BMP-2-Mediated Regeneration of Large-Scale Cranial Defects in the Canine: An Examination of Different Carriers

Kinsella, Christopher R.; Bykowski, Michael R.; Lin, Alexander Y.; Cray, James J.; Durham, Emily L.; Smith, Darren M.; DeCesare, Gary E.; Mooney, Mark P.; Cooper, Gregory M.; Losee, Joseph E.

doi:10.1097/prs.0b013e31820cf2c9

Cited by 27 publications

(27 citation statements)

References 18 publications

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“…RhBMP2, as it is currently available (INFUSE, Medtronic Sofamor Danek, Memphis, TN), is delivered at approximately 1.5mg/cc 3 with patients receiving 2-14mg per treatment 4 . In these concentrations and doses, it has demonstrated efficacy in bone regeneration and bony union 5 , but not without significant side effects 6 including heterotopic ossification (HO) 7-9 , transient bone resorption 10 , wound complications 11 , local inflammation 12 and seroma formation 4, 13, 14 . Such side effects are poorly tolerated in anatomic regions requiring precise control over bone morphology and geometry, like the head and neck.…”

Section: Introductionmentioning

confidence: 99%

“…This is especially important in the pediatric patient, with animal studies suggesting an interaction of rhBMP2 and the growing brain 15 and the premature fusion of cranial sutures 16 . There have been numerous attempts to achieve the ideal delivery— timing, concentration, dose, vehicle-- of rhBMP2 for the repair of calvarial defects, but the ideal system remains elusive 9, 13, 14, 17 .…”

Section: Introductionmentioning

confidence: 99%

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Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres

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Gerety

Sherif

et al. 2014

Plastic and Reconstructive Surgery

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Background Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. Methods rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by μCT, histology, and finite element analysis. Results RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by μCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Conclusions Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Level of Evidence Animal Study

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres

Wink

Gerety

Sherif

et al. 2014

Plastic and Reconstructive Surgery

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“…Despite its reliance on the actions of native progenitor cells, rhBMP-2 therapy has been shown experimentally to be a promising treatment modality Volume 131, Number 4 • BMP2 Reconstruction: Durectomy 515e in defects complicated by chronic scar and by radiation treatment. 9 Bone regeneration in cranioplasty depends on the bone margins and the dura, which contribute cells and osteogenic precursors to initiate bone healing. [12][13][14] Maintenance of dural integrity is essential for complete bone regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Use of rhBMP-2/absorbable collagen sponge in these scenarios appears to be a viable alternative to autograft in providing bony coverage. The purpose of this study was to investigate the effectiveness of rhBMP-2/absorbable collagen sponge therapy for bone regeneration in calvarial defects complicated by durectomy.…”

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confidence: 98%

Novel Animal Model of Calvarial Defect

MacIsaac¹,

Levine²,

Smith³

et al. 2013

Plastic and Reconstructive Surgery

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“…These materials add compression resistance to the site and can potentially reduce the volume of rhBMP-2/ACS required to fill the defect. In this setting, several positive reports have emerged describing the use of a graft comprising rhBMP-2/ACS in which the sponge is wrapped around morselized granules (Dawson et al, 2009;Jones et al, 2008;Kinsella et al, 2011;Suh et al, 2002). The biological premise of this method is to distribute the biologically active rhBMP-2 bound to the ACS around the periphery of the graft where it will have greatest access to a responsive cell population, while providing an osteoconductive core within the defect site which will promote ingrowth of an osteogenic response that begins on the surface into the center of the defect.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of rhBMP-2/collagen/TCP-HA bone graft with and without bone marrow cells in the canine femoral multi defect model

Luangphakdy

Shinohara

Pan

et al. 2015

eCM

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Recombinant human bone morphogenetic protein-2, when applied to an absorbable type 1 bovine collagen sponge (rhBMP-2/ACS) is an effective therapy in many bone grafting settings. Bone marrow aspirate (BMA) has also been used as a source of transplantable osteogenic connective tissue progenitors. This study was designed to characterize the performance of a scaffold comprising rhBMP-2/ACS in which the sponge wraps around tricalcium phosphate hydroxyapatite granules (rhBMP-2/ ACS/TCP-HA) and to test the hypothesis that addition of BMA will improve the performance of this construct in the Canine Femoral Multi Defect Model. In each subject, two sites were grafted with rhBMP-2/ACS/TCP-HA scaffold loaded with BMA clot and two other sites with rhBMP-2/ACS/TCP-HA scaffold loaded with wound blood (WB). After correction for unresorbed TCP-HA granules, sites grafted with rhBMP-2/ACS/TCP-HA+BMA and rhBMP-2/ACS/TCP-HA+WB were similar, with mean percent bone volumes of 10.9 % ± 1.2 and 11.2 % ± 1.2, respectively. No differences were seen in quantitative histomorphometry. While bone formation using both constructs was robust, this study did not support the hypothesis that the addition of unprocessed bone marrow aspirate clot improved bone regeneration in a site engrafted with rhBMP-2/ACS/TCP-HA+BMA. In contrast to prior studies using this model, new bone formation was greater at the center of the defect where TCP-HA was distributed. This finding suggests a potential synergy between rhBMP-2 and the centrally placed ceramic and cellular components of the graft construct. Further optimization may also require more uniform distribution of TCP-HA, alternative cell delivery strategies, and a more rigorous large animal segmental defect model.

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BMP-2-Mediated Regeneration of Large-Scale Cranial Defects in the Canine: An Examination of Different Carriers

Cited by 27 publications

References 18 publications

Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres

Sustained Delivery of rhBMP-2 by Means of Poly(Lactic-co-Glycolic Acid) Microspheres

Novel Animal Model of Calvarial Defect

Evaluation of rhBMP-2/collagen/TCP-HA bone graft with and without bone marrow cells in the canine femoral multi defect model

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