title: N-methyl pyrrolidone/bone morphogenetic protein-2 double delivery with in situ forming implants.
abstract: 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 50mol% lactide performed better than the one having 75mol% 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.
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center for Dental Medicine, Oral Biotechnology & Bioengineering, Frauenklinikstrasse 24, 8091 Zürich, Switzerland.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Karfeld-Sulzer
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center for Dental Medicine, Oral Biotechnology & Bioengineering, Frauenklinikstrasse 24, 8091 Zürich, Switzerland.
authors.forename: Chafik
authors.initials: C
authors.lastname: Ghayor
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center for Dental Medicine, Oral Biotechnology & Bioengineering, Frauenklinikstrasse 24, 8091 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Siegenthaler
authors.affiliation: University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Institute for Medical and Analytical Technologies, Muttenz, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: de Wild
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH, Zurich, Zurich, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center for Dental Medicine, Oral Biotechnology & Bioengineering, Frauenklinikstrasse 24, 8091 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland. Electronic address: franz.weber@zzm.uzh.ch.
authors.forename: Franz E
authors.initials: FE
authors.lastname: Weber
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000494:pharmacology; D004343:Drug Implants / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D011098:Polyglactin 910 / Q000737:chemistry*; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012886:Skull / Q000187:drug effects* / Q000293:injuries* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D011098:Polyglactin 910; C038678:N-methylpyrrolidone
keywords: Bone morphogenetic proteins; Bone regeneration; Double delivery; Glycolide; Lactide; N-methylpyrrolidone; Poly(lactide-co-glycolide)