Abstract

Using phantom samples, we investigated the feasibility of spatially-offset Raman spectroscopy (SORS) as a tool for monitoring non-invasively the mineralization of bone tissue engineering scaffold in-vivo. The phantom samples consisted of 3D-printed scaffolds of poly-caprolactone (PCL) and hydroxyapatite (HA) blends, with varying concentrations of HA, to mimic the mineralisation process. The scaffolds were covered by a 4 mm layer of skin to simulate the real in-vivo measurement conditions. At a concentration of HA approximately 1/3 that of bone (~0.6 g/cm3), the characteristic Raman band of HA (960 cm−1) was detectable when the PCL:HA layer was located at 4 mm depth within the scaffold (i.e. 8 mm below the skin surface). For the layers of the PCL:HA immediately under the skin (i.e. top of the scaffold), the detection limit of HA was 0.18 g/cm3, which is approximately one order of magnitude lower than that of bone. Similar results were also found for the phantoms simulating uniform and inward gradual mineralisation of the scaffold, indicating the suitability of SORS to detect early stages of mineralisation. Nevertheless, the results also show that the contribution of the materials surrounding the scaffold can be significant and methods for subtraction need to be investigated in the future. In conclusion, these results indicate that spatially-offset Raman spectroscopy is a promising technique for in-vivo longitudinal monitoring scaffold mineralization and bone re-growth.

Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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References

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2018 (2)

G. Caliaperoumal, M. Souyet, M. Bensidhoum, H. Petite, and F. Anagnostou, “Type 2 diabetes impairs angiogenesis and osteogenesis in calvarial defects: MicroCT study in ZDF rats,” Bone 112, 161–172 (2018).
[Crossref] [PubMed]

H. Markides, J. S. McLaren, N. D. Telling, N. Alom, E. A. Al-Mutheffer, R. O. C. Oreffo, A. Zannettino, B. E. Scammell, L. J. White, and A. J. El Haj, “Translation of remote control regenerative technologies for bone repair,” NPJ Regen. Med. 3(1), 9 (2018).
[Crossref] [PubMed]

2017 (2)

Z. Liao, F. Sinjab, A. Nommeots-Nomm, J. Jones, L. Ruiz-Cantu, J. Yang, F. Rose, and I. Notingher, “Feasibility of spatially offset raman spectroscopy for in vitro and in vivo monitoring mineralization of bone tissue engineering scaffolds,” Anal. Chem. 89(1), 847–853 (2017).
[Crossref] [PubMed]

D. Shipp, F. Sinjab, and I. Notingher, “Raman spectroscopy: Techniques and applications in the life sciences,” Adv. Opt. Photonics 9(2), 315–428 (2017).
[Crossref]

2016 (1)

2015 (1)

P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
[Crossref] [PubMed]

2014 (2)

J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
[Crossref] [PubMed]

K. Buckley, J. G. Kerns, A. W. Parker, A. E. Goodship, and P. Matousek, “Decomposition of in vivo spatially offset raman spectroscopy data using multivariate analysis techniques,” J. Raman Spectrosc. 45(2), 188–192 (2014).
[Crossref]

2013 (2)

S. Jo, S. M. Kang, S. A. Park, W. D. Kim, J. Kwak, and H. Lee, “Enhanced adhesion of preosteoblasts inside 3D PCL scaffolds by polydopamine coating and mineralization,” Macromol. Biosci. 13(10), 1389–1395 (2013).
[Crossref] [PubMed]

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[Crossref] [PubMed]

2011 (2)

R. Dimitriou, E. Jones, D. McGonagle, and P. V. Giannoudis, “Bone regeneration: current concepts and future directions,” BMC Med. 9(1), 66 (2011).
[Crossref] [PubMed]

J. D. Boerckel, Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. García, and R. E. Guldberg, “Effects of protein dose and delivery system on BMP-mediated bone regeneration,” Biomaterials 32(22), 5241–5251 (2011).
[Crossref] [PubMed]

2010 (5)

M. L. Bouxsein, S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller, “Guidelines for assessment of bone microstructure in rodents using micro-computed tomography,” J. Bone Miner. Res. 25(7), 1468–1486 (2010).
[Crossref] [PubMed]

P. I. Okagbare, F. W. Esmonde-White, S. A. Goldstein, and M. D. Morris, “Development of non-invasive Raman spectroscopy for in vivo evaluation of bone graft osseointegration in a rat model,” Analyst (Lond.) 135(12), 3142–3146 (2010).
[Crossref] [PubMed]

P. Niemeyer, K. Fechner, S. Milz, W. Richter, N. P. Suedkamp, A. T. Mehlhorn, S. Pearce, and P. Kasten, “Comparison of mesenchymal stem cells from bone marrow and adipose tissue for bone regeneration in a critical size defect of the sheep tibia and the influence of platelet-rich plasma,” Biomaterials 31(13), 3572–3579 (2010).
[Crossref] [PubMed]

S. Karmakar, J. Kay, and E. M. Gravallese, “Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention,” Rheum. Dis. Clin. North Am. 36(2), 385–404 (2010).
[Crossref] [PubMed]

O. Hartman, C. Zhang, E. L. Adams, M. C. Farach-Carson, N. J. Petrelli, B. D. Chase, and J. F. Rabolt, “Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model,” Biomaterials 31(21), 5700–5718 (2010).
[Crossref] [PubMed]

2009 (1)

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of basal cell carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[Crossref] [PubMed]

2008 (2)

L. C. Palmer, C. J. Newcomb, S. R. Kaltz, E. D. Spoerke, and S. I. Stupp, “Biomimetic systems for hydroxyapatite mineralization inspired by bone and enamel,” Chem. Rev. 108(11), 4754–4783 (2008).
[Crossref] [PubMed]

M. M. Stevens, “Biomaterials for bone tissue engineering,” Mater. Today 11(5), 18–25 (2008).
[Crossref]

2006 (2)

T. Diab, K. W. Condon, D. B. Burr, and D. Vashishth, “Age-related change in the damage morphology of human cortical bone and its role in bone fragility,” Bone 38(3), 427–431 (2006).
[Crossref] [PubMed]

P. Matousek, E. R. Draper, A. E. Goodship, I. P. Clark, K. L. Ronayne, and A. W. Parker, “Noninvasive Raman spectroscopy of human tissue in vivo,” Appl. Spectrosc. 60(7), 758–763 (2006).
[Crossref] [PubMed]

2005 (2)

2003 (2)

I. Notingher, J. Jones, S. Verrier, I. Bisson, P. Embanga, P. Edwards, J. M. Polak, and L. L. Hench, “P. EdwardAs, J. Polak, and L. Hench, “Application of ftir and raman spectroscopy to characterisation of bioactive materials and living cells,” J. Spectrosc. 17(2-3), 275–288 (2003).
[Crossref]

S. R. Stock, D. Blackburn, M. Gradassi, and H.-G. Simon, “Bone formation during forelimb regeneration: a microtomography (microCT) analysis,” Dev. Dyn. 226(2), 410–417 (2003).
[Crossref] [PubMed]

2002 (2)

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

I. Notingher, A. Boccaccini, J. Jones, V. Maquet, and L. Hench, “Application of raman microspectroscopy to the characterisation of bioactive materials,” Mater. Charact. 49(3), 255–260 (2002).
[Crossref]

2001 (1)

S. C. Rizzi, D. Heath, A. Coombes, N. Bock, M. Textor, and S. Downes, “Biodegradable polymer/hydroxyapatite composites: surface analysis and initial attachment of human osteoblasts,” J. Biomed. Mater. Res. 55, 475–486 (2001).

1998 (2)

J. Aerssens, S. Boonen, G. Lowet, and J. Dequeker, “Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research,” Endocrinology 139(2), 663–670 (1998).
[Crossref] [PubMed]

C. Bosch, B. Melsen, and K. Vargervik, “Importance of the critical-size bone defect in testing bone-regenerating materials,” J. Craniofac. Surg. 9(4), 310–316 (1998).
[Crossref] [PubMed]

Adams, E. L.

O. Hartman, C. Zhang, E. L. Adams, M. C. Farach-Carson, N. J. Petrelli, B. D. Chase, and J. F. Rabolt, “Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model,” Biomaterials 31(21), 5700–5718 (2010).
[Crossref] [PubMed]

Aerssens, J.

J. Aerssens, S. Boonen, G. Lowet, and J. Dequeker, “Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research,” Endocrinology 139(2), 663–670 (1998).
[Crossref] [PubMed]

Al-Mutheffer, E. A.

H. Markides, J. S. McLaren, N. D. Telling, N. Alom, E. A. Al-Mutheffer, R. O. C. Oreffo, A. Zannettino, B. E. Scammell, L. J. White, and A. J. El Haj, “Translation of remote control regenerative technologies for bone repair,” NPJ Regen. Med. 3(1), 9 (2018).
[Crossref] [PubMed]

Alom, N.

H. Markides, J. S. McLaren, N. D. Telling, N. Alom, E. A. Al-Mutheffer, R. O. C. Oreffo, A. Zannettino, B. E. Scammell, L. J. White, and A. J. El Haj, “Translation of remote control regenerative technologies for bone repair,” NPJ Regen. Med. 3(1), 9 (2018).
[Crossref] [PubMed]

Amit, Y.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Anagnostou, F.

G. Caliaperoumal, M. Souyet, M. Bensidhoum, H. Petite, and F. Anagnostou, “Type 2 diabetes impairs angiogenesis and osteogenesis in calvarial defects: MicroCT study in ZDF rats,” Bone 112, 161–172 (2018).
[Crossref] [PubMed]

Arbel, R.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Aro, H.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
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P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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Atar, D.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Bayston, R.

J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
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Béhé, M.

P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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G. Caliaperoumal, M. Souyet, M. Bensidhoum, H. Petite, and F. Anagnostou, “Type 2 diabetes impairs angiogenesis and osteogenesis in calvarial defects: MicroCT study in ZDF rats,” Bone 112, 161–172 (2018).
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S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
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Boerckel, J. D.

J. D. Boerckel, Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. García, and R. E. Guldberg, “Effects of protein dose and delivery system on BMP-mediated bone regeneration,” Biomaterials 32(22), 5241–5251 (2011).
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Boonen, S.

J. Aerssens, S. Boonen, G. Lowet, and J. Dequeker, “Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research,” Endocrinology 139(2), 663–670 (1998).
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S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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M. L. Bouxsein, S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller, “Guidelines for assessment of bone microstructure in rodents using micro-computed tomography,” J. Bone Miner. Res. 25(7), 1468–1486 (2010).
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Burr, D. B.

T. Diab, K. W. Condon, D. B. Burr, and D. Vashishth, “Age-related change in the damage morphology of human cortical bone and its role in bone fragility,” Bone 38(3), 427–431 (2006).
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Caliaperoumal, G.

G. Caliaperoumal, M. Souyet, M. Bensidhoum, H. Petite, and F. Anagnostou, “Type 2 diabetes impairs angiogenesis and osteogenesis in calvarial defects: MicroCT study in ZDF rats,” Bone 112, 161–172 (2018).
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Chase, B. D.

O. Hartman, C. Zhang, E. L. Adams, M. C. Farach-Carson, N. J. Petrelli, B. D. Chase, and J. F. Rabolt, “Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model,” Biomaterials 31(21), 5700–5718 (2010).
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Chiron, P.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Choong, P.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Christiansen, B. A.

M. L. Bouxsein, S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller, “Guidelines for assessment of bone microstructure in rodents using micro-computed tomography,” J. Bone Miner. Res. 25(7), 1468–1486 (2010).
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Cinats, J.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Cinelli, P.

P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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Clark, I. P.

Condon, K. W.

T. Diab, K. W. Condon, D. B. Burr, and D. Vashishth, “Age-related change in the damage morphology of human cortical bone and its role in bone fragility,” Bone 38(3), 427–431 (2006).
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Coombes, A.

S. C. Rizzi, D. Heath, A. Coombes, N. Bock, M. Textor, and S. Downes, “Biodegradable polymer/hydroxyapatite composites: surface analysis and initial attachment of human osteoblasts,” J. Biomed. Mater. Res. 55, 475–486 (2001).

Courtenay, B.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Cox, H. C.

J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
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Csimma, C.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Daneel, P. J.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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J. Aerssens, S. Boonen, G. Lowet, and J. Dequeker, “Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research,” Endocrinology 139(2), 663–670 (1998).
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G. Penel, C. Delfosse, M. Descamps, and G. Leroy, “Composition of bone and apatitic biomaterials as revealed by intravital Raman microspectroscopy,” Bone 36(5), 893–901 (2005).
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Diab, T.

T. Diab, K. W. Condon, D. B. Burr, and D. Vashishth, “Age-related change in the damage morphology of human cortical bone and its role in bone fragility,” Bone 38(3), 427–431 (2006).
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Draper, E. R.

Dupont, K. M.

J. D. Boerckel, Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. García, and R. E. Guldberg, “Effects of protein dose and delivery system on BMP-mediated bone regeneration,” Biomaterials 32(22), 5241–5251 (2011).
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Edwards, P.

I. Notingher, J. Jones, S. Verrier, I. Bisson, P. Embanga, P. Edwards, J. M. Polak, and L. L. Hench, “P. EdwardAs, J. Polak, and L. Hench, “Application of ftir and raman spectroscopy to characterisation of bioactive materials and living cells,” J. Spectrosc. 17(2-3), 275–288 (2003).
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P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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H. Markides, J. S. McLaren, N. D. Telling, N. Alom, E. A. Al-Mutheffer, R. O. C. Oreffo, A. Zannettino, B. E. Scammell, L. J. White, and A. J. El Haj, “Translation of remote control regenerative technologies for bone repair,” NPJ Regen. Med. 3(1), 9 (2018).
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Esmonde-White, F. W.

P. I. Okagbare, F. W. Esmonde-White, S. A. Goldstein, and M. D. Morris, “Development of non-invasive Raman spectroscopy for in vivo evaluation of bone graft osseointegration in a rat model,” Analyst (Lond.) 135(12), 3142–3146 (2010).
[Crossref] [PubMed]

Everall, N.

Farach-Carson, M. C.

O. Hartman, C. Zhang, E. L. Adams, M. C. Farach-Carson, N. J. Petrelli, B. D. Chase, and J. F. Rabolt, “Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model,” Biomaterials 31(21), 5700–5718 (2010).
[Crossref] [PubMed]

Fechner, K.

P. Niemeyer, K. Fechner, S. Milz, W. Richter, N. P. Suedkamp, A. T. Mehlhorn, S. Pearce, and P. Kasten, “Comparison of mesenchymal stem cells from bone marrow and adipose tissue for bone regeneration in a critical size defect of the sheep tibia and the influence of platelet-rich plasma,” Biomaterials 31(13), 3572–3579 (2010).
[Crossref] [PubMed]

Feibel, R.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Finney, W. F.

García, A. J.

J. D. Boerckel, Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. García, and R. E. Guldberg, “Effects of protein dose and delivery system on BMP-mediated bone regeneration,” Biomaterials 32(22), 5241–5251 (2011).
[Crossref] [PubMed]

Gekle, C.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Genant, H. K.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Geulette, B.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Ghita, A.

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of basal cell carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
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Giannoudis, P. V.

R. Dimitriou, E. Jones, D. McGonagle, and P. V. Giannoudis, “Bone regeneration: current concepts and future directions,” BMC Med. 9(1), 66 (2011).
[Crossref] [PubMed]

Gibson, G.

Goldstein, S. A.

P. I. Okagbare, F. W. Esmonde-White, S. A. Goldstein, and M. D. Morris, “Development of non-invasive Raman spectroscopy for in vivo evaluation of bone graft osseointegration in a rat model,” Analyst (Lond.) 135(12), 3142–3146 (2010).
[Crossref] [PubMed]

Goodship, A. E.

J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
[Crossref] [PubMed]

K. Buckley, J. G. Kerns, A. W. Parker, A. E. Goodship, and P. Matousek, “Decomposition of in vivo spatially offset raman spectroscopy data using multivariate analysis techniques,” J. Raman Spectrosc. 45(2), 188–192 (2014).
[Crossref]

P. Matousek, E. R. Draper, A. E. Goodship, I. P. Clark, K. L. Ronayne, and A. W. Parker, “Noninvasive Raman spectroscopy of human tissue in vivo,” Appl. Spectrosc. 60(7), 758–763 (2006).
[Crossref] [PubMed]

P. Matousek, I. P. Clark, E. R. Draper, M. D. Morris, A. E. Goodship, N. Everall, M. Towrie, W. F. Finney, and A. W. Parker, “Subsurface probing in diffusely scattering media using spatially offset Raman spectroscopy,” Appl. Spectrosc. 59(4), 393–400 (2005).
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Govender, S.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Gradassi, M.

S. R. Stock, D. Blackburn, M. Gradassi, and H.-G. Simon, “Bone formation during forelimb regeneration: a microtomography (microCT) analysis,” Dev. Dyn. 226(2), 410–417 (2003).
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Gravallese, E. M.

S. Karmakar, J. Kay, and E. M. Gravallese, “Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention,” Rheum. Dis. Clin. North Am. 36(2), 385–404 (2010).
[Crossref] [PubMed]

Gravel, C.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Guldberg, R. E.

J. D. Boerckel, Y. M. Kolambkar, K. M. Dupont, B. A. Uhrig, E. A. Phelps, H. Y. Stevens, A. J. García, and R. E. Guldberg, “Effects of protein dose and delivery system on BMP-mediated bone regeneration,” Biomaterials 32(22), 5241–5251 (2011).
[Crossref] [PubMed]

M. L. Bouxsein, S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller, “Guidelines for assessment of bone microstructure in rodents using micro-computed tomography,” J. Bone Miner. Res. 25(7), 1468–1486 (2010).
[Crossref] [PubMed]

Haas, N.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Hammacher, E.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Hardy, P.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Hartman, O.

O. Hartman, C. Zhang, E. L. Adams, M. C. Farach-Carson, N. J. Petrelli, B. D. Chase, and J. F. Rabolt, “Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model,” Biomaterials 31(21), 5700–5718 (2010).
[Crossref] [PubMed]

Heath, D.

S. C. Rizzi, D. Heath, A. Coombes, N. Bock, M. Textor, and S. Downes, “Biodegradable polymer/hydroxyapatite composites: surface analysis and initial attachment of human osteoblasts,” J. Biomed. Mater. Res. 55, 475–486 (2001).

Hench, L.

I. Notingher, A. Boccaccini, J. Jones, V. Maquet, and L. Hench, “Application of raman microspectroscopy to the characterisation of bioactive materials,” Mater. Charact. 49(3), 255–260 (2002).
[Crossref]

Hench, L. L.

I. Notingher, J. Jones, S. Verrier, I. Bisson, P. Embanga, P. Edwards, J. M. Polak, and L. L. Hench, “P. EdwardAs, J. Polak, and L. Hench, “Application of ftir and raman spectroscopy to characterisation of bioactive materials and living cells,” J. Spectrosc. 17(2-3), 275–288 (2003).
[Crossref]

Holt, M.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
[Crossref] [PubMed]

Jepsen, K. J.

M. L. Bouxsein, S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller, “Guidelines for assessment of bone microstructure in rodents using micro-computed tomography,” J. Bone Miner. Res. 25(7), 1468–1486 (2010).
[Crossref] [PubMed]

Jo, S.

S. Jo, S. M. Kang, S. A. Park, W. D. Kim, J. Kwak, and H. Lee, “Enhanced adhesion of preosteoblasts inside 3D PCL scaffolds by polydopamine coating and mineralization,” Macromol. Biosci. 13(10), 1389–1395 (2013).
[Crossref] [PubMed]

Jones, E.

R. Dimitriou, E. Jones, D. McGonagle, and P. V. Giannoudis, “Bone regeneration: current concepts and future directions,” BMC Med. 9(1), 66 (2011).
[Crossref] [PubMed]

Jones, J.

Z. Liao, F. Sinjab, A. Nommeots-Nomm, J. Jones, L. Ruiz-Cantu, J. Yang, F. Rose, and I. Notingher, “Feasibility of spatially offset raman spectroscopy for in vitro and in vivo monitoring mineralization of bone tissue engineering scaffolds,” Anal. Chem. 89(1), 847–853 (2017).
[Crossref] [PubMed]

I. Notingher, J. Jones, S. Verrier, I. Bisson, P. Embanga, P. Edwards, J. M. Polak, and L. L. Hench, “P. EdwardAs, J. Polak, and L. Hench, “Application of ftir and raman spectroscopy to characterisation of bioactive materials and living cells,” J. Spectrosc. 17(2-3), 275–288 (2003).
[Crossref]

I. Notingher, A. Boccaccini, J. Jones, V. Maquet, and L. Hench, “Application of raman microspectroscopy to the characterisation of bioactive materials,” Mater. Charact. 49(3), 255–260 (2002).
[Crossref]

Josten, C.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Kaltz, S. R.

L. C. Palmer, C. J. Newcomb, S. R. Kaltz, E. D. Spoerke, and S. I. Stupp, “Biomimetic systems for hydroxyapatite mineralization inspired by bone and enamel,” Chem. Rev. 108(11), 4754–4783 (2008).
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Kang, S. M.

S. Jo, S. M. Kang, S. A. Park, W. D. Kim, J. Kwak, and H. Lee, “Enhanced adhesion of preosteoblasts inside 3D PCL scaffolds by polydopamine coating and mineralization,” Macromol. Biosci. 13(10), 1389–1395 (2013).
[Crossref] [PubMed]

Karmakar, S.

S. Karmakar, J. Kay, and E. M. Gravallese, “Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention,” Rheum. Dis. Clin. North Am. 36(2), 385–404 (2010).
[Crossref] [PubMed]

Kasten, P.

P. Niemeyer, K. Fechner, S. Milz, W. Richter, N. P. Suedkamp, A. T. Mehlhorn, S. Pearce, and P. Kasten, “Comparison of mesenchymal stem cells from bone marrow and adipose tissue for bone regeneration in a critical size defect of the sheep tibia and the influence of platelet-rich plasma,” Biomaterials 31(13), 3572–3579 (2010).
[Crossref] [PubMed]

Kay, J.

S. Karmakar, J. Kay, and E. M. Gravallese, “Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention,” Rheum. Dis. Clin. North Am. 36(2), 385–404 (2010).
[Crossref] [PubMed]

Kerns, J. G.

K. Buckley, J. G. Kerns, A. W. Parker, A. E. Goodship, and P. Matousek, “Decomposition of in vivo spatially offset raman spectroscopy data using multivariate analysis techniques,” J. Raman Spectrosc. 45(2), 188–192 (2014).
[Crossref]

Ketterl, R. L.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
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M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of basal cell carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
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J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
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Raschke, M.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Reynders, P.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Richter, W.

P. Niemeyer, K. Fechner, S. Milz, W. Richter, N. P. Suedkamp, A. T. Mehlhorn, S. Pearce, and P. Kasten, “Comparison of mesenchymal stem cells from bone marrow and adipose tissue for bone regeneration in a critical size defect of the sheep tibia and the influence of platelet-rich plasma,” Biomaterials 31(13), 3572–3579 (2010).
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Rommens, P. M.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Ronayne, K. L.

Rondia, J.

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Rose, F.

Z. Liao, F. Sinjab, A. Nommeots-Nomm, J. Jones, L. Ruiz-Cantu, J. Yang, F. Rose, and I. Notingher, “Feasibility of spatially offset raman spectroscopy for in vitro and in vivo monitoring mineralization of bone tissue engineering scaffolds,” Anal. Chem. 89(1), 847–853 (2017).
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Rossouw, W. C.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Rowlands, C. J.

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
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Ruff, S.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Ruiz-Cantu, L.

Z. Liao, F. Sinjab, A. Nommeots-Nomm, J. Jones, L. Ruiz-Cantu, J. Yang, F. Rose, and I. Notingher, “Feasibility of spatially offset raman spectroscopy for in vitro and in vivo monitoring mineralization of bone tissue engineering scaffolds,” Anal. Chem. 89(1), 847–853 (2017).
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Rüter, A.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Santavirta, S.

S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Börner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. van der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Rüter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, T. Wisniewski, and BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group, “Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients,” J. Bone Joint Surg. Am. 84(12), 2123–2134 (2002).
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Scammell, B. E.

H. Markides, J. S. McLaren, N. D. Telling, N. Alom, E. A. Al-Mutheffer, R. O. C. Oreffo, A. Zannettino, B. E. Scammell, L. J. White, and A. J. El Haj, “Translation of remote control regenerative technologies for bone repair,” NPJ Regen. Med. 3(1), 9 (2018).
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J. S. McLaren, L. J. White, H. C. Cox, W. Ashraf, C. V. Rahman, G. W. Blunn, A. E. Goodship, R. A. Quirk, K. M. Shakesheff, R. Bayston, and B. E. Scammell, “A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model,” Eur. Cell. Mater. 27, 332–349 (2014).
[Crossref] [PubMed]

Schibli, R.

P. S. Lienemann, S. Metzger, A.-S. Kiveliö, A. Blanc, P. Papageorgiou, A. Astolfo, B. R. Pinzer, P. Cinelli, F. E. Weber, R. Schibli, M. Béhé, and M. Ehrbar, “Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering,” Sci. Rep. 5(1), 10238 (2015).
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Schildhauer, T. A.

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Wentzensen, A.

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Williams, H.

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Figures (7)

Fig. 1
Fig. 1 Representative images of the 3D printed PCL:HA scaffolds used in this study. a) μCT 3D reconstruction image of a PCL:HA 1:4 scaffold (1 x 1 x 0.5 cm3), porosity = 64.7%; b) Images from dissecting microscope of a PCL:HA (1:4) scaffold (1 x 1 x 1 cm3). c) Scanning electron microscopy of a PCL:HA scaffold with 1:2 blend ratio.
Fig. 2
Fig. 2 a) Diagram of the head of a femur with a critical defect drilled into it with the position of the scaffold shown. b) Close up of the defect filled with a PCL scaffold. c) A schematic of a defect in the same orientation as the phantom for comparison. d) A schematic of the phantom used in this study, designed to mimic a critical defect. e) Raman spectra of the materials that make up the phantom (spectra normalized between 0 and 1 and shifted vertically for clarity).
Fig. 3
Fig. 3 a) Schematic of the phantom with a single 2 mm thick PCL:HA scaffold layer at 0, 4 and 8 mm depth. b) SORS spectra for 4:1 PCL:HA ratio scaffolds at 0, 4, and 8mm depths. c) SORS spectra for 1:4 PCL:HA. The blue lines are the spectra of the phantoms containing the blended PCL:HA layers; the red line are for PCL only scaffolds (control). The black lines present the difference spectra blue minus red lines in the 830-1000 cm−1 region (2x magnified).
Fig. 4
Fig. 4 The ratio between the intensity of the 960 cm−1 band in the difference spectra and the 1445 cm−1 band in the spectra of the PCL:HA samples. Error bars represent the standard error of the mean for 18 repeat measurements.
Fig. 5
Fig. 5 a) A schematic of the phantoms used for the uniform mineralization model. b) SORS spectra of the phantoms mimicking the uniform mineralisation model. Blue lines: SORS spectra of PCL:HA scaffolds, Red lines: SORS spectra of the PCL-only scaffold in the phantom; Black line the difference between the blue and red lines in the 830-1000 cm−1 range.
Fig. 6
Fig. 6 a) A schematic of the phantoms used for the gradual inward mineralization model. The 7 stages are shown with the shade of the layers of the phantom indicating the concentration of HA in the PCL/HA scaffold with a key of the colors used. c) SORS spectra for the graduated mineralisation model. The blue line is read with the blended material and the red line is the PCL only scaffold in the phantom. The black line is the difference between the two.
Fig. 7
Fig. 7 Analysis of the SORS spectra for the gradual inward mineralization model. The ratio between the intensity of the 960 cm−1 band in the difference spectra (PCL:HA minus PCL-only scaffolds) and the 1445cm−1 band in the spectra of the sample containing HA. Each stage from 1 to 7 represents an increase in HA concentration. Error bars represent the standard error of the mean for 18 repeat measurements.

Tables (1)

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Table 1 Scaffold and bone samples used in this study

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