N-Methyl Pyrrolidone as a Potent Bone Morphogenetic Protein Enhancer for Bone Tissue Regeneration

Miguel, Blanca San; Ghayor, Chafik; Ehrbar, Martin; Jung, Ronald E.; Zwahlen, Roger A.; Hortschansky, Peter; Schmoekel, Hugo G.; Weber, Franz E.

doi:10.1089/ten.tea.2009.0009

Cited by 58 publications

(88 citation statements)

References 32 publications

(27 reference statements)

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“…NMP at concentrations between 1 and 5 mM enhances BMP activity two to eight times and is most efficient at low BMP concentrations [9]. RG502, the 50 mol% lactide ISFI, may provide more optimal NMP concentrations for the greatest BMP enhancement due to its almost linear NMP release from the beginning up to 100% release on day 14 ( Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, our laboratory discovered the enhancing effects of N-methyl pyrrolidone (NMP) on rhBMP-2, which offers a means to lower the efficacious delivered BMP dose [9]. NMP has been demonstrated to both increase bone forming activities of osteoblasts and decrease bone resorption of osteoclasts [10].…”

Section: Introductionmentioning

confidence: 99%

“…NMP has been demonstrated to both increase bone forming activities of osteoblasts and decrease bone resorption of osteoclasts [10]. An in vivo study using a rabbit calvarial defect model showed significantly higher bone regeneration with NMP alone by increasing the activity of the natural locally deposited autologous BMP [9].…”

Section: Introductionmentioning

confidence: 99%

“…Instead of using the ISFI system to deliver a classical drug, we have explored this technology to extend the release of NMP, which itself is a bioactive substance [9,10]. By examining the dependence of the release profile on polymer properties, we have prolonged the release of NMP from hours to a few weeks.…”

Section: Introductionmentioning

confidence: 99%

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N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants

Karfeld-Sulzer

Ghayor

Siegenthaler

et al. 2015

Journal of Controlled Release

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Bone morphogenetic proteins (BMPs) are growth and differentiation factors involved during development in morphogenesis, organogenesis and later mainly in regeneration processes, in particular in bone where they are responsible for osteoinduction. For more than a decade, recombinant human (rh)BMP-2 has been used in the clinic for lumbar spinal fusion at non-physiological high dosages that appear to be causative for side effects, like male sterility. A possible strategy to reduce the effective amount of rhBMP-2 in the clinic is the co-delivery with an enhancer of BMPs' activity. In an earlier study, we showed that N-methylpyrrolidone (NMP) enhances BMP activity in vitro and in vivo. Here we report on the development of a slow and sustained double delivery of rhBMP-2 and NMP via an in situ forming implant based on poly(lactide-co-glycolide). The results showed that the release of NMP can be adjusted by varying the lactide/glycolide ratio and the polymer's molecular weight. The same applied to rhBMP-2, with release rates that could be sustained from two to three weeks. In the in vivo model of a critical size defect in the calvarial bone of rabbits, the implant containing 50 mol% lactide performed better than the one having 75 mol% lactide in terms of defect bridging and extent of bony regenerated area. In situ forming implants for the double delivery of the BMP enhancer NMP and rhBMP-2 appear to be promising delivery systems in bone regeneration. ABSTRACTBone morphogenetic proteins (BMPs) are growth and differentiation factors involved during development in morphogenesis, organogenesis and later mainly in regeneration processes, in particular in bone where they are responsible for osteoinduction. For more than a decade, recombinant human (rh)BMP-2 has been used in the clinic for lumbar spinal fusion at non-physiological high dosages that appear to be causative for side effects, like male sterility. A possible strategy to reduce the effective amount of rhBMP-2 in the clinic is the co-delivery with an enhancer of BMPs' activity. In an earlier study, we showed that N-methylpyrrolidone (NMP) enhances BMP activity in vitro and in vivo. Here we report on the development of a slow and sustained double delivery of rhBMP-2 and NMP via an in situ forming implant based on poly(lactide-co-glycolide). The results showed that the release of NMP can be adjusted by varying the lactide/glycolide ratio and the polymer's molecular weight. The same applied to rhBMP-2, with release rates that could be sustained from two to three weeks. In the in vivo model of a critical size defect in the calvarial bone of rabbits, the implant containing 50 mol% lactide performed better than the one having 75 mol% lactide in terms of defect bridging and extent of bony regenerated area. In situ forming implants for the double delivery of the BMP enhancer NMP and rhBMP-2 appear to be promising delivery systems in bone regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants

Karfeld-Sulzer

Ghayor

Siegenthaler

et al. 2015

Journal of Controlled Release

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“…Recently, NMP has been reported to have the pharmaceutical property of enhancing bone regeneration in a rabbit calvarial defect model in vivo (Miguel et al, 2009). Therefore, NMP might be useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption.…”

Section: Introductionmentioning

confidence: 99%

N-methyl pyrrolidone (NMP) ameliorates the hypoxia-reduced osteoblast differentiation via inhibiting the NF-κB signaling

Zhao

et al. 2016

J. Toxicol. Sci.

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-Ischemic-hypoxic condition for local osteoblasts and bone mesenchymal stem cells during bone fracture inhibits bone repairing. N-methyl pyrrolidone (NMP) has been approved as a safe and biologically inactive small chemical molecule, and might be useful for bone fracture repairing. In the present study, we investigated the effect of NMP on the hypoxia-reduced cellular viability and the expression of differentiation-associated markers, such as bone morphogenetic protein 2 (BMP-2), propeptide of type I procollagen I (PINP), alkaline phosphatase (ALP) or runt-related transcription factor 2 (Runx2) in the osteoblasts, and then we examined the molecular mechanism underlining such effect in the human osteoblastic hFOB 1.19 cells. Our results demonstrated that NMP significantly blocked the hypoxia-induced cell viability reduction and inhibited the hypoxia-caused expression downregulation of BMP-2, PINP, ALP and Runx2 in hFOB 1.19 cells. Then we confirmed the involvement of nuclear factor κB (NF-κB) pathway in the regulation by NMP on the hypoxia-mediated the reduction of osteoblast differentiation. The upregulated expression and transcriptional activity of NF-κB, while the downregulated inhibitory κB expression by the hypoxia treatment was reversed by the treatment with 10 mM NMP. In conclusion, our study found a protective role of NMP in osteoblast differentiation in response to hypoxia, and such protection was through inhibiting the NF-κB signaling. This suggests that NMP might be a protective agent in bone fracture repairing.

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N‐Methyl‐2‐pyrrolidon (Dampf) [MAK Value Documentation in German language, 2019]

Hartwig

2019

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the workplace (MAK value) of N‐methyl‐2‐pyrrolidone [ 872‐50‐4 ]. The critical effects in rats are irritation of the upper respiratory tract, foetotoxicity and neurotoxicity. Male volunteers did not show adverse irritant or cognitive effects after 8‐hour exposure to N‐methyl‐2‐pyrrolidone at a concentration of 20 ml/m 3 with and without exposure peaks of 40 ml/m 3 and with physical workload. A MAK value of 20 ml/m 3 had been set for N‐methyl‐2‐pyrrolidone vapour. This value has now been confirmed even considering the increased respiratory volume at the workplace (see List of MAK and BAT Values, Section I b and I c). Exposure to N‐methyl‐2‐pyrrolidone aerosols increases the intake by dermal absorption but there is no information indicating by how much. Therefore, the MAK value is only valid for the vapour of N‐methyl‐2‐pyrrolidone and exposure to aerosols or vapour/aerosol mixtures must be controlled by biomonitoring methods. As the critical effect of N‐methyl‐2‐pyrrolidone is assumed to be local, Peak Limitation Category I has been designated. The excursion factor of 2 is retained.

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N-Methyl Pyrrolidone as a Potent Bone Morphogenetic Protein Enhancer for Bone Tissue Regeneration

Cited by 58 publications

References 32 publications

N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants

N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants

N-methyl pyrrolidone (NMP) ameliorates the hypoxia-reduced osteoblast differentiation via inhibiting the NF-κB signaling

N‐Methyl‐2‐pyrrolidon (Dampf) [MAK Value Documentation in German language, 2019]

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