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Hulsart Billström, GryORCID iD iconorcid.org/0000-0003-2422-831x
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Publications (10 of 30) Show all publications
Hulsart Billström, G., Stelzl, C., Procter, P., Pujari-Palmer, M., Insley, G., Engqvist, H. & Larsson, S. (2020). In vivo safety assessment of a bio-inspired bone adhesive. Journal of materials science. Materials in medicine, 31(2), Article ID 24.
Open this publication in new window or tab >>In vivo safety assessment of a bio-inspired bone adhesive
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2020 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 31, no 2, article id 24Article in journal (Refereed) Published
Abstract [en]

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the alpha-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue. 

Place, publisher, year, edition, pages
SPRINGER, 2020
National Category
Medical Materials
Identifiers
urn:nbn:se:uu:diva-407133 (URN)10.1007/s10856-020-6362-3 (DOI)000511787900001 ()32036502 (PubMedID)
Funder
Swedish Research Council, RMA15-390 0110
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2020-03-20Bibliographically approved
Hulsart Billström, G., Janson, O., Engqvist, H., Welch, K. & Hong, J. (2019). Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces. Journal of materials science. Materials in medicine, 30(6), Article ID 66.
Open this publication in new window or tab >>Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces
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2019 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 30, no 6, article id 66Article in journal (Refereed) Published
Abstract [en]

The release of growth factors from platelets, mediated by the coagulation and the complement system, plays an important role in the bone formation around implants. This study aimed at exploring the thromboinflammatory response of H2O2-alkali soaked commercially pure titanium grade 2 discs exposed to whole human blood, as a way to assess the bioactivity of the discs. Commercially pure titanium grade 2 discs were modified by soaking in H2O2, NaOH and Ca(OH)2. The platelet aggregation, coagulation activation and complement activation was assessed by exposing the discs to fresh whole blood from human donors. The platelet aggregation was examined by a cell counter and the coagulation and complement activation were assessed by ELISA-measurements of the concentration of thrombin-antithrombin complex, C3a and terminal complement complex. The modified surface showed a statistically significant increased platelet aggregation, coagulation activation and complement activation compared to unexposed blood. The surface also showed a statistically significant increase of coagulation activation compared to PVC. The results of this study showed that the H2O2-alkali soaked surfaces induced a thromboinflammatory response that indicates that the surfaces are bioactive.

National Category
Other Materials Engineering Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-358034 (URN)10.1007/s10856-019-6248-4 (DOI)000468976700001 ()31127371 (PubMedID)
Funder
Swedish Research Council, 2016-2075-5.1; 2016-04519Vinnova
Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2019-06-25Bibliographically approved
Rothenbucher, T. S. P., Ledin, J., Gibbs, D., Engqvist, H., Persson, C. & Hulsart Billström, G. (2019). Zebrafish embryo as a replacement model for initial biocompatibility studies of biomaterials and drug delivery systems. Acta Biomaterialia, 100, 235-243
Open this publication in new window or tab >>Zebrafish embryo as a replacement model for initial biocompatibility studies of biomaterials and drug delivery systems
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2019 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 100, p. 235-243Article in journal (Refereed) Published
Abstract [en]

The development of new biomaterials and drug delivery systems necessitates animal experimentation to demonstrate biocompatibility and therapeutic efficacy. Reduction and replacement of the requirement to conduct experiment using full-grown animals has been achieved through utilising zebrafish embryos, a promising bridge model between in vitro and in vivo research. In this review, we consider how zebrafish embryos have been utilised to test both the biocompatibility of materials developed to interact with the human body and drug release studies. Furthermore, we outline the advantages and limitations of this model and review legal and ethical issues. We anticipate increasing application of the zebrafish model for biomaterial evaluation in the near future. Statement of significance This review aims to evaluate the potential application and suitability of the zebrafish model in the development of biomaterials and drug delivery systems. It creates scientific impact and interest because replacement models are desirable to the society and the scientific community. The continuous development of biomaterials calls for the need to provide solutions for biological testing. This review covers the topic of how the FET model can be applied to evaluate biocompatibility. Further, it explores the zebrafish from the wild-type to the mutant form, followed by a discussion about the ethical considerations and concerns when using the FET model. (C) 2019 Published by Elsevier Ltd on behalf of Acta Materialia Inc.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Zebrafish, High-throughput, FET test, Fish embryo toxicity, 3Rs
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-400726 (URN)10.1016/j.actbio.2019.09.038 (DOI)000501646900021 ()31585201 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RMA15-0110
Available from: 2020-01-28 Created: 2020-01-28 Last updated: 2020-01-28Bibliographically approved
Procter, P., Pujari-Palmer, M., Hulsart Billström, G., Insley, G., Larsson, S. & Engqvist, H. (2018). A new ex-vivo murine model for evaluation of adhesiveness of a novel biomimetic bone glue. In: : . Paper presented at 34th Annual Meeting of Orthopaedic Trauma association, October 17 – 20, 2018, Kissimmee (Orlando), FL, USA.
Open this publication in new window or tab >>A new ex-vivo murine model for evaluation of adhesiveness of a novel biomimetic bone glue
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2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Keywords
Tissue adhesive, biomaterial, calcium phosphate
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-366372 (URN)
Conference
34th Annual Meeting of Orthopaedic Trauma association, October 17 – 20, 2018, Kissimmee (Orlando), FL, USA
Funder
Swedish Foundation for Strategic Research , RMA15-0110
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-03-06Bibliographically approved
Skjöldebrand, C., Hulsart Billström, G., Engqvist, H. & Persson, C. (2018). Biocompatibility of co-sputtered Si-Fe-C-N coatings. In: : . Paper presented at 11th annual meeting, Scandinavian Society for Biomaterials, Gullmarsstrand, 25-27 April, 2018.
Open this publication in new window or tab >>Biocompatibility of co-sputtered Si-Fe-C-N coatings
2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

INTRODUCTION: Hip joint arthroplasty is a common and increasingly frequent procedure that can relieve pain and restore mobility for individuals with e.g. severe osteoarthritis. While the procedure is common and to a large extent considered successful there is a need to prolong the lifespan of the implants to meet the need of a more active patient group, living longer. One of the main limiting factors behind the implant lifetime is the generation of particulate and ionic wear debris that causes an activation of the immune system. This debris originates in the articulating surfaces and one attempt to minimize the generation of debris is to deposit a ceramic coating on metal implant parts. The hard ceramic coatings, such as silicon nitride, could improve the wear resistance as well as act as a barrier for metal ion release.1,2 The silicon nitride coatings in this study were co-deposited with Fe and C in order to increase the deposition rate and tune the dissolution rate.

METHODS: The coatings were deposited using reactive magnetron sputtering onto silicon wafer substrates. The Si target (99.99% purity) was powered with pulsed DC at 200 W, 200 kHz and 2 µs. The Fe target (99.99% purity) and C target (99.99% purity) were powered by DC aggregates at 25 W and 65 W respectively. The targets were positioned at an angle (38.81˚) and no rotation was used during deposition. Nitrogen was introduced as a reactive gas in addition to the inert Ar at a ratio of 0.3. The deposition time was 10 000 s.

Based on the intended compositional gradients five points (4 corners in a square spaced 40 mm apart and the middle) on the sample were selected. No two points on the sample are identical and could be treated like individual samples.

The composition was determined using ERDA and the surface properties were estimated with atomic force microscopy (AFM) in non-contact mode.

The biocompatibility was assessed in vitro with osteo-progenitor cells from mouse (MC3T3)..

RESULTS: The ERDA investigation revealed clear compositional gradients. The Si content ranged from 26 at.% in point 4 to 34 at.% in point 1. The Fe content changed in a complementary manner with a maximum of 20 at.% in point 4 and a minimum of 10 at.% in point 1. The carbon content ranged from 8 at.% in point 1 to 14 in point 4. In addition to the expected gradients the N content ranged from 40 at.% to 47 at.%.

Despite the differences in composition the surface appearance and roughness remained similar for all the points (1-5) (Figure 1).

The cell study showed surviving cells that adhered to the Si-N-Fe-C surface for all five points.

DISCUSSION & CONCLUSIONS: Co-sputtering yielded compositional gradients along the silicon wafer. The unexpected gradient of N-content – N was present as a gas - is likely due to the ability of Si to form nitrides as seen from the low enthalpy of formation for Si3N4 (-743 kJ/mol). The low surface roughness is likely a consequence of the smooth Si-wafer substrate, it is however reasonable to assume that a polished metal substrate would also yield low surface roughness. The adhesion of the cells indicates biocompatibility. In summary the low surface roughness combined with the biocompatibility make the coatings interesting for further investigations.

 

REFERENCES

1.  Pettersson, M. et al. (2016) Mater. Sci. Eng. C. Mater. Biol. Appl. 62, 497–505 .

2.  Pettersson, M. et al. (2013) J. Mech. Behav. Biomed. Mater. 25, 41–7.

 

ACKNOWLEDGEMENTS: The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under the LifeLongJoints Project, Grant Agreement no. GA-310477.

National Category
Medical Materials Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-367366 (URN)
Conference
11th annual meeting, Scandinavian Society for Biomaterials, Gullmarsstrand, 25-27 April, 2018
Funder
EU, FP7, Seventh Framework Programme, GA-310477
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2018-12-05
Skjöldebrand, C., Hulsart Billström, G., Engqvist, H. & Persson, C. (2018). Combinatorial coating development of Si-N-Fe-C coatings for joint implants. In: : . Paper presented at 29th Annual Congress of the European Society for Biomaterials, Masstricht, 11-13 April, 2018. Maastricht
Open this publication in new window or tab >>Combinatorial coating development of Si-N-Fe-C coatings for joint implants
2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

INTRODUCTION

Joint replacements of hip and knee are generally considered successful procedures, with a survival rate of approximately 95% after 10 years. However, the increasing, more active elderly population puts higher demands on implants, which need to last longer. Some of the main limiting factors for the longevity of these implants are the generation of wear debris and release of metal ions. These wear particles and ion release could be reduced with the use of ceramic coatings e.g. silicon nitride. Silicon nitride coatings have in laboratory investigations been shown to reduce the wear rate1 and act as a barrier for metal ions and therefore warrant further investigation for use in joint implants. An addition of the biocompatible elements Fe and C could be used to tune the dissolution rate and increase the deposition rate.

METHODS

Coatings were deposited on silicon wafer substrates using magnetron co-sputtering. The targets used were Si (99.99%purity) powered by a pulsed DC aggregate at 200 W, 200 kHz and 2µs. The two other targets C and Fe were powered by DC aggregates at 65 W and 25 W respectively. During deposition N2 was introduced as reactive gas. Elemental gradients were obtained by angling of the targets and the use of no rotation.

The coatings were investigated using elastic recoil detection analysis (ERDA), atomic force microscopy (AFM), scanning electron microscopy (SEM) and nanoindentation in five different points on the sample. The different points were chosen at coordinates (0,0), (0,40), (40,0), (40,40) and (20,20) based on a coordinate system with origin in the lower left corner.

The cytotoxicity of the coatings was evaluated in vitro with mouse osteoprogenitor cells (MC3T3).

RESULTS AND DISCUSSION

Figure 1: Si, Fe, N and C composition over the substrate.

Clear elemental gradients could be obtained with 26 wt.% < Si < 34 wt.%, 10 wt.% < Fe < 20 wt.%, 8 wt.% < C < 14 wt.% and 40 wt.% < N < 47 wt.% (figure 1). The coatings appeared dense in SEM surface analysis, with a smooth surface for all investigated points (Ra ~ 2 nm, AFM). The cross-sectional morphology was slightly columnar with broader columns for higher Fe content. The modulus (202 GPa < M < 221 GPa) correlated positively to the Si content and negatively to the Fe content while for the hardness (14 GPa < H < 18 GPa) no statistically significant correlations were found.  This can be compared to earlier coatings, only containing Si and N, which have showed a Young’s modulus of 170-240 GPa and a hardness of 12-26 GPa2, as well as the currently used metals such as CoCrMo, showing a Young’s modulus of 293 GPa and a hardness of 6 GPa2 .

The in vitro evaluation indicated biocompatibility with viable cells that adhered and spread across the surface.

CONCLUSIONS

Si-N-Fe-C coatings show promise for applications exposed to wear with their low surface roughness, high hardness, high modulus and biocompatibility. These combined merit further investigations into the suitability of Si-N-Fe-C coatings for joint implants.

REFERENCES

1.           Pettersson, M. et al. Mechanical and tribological behavior of silicon nitride and silicon carbon nitride coatings for total joint replacements. J. Mech. Behav. Biomed. Mater. 25, 41–7 (2013).

2.           Skjöldebrand, C. et al. Influence of substrate heating and nitrogen flow on the composition, morphological and mechanical properties of SiNx coatings aimed for joint replacements. Materials (Basel). 10, 1–11 (2017).

 

ACKNOWLEDGEMENTS

The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under the LifeLongJoints Project, Grant Agreement no. GA-310477.

Place, publisher, year, edition, pages
Maastricht: , 2018
National Category
Medical Materials Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-367364 (URN)
Conference
29th Annual Congress of the European Society for Biomaterials, Masstricht, 11-13 April, 2018
Funder
EU, FP7, Seventh Framework Programme, GA-310477
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2018-12-05
Procter, P., Pujari-Palmer, M., Hulsart Billström, G., Larsson, S., Insley, G. & Engqvist, H. (2018). Designing A Commercial Biomaterial For A Specific Unmet Clinical Need –: An Adhesive Odyssey. In: : . Paper presented at 26th EORS Annual Meeting 25th – 28th September 2018, Galway, Ireland.
Open this publication in new window or tab >>Designing A Commercial Biomaterial For A Specific Unmet Clinical Need –: An Adhesive Odyssey
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2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

There are clinical situations in fracture repair, e.g. osteochondral fragments, where current implant hardware is insufficient. The proposition of an adhesive enabling fixation and healing has been considered but no successful candidate has emerged thus far. The many preclinical and few clinical attempts include fibrin glue, mussel adhesive and even “Kryptonite” (US bone void filler). The most promising recent attempts are based on phosphorylating amino acids, part of a common cellular adhesion mechanism linking mussels, caddis fly larvae, and mammals. Rapid high bond strength development in the wetted fatty environment of fractured bone, that is sustained during biological healing, is challenging to prove both safety and efficacy. Additionally, there are no “predicate” preclinical animal and human models which led the authors to develop novel evaluations for an adhesive candidate “OsStictm” based on calcium salts and amino acids. Adhesive formulations were evaluated in both soft (6/12 weeks) and hard tissue (3,7,10,14 & 42 days) safety studies in murine models. The feasibility of a novel adhesiveness test, initially proven in murine cadaver femoral bone, is being assessed in-vivo (3,7,10,14 & 42 days) in bilateral implantations with a standard tissue glue as the control. In parallel an ex-vivo human bone model using freshly harvested human donor bone is under development to underwrite the eventual clinical application of such an adhesive. This is part of a risk mitigation project bridging between laboratory biomaterial characterisation and a commercial biomaterial development where safety and effectiveness have to meet today´s new medical device requirements.

Keywords
Tissue adhesive, biomaterial, calcium phosphate
National Category
Medical Materials Composite Science and Engineering Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-366369 (URN)
Conference
26th EORS Annual Meeting 25th – 28th September 2018, Galway, Ireland
Funder
Swedish Foundation for Strategic Research , RMA15-0110
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-03-06Bibliographically approved
Robo, C., Hulsart Billström, G., Nilsson, M. & Persson, C. (2018). In vivo response to a low-modulus PMMA bone cement in an ovine model. Acta Biomaterialia, 72, 362-370
Open this publication in new window or tab >>In vivo response to a low-modulus PMMA bone cement in an ovine model
2018 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 72, p. 362-370Article in journal (Refereed) Published
Abstract [en]

Poly(methyl methacrylate) (PMMA) is the most commonly used material for the treatment of osteoporosis-induced vertebral compression fractures. However, its high stiffness may introduce an increased risk of adjacent vertebral fractures post-surgery. One alternative in overcoming this concern is the use of additives. This presents its own challenge in maintaining an adequate biocompatibility when modifying the base cement. The aim of this study was to evaluate the in vivobiocompatibility of linoleic acid (LA)-modified acrylic bone cement using a large animal model for the first time, in order to further advance towards clinical use. A worst-case approach was used, choosing a slow-setting base cement. The in vitro monomer release from the cements was also assessed. Additional material characterization, including mechanical tests, are summarized in Appendix A. Unmodified and LA-modified cements were injected into a total of 56 bone defects created in the femur and humerus of sheep. Histopathologic and histomorphometric analysis indicated that LA-modified cement showed a harmless tissue response similar to that of the unmodified cement. Adjacent bone remodeling was observed microscopically 4 weeks after implantation, suggesting a normal healing process of the bone tissues surrounding the implant. LA-modified cement exhibited lower mechanical properties, with a reduction in the elastic modulus of up to 65%. The handling properties were slightly modified without negatively affecting the injectability of the base cement. LA-modified bone cement showed good biocompatibility as well as bone compliant mechanical properties and may therefore be a promising material for the treatment of osteoporotic vertebral fractures. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Poly (methyl methacrylate), bone cement, low-modulus, In vivo, linoleic acid
National Category
Other Materials Engineering Medical Materials Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-349033 (URN)10.1016/j.actbio.2018.03.014 (DOI)000432766900031 ()29559365 (PubMedID)
Funder
VINNOVA, 2010-02073
Available from: 2018-04-20 Created: 2018-04-20 Last updated: 2018-12-05
Hulsart Billström, G., Selvaraju, R., Estrada, S., Lubberink, M., Asplund, V., Bergman, K., . . . Antoni, G. (2018). Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept. Journal of Controlled Release, 285, 178-186
Open this publication in new window or tab >>Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

Keywords
Bone morphogenetic protein 2, Bone tissue engineering, Hydrogel, Micro computed tomography, Positron emission tomography, Single-photon emission computed tomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356465 (URN)10.1016/j.jconrel.2018.07.012 (DOI)000441737400015 ()30005906 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 262948
Note

G. Hulsart-Billström and R. K. Selvaraju contributed equally to this work and should be regarded as joint first authors.

Available from: 2018-07-28 Created: 2018-07-28 Last updated: 2018-10-10Bibliographically approved
Yan, H., Casalini, T., Hulsart Billström, G., Wang, S., Oommen, O. P., Salvalaglio, M., . . . Varghese, O. P. (2018). Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation. Biomaterials, 161, 190-202
Open this publication in new window or tab >>Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation
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2018 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 161, p. 190-202Article in journal (Refereed) Published
Abstract [en]

Synthetic scaffolds that possess an intrinsic capability to protect and sequester sensitive growth factors is a primary requisite for developing successful tissue engineering strategies. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) is highly susceptible to premature degradation and to provide a meaningful clinical outcome require high doses that can cause serious side effects. We discovered a unique strategy to stabilize and sequester rhBMP-2 by enhancing its molecular interactions with hyaluronic acid (HA), an extracellular matrix (ECM) component. We found that by tuning the initial protonation state of carboxylic acid residues of HA in a covalently crosslinked hydrogel modulate BMP-2 release at physiological pH by minimizing the electrostatic repulsion and maximizing the Van der Waals interactions. At neutral pH, BMP-2 release is primarily governed by Fickian diffusion, whereas at acidic pH both diffusion and electrostatic interactions between HA and BMP-2 become important as confirmed by molecular dynamics simulations. Our results were also validated in an in vivo rat ectopic model with rhBMP-2 loaded hydrogels, which demonstrated superior bone formation with acidic hydrogel as compared to the neutral counterpart. We believe this study provides new insight on growth factor stabilization and highlights the therapeutic potential of engineered matrices for rhBMP-2 delivery and may help to curtail the adverse side effects associated with the high dose of the growth factor.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-343820 (URN)10.1016/j.biomaterials.2018.01.041 (DOI)000427100300017 ()29421555 (PubMedID)
Funder
Swedish Foundation for Strategic Research , 139400126, 139400127EU, FP7, Seventh Framework Programme, NMP3-LA-2011-262948
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-03-01 Created: 2018-03-01 Last updated: 2018-05-16Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-2422-831x

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