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Organisationseinheit der BAM
Large animal models are highly recommended for meaningful preclinical studies, including the optimization of cement augmentation for vertebral body defects by vertebroplasty/kyphoplasty.
The aim of this study was to perform a systematic characterization of a strictly minimally invasive in vivo large animal model for lumbar ventrolateral vertebroplasty.
This is a prospective experimental animal study.
Lumbar defects (diameter 5 mm; depth approximately 14 mm) were created by a ventrolateral percutaneous approach in aged, osteopenic, female sheep (40 Merino sheep; 6–9 years; 68–110 kg). L1 remained untouched, L2 was left with an empty defect, and L3 carried a defect injected with a brushite-forming calcium phosphate cement (CPC). Trauma/functional impairment, surgical techniques (including drill sleeve and working canula with stop), reproducibility, bone defects, cement filling, and functional cement augmentation were documented by intraoperative incision-to-suture time and X-ray, postoperative trauma/impairment scores, and ex vivo osteodensitometry, microcomputed tomography (CT), histology, static/fluorescence histomorphometry, and biomechanical testing.
Minimally invasive vertebroplasty resulted in short operation times (28±2 minutes; mean±standard error of the mean) and X-ray exposure (1.59±0.12 minutes), very limited local trauma (score 0.00±0.00 at 24 hours), short postoperative recovery (2.95±0.29 hours), and rapid decrease of the postoperative impairment score to 0 (3.28±0.36 hours). Reproducible defect creation and cement filling were documented by intraoperative X-ray and ex vivo conventional/micro-CT. Vertebral cement augmentation and osteoconductivity of the CPC was verified by osteodensitometry (CPC>control), micro-CT (CPC>control and empty defect), histology/static histomorphometry (CPC>control and empty defect), fluorescence histomorphometry (CPC>control; all p<.05 for 3 and 9 months), and compressive strength measurements (CPC numerically higher than control; 102% for 3 months and 110% for 9 months).
This first-time systematic clinical assessment of a minimally invasive, ventrolateral, lumbar vertebroplasty model in aged, osteopenic sheep resulted in short operation times, rapid postoperative recovery, and high experimental reproducibility. This model represents an optimal basis for standardized evaluation of future studies on vertebral augmentation with resorbable and osteoconductive CPC.
BACKGROUND CONTEXT:
Bioresorbable calcium phosphate cement (CPC) may be suitable for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures. However, additional targeted de-
livery 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 500g 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 5–100g 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 ≤100g 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:
Biodegradable calcium phosphate cement (CPC) represents a promising option for the surgical treatment of osteoporotic vertebral fractures. Because of augmented local bone catabolism, however, additional targeted delivery of bone morphogenetic proteins with the CPC may be needed to promote rapid and complete bone regeneration.
PURPOSE:
In the present study, an injectable, poly(l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement (CPC) containing the bone morphogenetic Protein GDF5 was tested in a sheep lumbar osteopenia model.
STUDY DESIGN/SETTING:
This is a prospective experimental animal study
METHODS:
Defined bone defects (diameter 5 mm) were placed in aged, osteopenic female sheep.
Defects were treated with fiber-reinforced CPC alone (L4; CPC+ fibers) or with CPC containing different dosages of GDF5 (L5; CPC+ fibers + GDF5; 1, 5, 100, and 500g GDF5; n =
5 or 6 each).
The results were compared with those of untouched controls (L1). Three and 9 months postoperation, structural and functional effects of the CPC (±GDF5) were assessed ex vivo by measuring
(1) bone mineral density (BMD);
(2) bone structure, that is, bone volume/total volume (assessed by micro-computed tomography and histomorphometry), trabecular thickness, and trabecular number;
(3) bone formation, that is, osteoid volume/bone volume, osteoid surface/bone surface, osteoid thickness, mineralized 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), both CPC+ fibers (L4) and CPC+ fibers + GDF5 (L5) numerically or significantly improved all parameters of bone formation, bone resorption, and bone structure. These significant effects were observed both at 3 and 9 months, but for some parameters they were less pronounced at 9 months. Compared with CPC without GDF5, additional significant effects of CPC with GDF5 were demonstrated for BMD and parameters of bone formation and structure (bone volume/total volume, trabecular thickness, and trabecular number, as well as mineralized surface/bone surface). The GDF5 effects were dose-dependent (predominantly in the 5–100g range) at 3 and 9 months.
CONCLUSIONS:
GDF5 significantly enhanced the bone formation induced by a PLGA fiber-reinforced CPC in sheep lumbar osteopenia. The results indicated that a local dose as low as ≤100g
GDF5 may be sufficient to augment middle to long-term bone formation. The novel CPC+ GDF5 combination may thus qualify as an alternative to the bioinert, supraphysiologically stiff poly-(methyl methacrylate) cement currently applied for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures.
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.
Injectable, brushite-forming calcium phosphate cements (CPC) show potential for bone replacement, but they exhibit low mechanical strength. This study tested a CPC reinforced with poly(l-lactide-co-glycolide) acid (PLGA) fibers in a minimally invasive, sheep lumbar vertebroplasty model.
The study aimed to test the in vivo biocompatibility and osteogenic potential of a PLGA fiber-reinforced, brushite-forming CPC in a sheep large animal model.
Performance of calcium phosphate cements in the augmentation of sheep vertebrae - An ex vivo study
(2021)
Oil-based calcium phosphate cement (Paste-CPC) shows not only prolonged shelf life and injection times, but also improved cohesion and reproducibility during application, while retaining the advantages of fast setting, mechanical strength, and biocompatibility. In addition, poly(L-lactideco-glycolide) (PLGA) fiber reinforcement may decrease the risk for local extrusion. Bone defects (diameter 5 mm; depth 15 mm) generated ex vivo in lumbar (L) spines of female Merino sheep (2–4 years) were augmented using: (i) water-based CPC with 10% PLGA fiber reinforcement (L3); (ii) Paste-CPC (L4); or (iii) clinically established polymethylmethacrylate (PMMA) bone cement (L5). Untouched (L1) and empty vertebrae (L2) served as controls. Cement performance was analyzed using micro-computed tomography, histology, and biomechanical testing. Extrusion was comparable for Paste-CPC(-PLGA) and PMMA, but significantly lower for CPC + PLGA. Compressive strength and Young’s modulus were similar for Paste-CPC and PMMA, but significantly higher compared to those for empty defects and/or CPC + PLGA. Expectedly, all experimental groups showed significantly or numerically lower compressive strength and Young’s modulus than those of untouched controls. Ready-to-use Paste-CPC demonstrates a performance similar to that of PMMA, but improved biomechanics compared to those of water-based CPC + PLGA, expanding the therapeutic arsenal for bone defects. O, significantly lower extrusion of CPC + PLGA fibers into adjacent lumbar spongiosa may help to reduce the risk of local extrusion in spinal surgery.