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Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation : In-vitro and in-vivo carrier properties

Raina, Deepak Bushan LU ; Larsson, David LU ; Mrkonjic, Filip; Isaksson, Hanna LU ; Kumar, Ashok LU ; Lidgren, Lars LU and Tägil, Magnus LU (2018) In Journal of Controlled Release 272. p.83-96
Abstract

In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold + rhBMP-2 when compared to an approved absorbable collagen sponge (ACS) + rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2 + ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses.... (More)

In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold + rhBMP-2 when compared to an approved absorbable collagen sponge (ACS) + rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2 + ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses. The presence of tartrate resistant acid phosphatase staining in the rhBMP-2 group indicates osteoclastic resorption, which could be stalled by adding ZA, which by speculation could explain the net increase in mineralization. The new scaffold allowed for slow release of rhBMP-2 in-vitro (3.3 ± 0.1%) after 4 weeks. Using single photon emission computed tomography (SPECT), the release kinetics of 125I–rhBMP-2 in-vivo was followed for 4 weeks and a total of 65.3 ± 15.2% 125I–rhBMP-2 was released from the scaffolds. In-vitro 14C–ZA release curve shows an initial burst release on day 1 (8.8 ± 0.7%) followed by a slow release during the following 4 weeks (13 ± 0.1%). In-vivo, an initial release of 43.2 ± 7.6% of 14C–ZA was detected after 1 day, after which the scaffold retained the remaining ZA during 4-weeks. Taken together, our results show that the developed biomaterial is an efficient carrier for spatio-temporal delivery of rhBMP-2 and ZA leading to increased bone formation compared to commercially available carrier for rhBMP-2.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bone morphogenic protein (BMP), Cryogels, Gelatin, Hydroxyapatite, In-vivo BMP release, In-vivo ZA release, Zoledronic acid (ZA)
in
Journal of Controlled Release
volume
272
pages
14 pages
publisher
Elsevier
external identifiers
  • scopus:85040315693
ISSN
0168-3659
DOI
10.1016/j.jconrel.2018.01.006
language
English
LU publication?
yes
id
be1306b9-dc13-4ed6-a7ab-e01a4adac0e2
date added to LUP
2018-01-22 09:12:42
date last changed
2018-01-23 03:00:14
@article{be1306b9-dc13-4ed6-a7ab-e01a4adac0e2,
  abstract     = {<p>In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold + rhBMP-2 when compared to an approved absorbable collagen sponge (ACS) + rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2 + ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses. The presence of tartrate resistant acid phosphatase staining in the rhBMP-2 group indicates osteoclastic resorption, which could be stalled by adding ZA, which by speculation could explain the net increase in mineralization. The new scaffold allowed for slow release of rhBMP-2 in-vitro (3.3 ± 0.1%) after 4 weeks. Using single photon emission computed tomography (SPECT), the release kinetics of <sup>125</sup>I–rhBMP-2 in-vivo was followed for 4 weeks and a total of 65.3 ± 15.2% <sup>125</sup>I–rhBMP-2 was released from the scaffolds. In-vitro <sup>14</sup>C–ZA release curve shows an initial burst release on day 1 (8.8 ± 0.7%) followed by a slow release during the following 4 weeks (13 ± 0.1%). In-vivo, an initial release of 43.2 ± 7.6% of <sup>14</sup>C–ZA was detected after 1 day, after which the scaffold retained the remaining ZA during 4-weeks. Taken together, our results show that the developed biomaterial is an efficient carrier for spatio-temporal delivery of rhBMP-2 and ZA leading to increased bone formation compared to commercially available carrier for rhBMP-2.</p>},
  author       = {Raina, Deepak Bushan and Larsson, David and Mrkonjic, Filip and Isaksson, Hanna and Kumar, Ashok and Lidgren, Lars and Tägil, Magnus},
  issn         = {0168-3659},
  keyword      = {Bone morphogenic protein (BMP),Cryogels,Gelatin,Hydroxyapatite,In-vivo BMP release,In-vivo ZA release,Zoledronic acid (ZA)},
  language     = {eng},
  month        = {02},
  pages        = {83--96},
  publisher    = {Elsevier},
  series       = {Journal of Controlled Release},
  title        = {Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation : In-vitro and in-vivo carrier properties},
  url          = {http://dx.doi.org/10.1016/j.jconrel.2018.01.006},
  volume       = {272},
  year         = {2018},
}