIONS:BMP-2 significantly enhanced the bone formation induced by a PLGA fiber-reinforced CPC in sheep lumbar osteopenia. A single local dose as low as ≤100 µg BMP-2 was sufficient to augment middle to long-term bone formation. The novel CPC+BMP-2 may thus represent an alternative to the bioinert, supraphysiologically stiff polymethylmethacrylate cement presently used to treat osteoporotic vertebral fractures by vertebroplasty/kyphoplasty.
Keywords:
Bone morphogenetic protein 2; Bone regeneration; Calcium phosphate cement; Growth factor; Large animal model sheep; Osteoporotic vertebral fracture
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