The effect of an rhBMP-2 absorbable collagen sponge-targeted system on bone formation in vivo

Visser, Rick; Arrabal, Pilar M.; Becerra, José; Rinas, Ursula; Cifuentes, Manuel

doi:10.1016/j.biomaterials.2008.12.046

Cited by 101 publications

(86 citation statements)

References 34 publications

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“…1.5 ml of OptiMEM serum-free media (Gibco, Ireland) was then added to each well and incubated at 37°C for one hour. PEI-pDNA complexes were produced in OptiMEM at varying N/P ratios (5,7,10) and doses (1µg, 2µg, 4µg) of pDNA and incubated at room temperature for 30 minutes. The N/P ratio can be defined as moles of amines in PEI (N)/moles of phosphate in pDNA (P) and the term dose refers to the quantity of pDNA contained within the polyplex.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Scaffolds developed from biomaterials act as templates for tissue formation where the interaction between the scaffold, infiltrating cells and the aforementioned cues is intrinsic to its success. Biomaterial scaffolds for tissue engineering applications have primarily been modified to contain growth factors in the form of recombinant proteins to boost the therapeutic response [1][2][3][4][5]. However, using proteins in this environment is associated with a number of distinct disadvantages such as the large dose required, the need for repeated applications, poor distribution, expense, short half-life and protein instability [6].…”

Section: Introductionmentioning

confidence: 99%

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The development of non-viral gene-activated matrices for bone regeneration using polyethyleneimine (PEI) and collagen-based scaffolds

Tierney

Duffy

Hibbitts

et al. 2012

Journal of Controlled Release

124

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The healing potential of scaffolds for tissue engineering can be enhanced by combining them with genes to produce gene-activated matrices (GAMs) for tissue regeneration. We examined the potential of using polyethyleneimine (PEI) as a vector for transfection of mesenchymal stem cells (MSCs) in monolayer culture and in 3D collagen-based GAMs. PEI-pDNA polyplexes were fabricated at a range of N/P ratios and their optimal transfection parameters (N/P 7 ratio, 2µg dose) and transfection efficiencies (45 ± 3%) determined in monolayer culture. The polyplexes were then loaded onto collagen, collagen-glycosaminoglycan and collagen-nanohydroxyapatite scaffolds where gene expression was observed up to 21 days with a polyplex dose as low as 2µg. Transient expression profiles indicated that the GAMs act as a polyplex depot system whereby infiltrating cells become transfected over time as they migrate throughout the scaffold. The collagen-nHa GAM exhibited the most prolonged and elevated levels of transgene expression. This research has thus demonstrated that PEI is a highly efficient pDNA transfection agent for both MSC monolayer cultures and in the 3D GAM environment. By combining therapeutic gene therapy with highly engineered scaffolds, it is proposed that these GAMs might have immense capability to promote tissue regeneration.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The development of non-viral gene-activated matrices for bone regeneration using polyethyleneimine (PEI) and collagen-based scaffolds

Tierney

Duffy

Hibbitts

et al. 2012

Journal of Controlled Release

124

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“…In our study, the concentrations used of 5 mg/kg of AMD3100, 18 200 ng of SDF-1 per ACS implant, 45,46 and 10 mg of BMP-2 [47][48][49] were based on previous publications from other groups. Additionally, one publication described the release kinetics of SDF-1 from collagen scaffolds, reporting that there is a rapid release of 50% of the SDF-1 in the first 24 h, and, therefore, a high gradient, followed by a notably slower release of an additional 10% for at least a week thereafter.…”

Section: Sdf-1/cxcr4 Axis and Bone Formationmentioning

confidence: 99%

Modulation of Stromal Cell-Derived Factor-1/CXC Chemokine Receptor 4 Axis Enhances rhBMP-2-Induced Ectopic Bone Formation

Wise

Sumner²,

Virdi³

2012

Tissue Engineering Part A

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Enhancement of in vivo mobilization and homing of endogenous mesenchymal stem cells (MSCs) to an injury site is an innovative strategy for improvement of bone tissue engineering and repair. The present study was designed to determine whether mobilization by AMD3100 and/or local homing by delivery of stromal cellderived factor-1 (SDF-1) enhances recombinant human bone morphogenetic protein-2 (rhBMP-2) induced ectopic bone formation in an established rat model. Rats received an injection of either saline or AMD3100 treatment 1 h before harvesting of bone marrow for in vitro colony-forming unit-fibroblasts (CFU-F) culture or the in vivo subcutaneous implantation of absorbable collagen sponges (ACSs) loaded with saline, recombinant human bone morphogenetic protein-2 (rhBMP-2), SDF-1, or the combination of SDF-1 and rhBMP-2. AMD3100 treatment resulted in a significant decrease in CFU-F number, compared with saline, which confirmed that a single systemic AMD3100 treatment rapidly mobilized MSCs from the bone marrow. At 28 and 56 days, bone formation in the explanted ACS was assessed by microcomputed tomography (mCT) and histology. At 28 days, AMD3100 and/or SDF-1 had no statistically significant effect on bone volume (BV) or bone mineral content (BMC), but histology revealed more active bone formation with treatment of AMD3100, loading of SDF-1, or the combination of both AMD3100 and SDF-1, compared with saline-treated rhBMP-2 loaded ACS. At 56 days, the addition of AMD3100 treatment, loading of SDF-1, or the combination of both resulted in a statistically significant stimulatory effect on BV and BMC, compared with the saline-treated rhBMP-2 loaded ACS. Histology of the 56-day ACS were consistent with the mCT analysis, exhibiting more mature and mineralized bone formation with AMD3100 treatment, SDF-1 loading, or the combination of both, compared with the saline-treated rhBMP-2 loaded ACS. The present study is the first that provides evidence of the efficacy of AMD3100 and SDF-1 treatment to stimulate trafficking of MSCs to an ectopic implant site, in order to ultimately enhance rhBMP-2 induced long-term bone formation.

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“…Recombinant human BMP-2 is also used in bone repair in human clinical therapy 42,43 and a recent study employing BMP-2 fused to a collagen binding domain within a 3D collagen sponge showed that BMP-2 enhances its effect in bone remodeling. 44 Our process for obtaining neo-cartilage is, thus, ready to enter clinical trials in animals (e.g., horse), and, ultimately, can be tested in preclinical trials for future use in humans.…”

Section: Discussionmentioning

confidence: 99%

BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

Ollitrault

Legendre

Drougard

et al. 2015

Tissue Engineering Part C: Methods

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Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets.

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The effect of an rhBMP-2 absorbable collagen sponge-targeted system on bone formation in vivo

Cited by 101 publications

References 34 publications

The development of non-viral gene-activated matrices for bone regeneration using polyethyleneimine (PEI) and collagen-based scaffolds

The development of non-viral gene-activated matrices for bone regeneration using polyethyleneimine (PEI) and collagen-based scaffolds

Modulation of Stromal Cell-Derived Factor-1/CXC Chemokine Receptor 4 Axis Enhances rhBMP-2-Induced Ectopic Bone Formation

BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

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