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A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: Results of a multicentre analysis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Univ Southampton, Inst Dev Sci, Ctr Human Dev Stem Cells & Regenerat, Bone & Joint Res Grp, Southampton SO9 5NH, Hants, England.
Univ Southampton, Inst Dev Sci, Ctr Human Dev Stem Cells & Regenerat, Bone & Joint Res Grp, Southampton SO9 5NH, Hants, England..
Swiss Fed Inst Technol Zurich ETHZ, Inst Biomech, Vladimir Prelog Weg 3, CH-8093 Zurich, Switzerland.;Eindhoven Univ Technol, Dept Biomed Engn, POB 513, NL-5600 MB Eindhoven, Netherlands.;Eindhoven Univ Technol, Inst Complex Mol Syst, POB 513, NL-5600 MB Eindhoven, Netherlands..
Swiss Fed Inst Technol Zurich ETHZ, Inst Biomech, Vladimir Prelog Weg 3, CH-8093 Zurich, Switzerland..
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2016 (English)In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 31, 312-322 p.Article in journal (Refereed) Published
Abstract [en]

New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines.

Place, publisher, year, edition, pages
2016. Vol. 31, 312-322 p.
Keyword [en]
in vivo, in vitro, correlation, biomaterials, multicentre study
National Category
Biomaterials Science
URN: urn:nbn:se:uu:diva-306778DOI: 10.22203/eCM.v031a20ISI: 000384895100020PubMedID: 27215739OAI: diva2:1047019
EU, FP7, Seventh Framework Programme, 262948
Available from: 2016-11-16 Created: 2016-11-03 Last updated: 2017-01-08Bibliographically approved
In thesis
1. Bone Regeneration with Cell-free Injectable Scaffolds
Open this publication in new window or tab >>Bone Regeneration with Cell-free Injectable Scaffolds
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 67 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1287
bone tissue engineering, hydrogel, computed tomography, positron emission tomography, large femoral bone defect, rat model, hydrogel, in vivo, osteogenesis, bone regeneration, 3R, single-photon emission computed tomography, bone morphogenetic protein 2, calcium phosphates, injectable, bisphosphonate
National Category
Biomaterials Science Orthopedics
urn:nbn:se:uu:diva-310312 (URN)978-91-554-9786-6 (ISBN)
Public defence
2017-02-24, Enghoffsalen, Akademiska sjukhuset, ingång 50, Uppsala, 09:15 (Swedish)
EU, FP7, Seventh Framework Programme, EUFP7-NMP.20102.3-1; Grant 262948
Available from: 2017-02-02 Created: 2016-12-13 Last updated: 2017-02-07

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