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Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Centre of Biopathways and Biomaterials, Dept of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China .
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
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2011 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 7, no 8, 3042-3049 p.Article in journal (Refereed) Published
Abstract [en]

Current treatment of fractures often involves the use of bone graft or bone morphogenetic proteins (BMP) to induce fracture healing, especially in patients with a compromised healing capacity. BMP has to be delivered in conjunction with a carrier. Unfortunately, there are drawbacks and limitations with current carriers, including their bovine origin which carries the risk of an immunological response. The physical properties also limit the use to open surgical procedures, as it cannot be injected. New carriers with improved properties are therefore needed. The aim of this study was to assess the ectopic bone forming capability of various calcium phosphate compounds when used in conjunction with a hydrogel as the carrier for BMP-2. Five different ceramic additives were tested, including beta-tricalcium phosphate and four types of hydroxyapatite (HAP) (nanoHAP, HAP, clods of HAP >100 mu m, and the biomimetic HAP Ostim35 (R)). The compounds were injected into the thigh muscle of rats, where it formed a gel in situ. After 4 weeks bone formation was evaluated by peripheral quantitative computed tomography and histology. The major finding was that the 20 nm nanoHAP yielded a higher bone density than the other additives (P = 0.0008, ANOVA with Tukey's multiple comparison test). We hypothesize that the higher bone density induced by nanoHAP might be due to nanocrystals of calcium phosphate acting as direct building blocks for biomineralization.

Place, publisher, year, edition, pages
2011. Vol. 7, no 8, 3042-3049 p.
Keyword [en]
Calcium phosphates, Hydrogel, Injectable, Nanosized, In vivo
National Category
Medical and Health Sciences Polymer Chemistry Engineering and Technology
Research subject
Chemistry with specialization in Polymer Chemistry; Engineering Science with specialization in Materials Science
Identifiers
URN: urn:nbn:se:uu:diva-157018DOI: 10.1016/j.actbio.2011.04.021ISI: 000293259500004OAI: oai:DiVA.org:uu-157018DiVA: diva2:434776
Available from: 2011-08-16 Created: 2011-08-15 Last updated: 2017-12-08Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1287
Keyword
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
Identifiers
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)
Opponent
Supervisors
Funder
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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Hulsart-Billström, GryJonsson, Kenneth BÅberg, JonasLarsson, SuneHilborn, Jöns

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