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Critical assessment of rhBMP-2 mediated bone induction: An in vitro and in vivo evaluation.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2012 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 162, no 3, 646-653 p.Article in journal (Refereed) Published
Abstract [en]

Understanding the influence of formulation and storage conditions on rhBMP-2 bioactivity is extremely important for its clinical application. Reports in the literature show that different research groups employ different parameters such as formulation conditions, storage, doses for in vivo applications etc. that makes it difficult to correlate results from different experiments. We therefore decided to rationalize these anomalies by performing a basic study on such parameters using two commercially available BMPs. Our in vitro experiments suggest that BMPs from different sources have significant differences in their bioactivity. The clinically approved rhBMP-2 (InductOs®; BMP-P) showed superior stability, compared to rhBMP-2 from R&D Systems (BMP-R) at physiological pH (determined by ALP assay). This BMP-P also showed lower binding to polypropylene Eppendorf tube. The BMP-R almost lost its bioactivity within 30min at physiological pH and also shows more adhesion to plastic surfaces. This aggregation behavior was unequivocally ascertained by performing light scattering studies of the two BMPs, which revealed linear aggregation with time for BMP-R unlike BMP-P. The in vitro results were also reflected in the in vivo experiments, in a rat ectopic model with injectable hyaluronic acid (HA) hydrogel as BMP carrier. After 7weeks post-implantation we observed larger bone volume with oriented collagen in the BMP-P group but a smaller bone with disoriented collagen in the BMP-R case. Our results highlight the large difference in activity between seemingly identical substances and also the importance of proper handling of such sensitive proteins.

Place, publisher, year, edition, pages
2012. Vol. 162, no 3, 646-653 p.
National Category
Natural Sciences Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
URN: urn:nbn:se:uu:diva-181153DOI: 10.1016/j.jconrel.2012.08.004ISI: 000310506900021PubMedID: 22902595OAI: oai:DiVA.org:uu-181153DiVA: diva2:552952
Available from: 2012-09-17 Created: 2012-09-17 Last updated: 2013-02-11Bibliographically approved
In thesis
1. Bone Enhancement with BMP-2 for Safe Clinical Translation
Open this publication in new window or tab >>Bone Enhancement with BMP-2 for Safe Clinical Translation
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of bone regeneration. However, BMP-2 delivery in a conventional collagen scaffold needs a high dose to achieve an effective outcome. Moreover, such dosage may lead to serious side effects. The aim of the following thesis was to find clinically acceptable strategies reducing the required dose of BMP-2 by improving the delivery and optimizing the preclinical testing of the new approaches. In all the studies hyaluronic acid (HA) hydrogels was used as a carrier for BMP-2.

The HA hydrogel/BMP-2 construct was modified with bioactive matrix components in order to obtain an effective release of BMP-2 and an enhanced bone formation. The most promising were two strategies. In the first one, BMP-2, precomplexed with the glycosaminoglycans dermatan sulfate or heparin prior to loading it into HA hydrogel, protected and prolonged the delivery of the protein, resulting in twofold larger bone formation in comparison to non-complexed BMP-2. In the second strategy, the fibronectin fragment integrin-binding domain (FN) was covalently incorporated into HA hydrogel. The FN remarkably improved the capacity of the material to support the cells attachment and spreading, providing the formation of twice as much bone in comparison to non-functionalized HA hydrogel/BMP-2.

Furthermore, the importance of a proper design of the preclinical study for BMP-2 delivery systems was highlighted. Firstly, proper physicochemical handling of BMP-2 showed the improvement in further in vivo activity.  The use of glass storage vials and an acidic formulation buffer was superior to plastic surfaces and physiological pH. Secondly, while regenerative medicine strategy testing required the use of animal models that matched the research questions related to clinical translation, two new animal models were developed. The subperiosteal mandibular and calvarial models in rats were found to be minimally invasive, convenient and rapid solution for the evaluation of a broad range of approaches including bone augmentation, replacement and regeneration. Both models are primarily relevant for the initial testing of the injectable bone engineering constructs. 

Those clinically translatable approaches presented here could prove to be a powerful platform for a wider use of BMP-2 in orthopedic, plastic surgery and regenerative medicine research.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 74 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1009
Bone repair, Bone healing, Bone morhogenetic protein-2, Osteogenesis, Extracelular matrix, Hyaluronan, Animal model
National Category
Orthopedics Biomaterials Science
Research subject
Orthopaedics; Engineering Science with specialization in Materials Science
urn:nbn:se:uu:diva-188027 (URN)978-91-554-8572-6 (ISBN)
Public defence
2013-02-08, Museum Gustavianum - Auditorium Minus, Akademigatan 3, Uppsala, 13:15 (English)
Available from: 2013-01-18 Created: 2012-12-12 Last updated: 2013-02-11Bibliographically approved

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