Novel Animal Model of Calvarial Defect in an Infected Unfavorable Wound: Reconstruction with rhBMP-2

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

doi:10.1097/prs.0b013e3181fed5c5

Cited by 19 publications

(7 citation statements)

References 25 publications

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“…In this study, we utilize a total dose of rhBMP2, which in our microspheres is spread out over approximately one month; this dose is approximately 10,000-100,000x less than the total dose that is clinically utilized 4 , the result being a significantly decreased local growth factor concentration. The dose in this study is also significantly lower than previously published work in this area 9, 13, 27-29 . Thus, we are beginning to ask and attempt to answer the question, what is the minimal dose and local concentration of rhBMP2 that can be delivered over time in order to induce bone regeneration without the production of unwanted side effects?…”

Section: Discussioncontrasting

confidence: 64%

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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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: Discussioncontrasting

confidence: 64%

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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“…Causes of craniofacial injury include trauma and tumor removal, contributing to prevalent mortality and morbidity [59, 60]. This is further complicated by factors that compromise the recipient wound bed or interfere with optimal healing (e.g., irradiation, infection, surgical damage) [3, 61, 62]. Autologous bone grafts remain the standard of care, although, the process of harvesting is associated with morbidity and a number of complications.…”

Section: Discussionmentioning

confidence: 99%

Inkjet-based biopatterning of SDF-1β augments BMP-2-induced repair of critical size calvarial bone defects in mice

Herberg¹,

Kondrikova²,

Periyasamy‐Thandavan³

et al. 2014

Bone

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Background A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. Methods Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. Results Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2 + SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1 + SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. Conclusions Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its’ effect on osteogenesis is not universal.

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“…Several experimental models have investigated how bone morphogenetic protein therapies can be safely expanded to address bony defects throughout the skeleton, including the calvaria. [7][8][9][10] Although the successful application of rhBMP-2 therapy to the calvaria would potentially obviate the need for autogenous tissue harvest, the unwanted effects of rhBMP-2 therapy must first be minimized before it can be considered a preferred therapy. The development of seromas and the formation of ectopic bone following rhBMP-2 treatment has been described previously.…”

mentioning

confidence: 99%

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

Kinsella

Bykowski

Lin

et al. 2011

Plastic and Reconstructive Surgery

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Novel Animal Model of Calvarial Defect in an Infected Unfavorable Wound: Reconstruction with rhBMP-2

Cited by 19 publications

References 25 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

Inkjet-based biopatterning of SDF-1β augments BMP-2-induced repair of critical size calvarial bone defects in mice

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

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