The effect on bone regeneration of a liposomal vector to deliver BMP-2 gene to bone grafts in peri-implant bone defects

Park, J.; Lutz, Rainer; Felszeghy, Endre; Wiltfang, Jens; Nkenke, Emeka; Neukam, F. W.; Schlegel, Karl Andreas

doi:10.1016/j.biomaterials.2007.02.009

Cited by 79 publications

(91 citation statements)

References 30 publications

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“…On one hand this finding is remarkable as there are previous studies showing beneficial effects of additional reagents such as liposomes [19,20] or polyethyleneimine based cationic polymers on BMP gene delivery and bone regeneration [20,19,27,28]. Administration of a BMP2 plasmid in combination with lipoplexes increased bone formation and osseointegration in a rat and pig [20,19] Another important finding of this study is the insignificant therapeutic effect of passive gene transfer when administering exclusive BMP2 and BMP7 plasmids. 3 out of 9 animals in the BMP2/7 group showed oligotrophic non unions.…”

Section: Discussionmentioning

confidence: 56%

“…The use of cationic polymers or lipoplexes and other reagents for non-viral gene delivery is a well established method which can significantly increase transfection efficacies in vitro and in vivo [16][17][18]. In recent years several studies succeeded to increase passive gene transfer by lipofection or cationic polymer based gene delivery in animal models: Critical size mandibular defects in rats were successfully treated by liposome-mediated gene transfer of BMP2 in an ex vivo setting [19]. In vivo experiments showed increased bone formation and osseointegration when using liposomal BMP2 vectors in calvaria defects in pigs [20].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Kaipel

Schützenberger

Hofmann

et al. 2014

International Orthopaedics (SICOT)

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PURPOSE: Treatment of large segmental bone defects still is a challenge in clinical routine.Application of Gene-activated matrices (GAMs) based on fibrin, BMP 2/7 plasmids and nonviral transfection reagents (cationic polymers) could be an innovative treatment strategy to overcome this problem.The aim of this study was to determine the therapeutic efficacy of fibrin GAMs with or without additional transfection reagents for bone morphogenic protein (BMP)2 and BMP7 plasmid co-delivery in a rat femur non-union model. METHODS:In this experimental study a critical size femoral defect was created in 27 rats. At 4 weeks after the surgery animals were separated into 4 groups and underwent a second operation. Fibrin clots containing BMP2 and BMP7 plasmids with and without cationic polymer were implanted into the femoral defect. Fibrin clots containing recombinant human (rh) BMP2 served as positive and clots without supplement as negative controls.RESULTS: At 8 weeks animals which received GAMs containing the cationic polymer and BMP 2/7 plasmids showed decreased bone volume compared to animals treated with GAMs and BMP2/7 only. Application of BMP2 and BMP7 plasmids in fibrin GAMs without cationic polymer lead to variable results. Animals which received rhBMP 2 protein showed increased bone volume and osseous unions were achieved in 2 out of 6 animals.2 CONCLUSIONS: Cationic polymers decrease therapeutic efficiency of fibrin GAM based BMP2/7 plasmid co-delivery in bone regeneration. Non-viral gene transfer of BMP2/7 plasmids needs alternative promoters (e.g. by sonoporation, electroporation) to promise beneficial clinical effects.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Kaipel

Schützenberger

Hofmann

et al. 2014

International Orthopaedics (SICOT)

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“…The mimipig was chosen as the test model, because its calvarial bone regenerate rate is similar to that in humans and previous studies have indicated that calvaria bone defects are acceptable model for peri-implant bone defects 11,26) . The critical size defect (CSD) was defined by Hollinger and Schmitz 27,28) as the bone defect of a large size where no spontaneous complete osseous regeneration of the created defects occurs during the lifetime of the animals, and CSD was adopted to test bone repair materials in a hierarchy of animal models.…”

Section: Discussionmentioning

confidence: 99%

“…After applying a local anesthesia (1% Lidocaine with 1:100,000 Adrenaline) to the frontal calvariae of the minipig, a 10 cm long sagittal incision was made on the forehead region under sterile conditions. With a trephine drill (8 mm in diameter, Straumman, Switzerland), four bone defects (8 mm in diameter, 4 mm in depth) on each minipig calvariae were formed according to previous reports 11,12) (Fig. 1a).…”

Section: Experimental Protocolsmentioning

confidence: 99%

BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

Sun

Wang

Zheng

et al. 2012

Dental Materials Journal

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This study aimed to compare the effects of bone morphogenetic protein BMP2/7 heterodimer and BMP homodimers on bone regeneration in bone defects model. Identical peri-implant bone defects model were created using proper controls on the frontal skull in 18 minipigs. Collagen sponges with low-dose (30 ng/mL) BMP2/7 heterodimer, BMP2 or BMP7 homodimer were filled in the defects. New bone formation and the expression of type I collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated after 2, 3, and 6 weeks of implantation. BMP2/7 resulted in significantly higher new bone areas percentage in the defect region than BMP2 and BMP7 (p<0.05). Immunohistochemical staining of Col1, ALP and OCN was stronger in BMP2/7 group than BMP2, BMP7 and control group (p<0.05). These results demonstrate that BMP2/7 heterodimer is a stronger inducer of osteoblastogenesis and could be applied at low dose to reduce the cost and side effects of BMP homodimers.

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“…Supernatants were collected after spinning at 10,000 rpm for 5 minutes at days 1,3,7,10,15,17,20,24,28,30,33,35,40, and 45. At each time point, the microspheres were resuspended in 1 mL of fresh PBS.…”

Section: In Vitro Release Assaymentioning

confidence: 99%

Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo

Qiao

Zhang²,

Jin³

et al. 2013

IJN

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Abstract:Repair of large bone defects is a major challenge, requiring sustained stimulation to continually promote bone formation locally. Bone morphogenetic protein 2 (BMP-2) plays an important role in bone development. In an attempt to overcome this difficulty of bone repair, we created a delivery system to slowly release human BMP-2 cDNA plasmid locally, efficiently transfecting local target cells and secreting functional human BMP-2 protein. For transfection, we used polyethylenimine (PEI) to create pBMP-2/PEI nanoparticles, and to ensure slow release we used poly(lactic-co-glycolic acid) (PLGA) to create microsphere encapsulated pBMP-2/ PEI nanoparticles, PLGA@pBMP-2/PEI. We demonstrated that pBMP-2/PEI nanoparticles could slowly release from the PLGA@pBMP-2/PEI microspheres for a long period of time. The 3-15 µm diameter of the PLGA@pBMP-2/PEI further supported this slow release ability of the PLGA@pBMP-2/PEI. In vitro transfection assays demonstrated that pBMP-2/PEI released from PLGA@pBMP-2/PEI could efficiently transfect MC3T3-E1 cells, causing MC3T3-E1 cells to secrete human BMP-2 protein, increase calcium deposition and gene expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), SP7 and I type collagen (COLL I), and finally induce MC3T3-E1 cell differentiation. Importantly, in vivo data from micro-computed tomography (micro-CT) and histological staining demonstrated that the human BMP-2 released from PLGA@pBMP-2/PEI had a long-term effect locally and efficiently promoted bone formation in the bone defect area compared to control animals. All our data suggest that our PLGA-nanoparticle delivery system efficiently and functionally delivers the human BMP-2 cDNA and has potential clinical application in the future after further modification.

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The effect on bone regeneration of a liposomal vector to deliver BMP-2 gene to bone grafts in peri-implant bone defects

Cited by 79 publications

References 30 publications

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo

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