Francesca Gunnella1, Elke Kunisch1, Stefan Maenz2, Victoria Horbert1, Long Xin1, Joerg Mika1, Juliane Borowski1, Sabine Bischoff3, Harald Schubert3, Andre Sachse4, Bernhard Illerhaus5, Jens Günster5, Jörg Bossert6, Klaus D Jandt7, Frank Plöger8, Raimund W Kinne9, Olaf Brinkmann10, Matthias Bungartz10. 1. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle," Klosterlausnitzner Str. 81, 07607, Eisenberg, Germany. 2. 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. 3. Institute of Laboratory Animal Sciences and Welfare, Jena University Hospital, Dornburger Str. 23, 07743, Jena, Germany. 4. Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle," Klosterlausnitzner Str. 81, 07607, Eisenberg, Germany. 5. BAM Bundesanstalt für Materialforschung und-prüfung (BAM), Unter den Eichen 44-46, 12203, Berlin, Germany. 6. Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743, Jena, Germany. 7. 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. 8. BIOPHARM GmbH, Handelsstr. 15, 69214, Heidelberg, Germany. 9. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle," Klosterlausnitzner Str. 81, 07607, Eisenberg, Germany. Electronic address: raimund.w.kinne@med.uni-jena.de. 10. Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle," Klosterlausnitzner Str. 81, 07607, Eisenberg, Germany; Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle," Klosterlausnitzner Str. 81, 07607, Eisenberg, Germany.
Abstract
BACKGROUND CONTEXT: Targeted delivery of osteoinductive bone morphogenetic proteins (eg, GDF5) in bioresorbable calcium phosphate cement (CPC), potentially suitable for vertebroplasty and kyphoplasty of osteoporotic vertebral fractures, may be required to counteract augmented local bone catabolism and to support complete bone regeneration. The biologically optimized GDF5 mutant BB-1 may represent an attractive drug candidate for this purpose. PURPOSE: The aim of the current study was to test an injectable, poly(l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming CPC containing low-dose BB-1 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 were filled with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of BB-1 (L5; CPC+fibers+BB-1; 5, 100, and 500 µg BB-1; n=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 (±BB-1) were analyzed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (BV/TV) (assessed by micro-CT and histomorphometry), trabecular thickness (Tb.Th), and trabecular number (Tb.N); (3) bone formation, that is, osteoid volume/bone volume (OV/BV), osteoid surface/bone surface (OS/BS), osteoid thickness, mineralizing surface/bone surface (MS/BS), 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+BB-1 (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 BB-1, additional significant effects of BB-1 were demonstrated for BMD, bone structure (BV/TV, Tb.Th, and Tb.N), and bone formation (OS/BS and MS/BS). The BB-1 effects on bone formation at 3 and 9 months were dose dependent, with 100 µg as the potentially optimal dosage. CONCLUSIONS: BB-1 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 BB-1 was sufficient to augment middle- to long-term bone formation. A CPC containing the novel GDF5 mutant BB-1 may thus represent an alternative to the bioinert, supraphysiologically stiff polymethylmethacrylate cement presently used to treat osteoporotic vertebral fractures by vertebroplasty and kyphoplasty.
BACKGROUND CONTEXT: Targeted delivery of osteoinductive bone morphogenetic proteins (eg, GDF5) in bioresorbable calcium phosphate cement (CPC), potentially suitable for vertebroplasty and kyphoplasty of osteoporotic vertebral fractures, may be required to counteract augmented local bone catabolism and to support complete bone regeneration. The biologically optimized GDF5 mutant BB-1 may represent an attractive drug candidate for this purpose. PURPOSE: The aim of the current study was to test an injectable, poly(l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming CPC containing low-dose BB-1 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 were filled with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of BB-1 (L5; CPC+fibers+BB-1; 5, 100, and 500 µg BB-1; n=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 (±BB-1) were analyzed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (BV/TV) (assessed by micro-CT and histomorphometry), trabecular thickness (Tb.Th), and trabecular number (Tb.N); (3) bone formation, that is, osteoid volume/bone volume (OV/BV), osteoid surface/bone surface (OS/BS), osteoid thickness, mineralizing surface/bone surface (MS/BS), 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+BB-1 (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 BB-1, additional significant effects of BB-1 were demonstrated for BMD, bone structure (BV/TV, Tb.Th, and Tb.N), and bone formation (OS/BS and MS/BS). The BB-1 effects on bone formation at 3 and 9 months were dose dependent, with 100 µg as the potentially optimal dosage. CONCLUSIONS:BB-1 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 BB-1 was sufficient to augment middle- to long-term bone formation. A CPC containing the novel GDF5 mutant BB-1 may thus represent an alternative to the bioinert, supraphysiologically stiff polymethylmethacrylate cement presently used to treat osteoporotic vertebral fractures by vertebroplasty and kyphoplasty.
Keywords:
Bone morphogenetic protein; Bone regeneration; Calcium phosphate cement; GDF-5 mutant; Large animal model sheep; Osteoporotic vertebral fracture
Authors: Isabel R Dias; José A Camassa; João A Bordelo; Pedro S Babo; Carlos A Viegas; Nuno Dourado; Rui L Reis; Manuela E Gomes Journal: Curr Osteoporos Rep Date: 2018-04 Impact factor: 5.096
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