Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions

Enrique Gómez-Barrena; Norma Padilla-Eguiluz; Philippe Rosset; Florian Gebhard; Philippe Hernigou; Nicola Baldini; Helène Rouard; Luc Sensebé; Rosa-María Gonzalo-Daganzo; Rosaria Giordano; Eduardo García-Rey; José Cordero-Ampuero; Juan Carlos Rubio-Suárez; Marta Dominguez García-Simón; Julien Stanovici; Christian Ehrnthaller; Markus Huber-Lang; Charles Henri Flouzat-Lachaniette; Nathalie Chevallier; Davide Maria Donati; Benedetta Spazzoli; Gabriela Ciapetti; Sandrine Fleury; Manuel-Nicolás Fernandez; José-Rafael Cabrera; Cristina Avendaño-Solá; Tiziana Montemurro; Carmen Panaitescu; Elena Veronesi; Markus Thomas Rojewski; Ramin Lotfi; Massimo Dominici; Hubert Schrezenmeier; Pierre Layrolle

doi:10.1016/j.injury.2020.02.070

Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions

Enrique Gómez-Barrena, Norma Padilla-Eguiluz, Philippe Rosset, Florian Gebhard, Philippe Hernigou, Nicola Baldini, Helène Rouard, Luc Sensebé, Rosa-María Gonzalo-Daganzo, Rosaria Giordano, Eduardo García-Rey, José Cordero-Ampuero, Juan Carlos Rubio-Suárez, Marta Dominguez García-Simón, Julien Stanovici, Christian Ehrnthaller, Markus Huber-Lang, Charles Henri Flouzat-Lachaniette, Nathalie Chevallier, Davide Maria DonatiBenedetta Spazzoli, Gabriela Ciapetti, Sandrine Fleury, Manuel-Nicolás Fernandez, José-Rafael Cabrera, Cristina Avendaño-Solá, Tiziana Montemurro, Carmen Panaitescu, Elena Veronesi, Markus Thomas Rojewski, Ramin Lotfi, Massimo Dominici, Hubert Schrezenmeier, Pierre Layrolle

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture.

PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni).

RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation.

CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.

Original language	English
Pages (from-to)	S.63-S.73
Number of pages	11
Journal	Injury
Volume	51
Issue number	suppl.1
Early online date	Feb 26 2020
DOIs	https://doi.org/10.1016/j.injury.2020.02.070
Publication status	Published - Apr 2020

Keywords

Bioceramics
Clinical Consolidation
Efficacy
Long Bone
MSC
Non-union
Radiological Consolidation
Treatment

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10.1016/j.injury.2020.02.070

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Gómez-Barrena, E., Padilla-Eguiluz, N., Rosset, P., Gebhard, F., Hernigou, P., Baldini, N., Rouard, H., Sensebé, L., Gonzalo-Daganzo, R-M., Giordano, R., García-Rey, E., Cordero-Ampuero, J., Rubio-Suárez, J. C., García-Simón, M. D., Stanovici, J., Ehrnthaller, C., Huber-Lang, M., Flouzat-Lachaniette, C. H., Chevallier, N., ... Layrolle, P. (2020). Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions. Injury, 51(suppl.1), S.63-S.73. https://doi.org/10.1016/j.injury.2020.02.070

Gómez-Barrena, E, Padilla-Eguiluz, N, Rosset, P, Gebhard, F, Hernigou, P, Baldini, N, Rouard, H, Sensebé, L, Gonzalo-Daganzo, R-M, Giordano, R, García-Rey, E, Cordero-Ampuero, J, Rubio-Suárez, JC, García-Simón, MD, Stanovici, J, Ehrnthaller, C, Huber-Lang, M, Flouzat-Lachaniette, CH, Chevallier, N, Donati, DM, Spazzoli, B, Ciapetti, G, Fleury, S, Fernandez, M-N, Cabrera, J-R, Avendaño-Solá, C, Montemurro, T, Panaitescu, C, Veronesi, E, Rojewski, MT, Lotfi, R, Dominici, M, Schrezenmeier, H & Layrolle, P 2020, 'Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions', Injury, vol. 51, no. suppl.1, pp. S.63-S.73. https://doi.org/10.1016/j.injury.2020.02.070

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abstract = "BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture.PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni).RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation.CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.",

keywords = "Bioceramics, Clinical Consolidation, Efficacy, Long Bone, MSC, Non-union, Radiological Consolidation, Treatment",

author = "Enrique G{\'o}mez-Barrena and Norma Padilla-Eguiluz and Philippe Rosset and Florian Gebhard and Philippe Hernigou and Nicola Baldini and Hel{\`e}ne Rouard and Luc Senseb{\'e} and Rosa-Mar{\'i}a Gonzalo-Daganzo and Rosaria Giordano and Eduardo Garc{\'i}a-Rey and Jos{\'e} Cordero-Ampuero and Rubio-Su{\'a}rez, {Juan Carlos} and Garc{\'i}a-Sim{\'o}n, {Marta Dominguez} and Julien Stanovici and Christian Ehrnthaller and Markus Huber-Lang and Flouzat-Lachaniette, {Charles Henri} and Nathalie Chevallier and Donati, {Davide Maria} and Benedetta Spazzoli and Gabriela Ciapetti and Sandrine Fleury and Manuel-Nicol{\'a}s Fernandez and Jos{\'e}-Rafael Cabrera and Cristina Avenda{\~n}o-Sol{\'a} and Tiziana Montemurro and Carmen Panaitescu and Elena Veronesi and Rojewski, {Markus Thomas} and Ramin Lotfi and Massimo Dominici and Hubert Schrezenmeier and Pierre Layrolle",

note = "Copyright {\textcopyright} 2020. Published by Elsevier Ltd.",

year = "2020",

month = apr,

doi = "10.1016/j.injury.2020.02.070",

language = "English",

volume = "51",

pages = "S.63--S.73",

journal = "Injury",

issn = "0020-1383",

publisher = "Elsevier Limited",

number = "suppl.1",

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TY - JOUR

T1 - Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions

AU - Gómez-Barrena, Enrique

AU - Padilla-Eguiluz, Norma

AU - Rosset, Philippe

AU - Gebhard, Florian

AU - Hernigou, Philippe

AU - Baldini, Nicola

AU - Rouard, Helène

AU - Sensebé, Luc

AU - Gonzalo-Daganzo, Rosa-María

AU - Giordano, Rosaria

AU - García-Rey, Eduardo

AU - Cordero-Ampuero, José

AU - Rubio-Suárez, Juan Carlos

AU - García-Simón, Marta Dominguez

AU - Stanovici, Julien

AU - Ehrnthaller, Christian

AU - Huber-Lang, Markus

AU - Flouzat-Lachaniette, Charles Henri

AU - Chevallier, Nathalie

AU - Donati, Davide Maria

AU - Spazzoli, Benedetta

AU - Ciapetti, Gabriela

AU - Fleury, Sandrine

AU - Fernandez, Manuel-Nicolás

AU - Cabrera, José-Rafael

AU - Avendaño-Solá, Cristina

AU - Montemurro, Tiziana

AU - Panaitescu, Carmen

AU - Veronesi, Elena

AU - Rojewski, Markus Thomas

AU - Lotfi, Ramin

AU - Dominici, Massimo

AU - Schrezenmeier, Hubert

AU - Layrolle, Pierre

PY - 2020/4

Y1 - 2020/4

N2 - BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture.PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni).RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation.CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.

AB - BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture.PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni).RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation.CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.

KW - Bioceramics

KW - Clinical Consolidation

KW - Efficacy

KW - Long Bone

KW - MSC

KW - Non-union

KW - Radiological Consolidation

KW - Treatment

U2 - 10.1016/j.injury.2020.02.070

DO - 10.1016/j.injury.2020.02.070

M3 - Article

C2 - 32139130

VL - 51

SP - S.63-S.73

JO - Injury

JF - Injury

SN - 0020-1383

IS - suppl.1

ER -

Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions

Abstract

Keywords

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