Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

Enrique Gómez-Barrena; Philippe Rosset; Florian Gebhard; Philippe Hernigou; Nicola Baldini; Helène Rouard; Luc Sensebé; Rosa M Gonzalo-Daganzo; Rosaria Giordano; Norma Padilla-Eguiluz; Eduardo García-Rey; José Cordero-Ampuero; Juan Carlos Rubio-Suárez; Julien Stanovici; Christian Ehrnthaller; Markus Huber-Lang; Charles Henri Flouzat-Lachaniette; Nathalie Chevallier; Davide Maria Donati; 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.biomaterials.2018.03.033

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

Enrique Gómez-Barrena, Philippe Rosset, Florian Gebhard, Philippe Hernigou, Nicola Baldini, Helène Rouard, Luc Sensebé, Rosa M Gonzalo-Daganzo, Rosaria Giordano, Norma Padilla-Eguiluz, Eduardo García-Rey, José Cordero-Ampuero, Juan Carlos Rubio-Suárez, Julien Stanovici, Christian Ehrnthaller, Markus Huber-Lang, Charles Henri Flouzat-Lachaniette, Nathalie Chevallier, Davide Maria Donati, Gabriela CiapettiSandrine 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: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis.

METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority.

FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging).

INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic.

FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

Original language	English
Journal	Biomaterials
DOIs	https://doi.org/10.1016/j.biomaterials.2018.03.033
Publication status	E-pub ahead of print - Mar 19 2018

Keywords

ATMP
Bioceramic
Bone tissue engineering
Clinical trial
Expanded autologous BM-hMSC
Non-union

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10.1016/j.biomaterials.2018.03.033

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Gómez-Barrena, E., Rosset, P., Gebhard, F., Hernigou, P., Baldini, N., Rouard, H., Sensebé, L., Gonzalo-Daganzo, R. M., Giordano, R., Padilla-Eguiluz, N., García-Rey, E., Cordero-Ampuero, J., Rubio-Suárez, J. C., Stanovici, J., Ehrnthaller, C., Huber-Lang, M., Flouzat-Lachaniette, C. H., Chevallier, N., Donati, D. M., ... Layrolle, P. (2018). Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. Biomaterials. https://doi.org/10.1016/j.biomaterials.2018.03.033

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. / Gómez-Barrena, Enrique; Rosset, Philippe; Gebhard, Florian; Hernigou, Philippe; Baldini, Nicola; Rouard, Helène; Sensebé, Luc; Gonzalo-Daganzo, Rosa M; Giordano, Rosaria; Padilla-Eguiluz, Norma; García-Rey, Eduardo; Cordero-Ampuero, José; Rubio-Suárez, Juan Carlos; Stanovici, Julien; Ehrnthaller, Christian; Huber-Lang, Markus; Flouzat-Lachaniette, Charles Henri; Chevallier, Nathalie; Donati, Davide Maria ; Ciapetti, Gabriela; Fleury, Sandrine; Fernandez, Manuel-Nicolás; Cabrera, José-Rafael; Avendaño-Solá, Cristina; Montemurro, Tiziana; Panaitescu, Carmen; Veronesi, Elena; Rojewski, Markus Thomas; Lotfi, Ramin; Dominici, Massimo; Schrezenmeier, Hubert; Layrolle, Pierre.

In: Biomaterials, 19.03.2018.

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

Gómez-Barrena, E, Rosset, P, Gebhard, F, Hernigou, P, Baldini, N, Rouard, H, Sensebé, L, Gonzalo-Daganzo, RM, Giordano, R, Padilla-Eguiluz, N, García-Rey, E, Cordero-Ampuero, J, Rubio-Suárez, JC, Stanovici, J, Ehrnthaller, C, Huber-Lang, M, Flouzat-Lachaniette, CH, Chevallier, N, Donati, DM , 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 2018, 'Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial', Biomaterials. https://doi.org/10.1016/j.biomaterials.2018.03.033

Gómez-Barrena E, Rosset P, Gebhard F, Hernigou P, Baldini N, Rouard H et al. Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. Biomaterials. 2018 Mar 19. https://doi.org/10.1016/j.biomaterials.2018.03.033

Gómez-Barrena, Enrique ; Rosset, Philippe ; Gebhard, Florian ; Hernigou, Philippe ; Baldini, Nicola ; Rouard, Helène ; Sensebé, Luc ; Gonzalo-Daganzo, Rosa M ; Giordano, Rosaria ; Padilla-Eguiluz, Norma ; García-Rey, Eduardo ; Cordero-Ampuero, José ; Rubio-Suárez, Juan Carlos ; Stanovici, Julien ; Ehrnthaller, Christian ; Huber-Lang, Markus ; Flouzat-Lachaniette, Charles Henri ; Chevallier, Nathalie ; Donati, Davide Maria ; Ciapetti, Gabriela ; Fleury, Sandrine ; Fernandez, Manuel-Nicolás ; Cabrera, José-Rafael ; Avendaño-Solá, Cristina ; Montemurro, Tiziana ; Panaitescu, Carmen ; Veronesi, Elena ; Rojewski, Markus Thomas ; Lotfi, Ramin ; Dominici, Massimo ; Schrezenmeier, Hubert ; Layrolle, Pierre. / Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. In: Biomaterials. 2018.

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title = "Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial",

abstract = "BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis.METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority.FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging).INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic.FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).",

keywords = "ATMP, Bioceramic, Bone tissue engineering, Clinical trial, Expanded autologous BM-hMSC, Non-union",

author = "Enrique G{\'o}mez-Barrena and Philippe Rosset and Florian Gebhard and Philippe Hernigou and Nicola Baldini and Hel{\`e}ne Rouard and Luc Senseb{\'e} and Gonzalo-Daganzo, {Rosa M} and Rosaria Giordano and Norma Padilla-Eguiluz and Eduardo Garc{\'i}a-Rey and Jos{\'e} Cordero-Ampuero and Rubio-Su{\'a}rez, {Juan Carlos} and Julien Stanovici and Christian Ehrnthaller and Markus Huber-Lang and Flouzat-Lachaniette, {Charles Henri} and Nathalie Chevallier and Donati, {Davide Maria} 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",

year = "2018",

month = mar,

day = "19",

doi = "10.1016/j.biomaterials.2018.03.033",

language = "English",

journal = "Biomaterials",

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publisher = "Elsevier BV",

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TY - JOUR

T1 - Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

AU - Gómez-Barrena, Enrique

AU - Rosset, Philippe

AU - Gebhard, Florian

AU - Hernigou, Philippe

AU - Baldini, Nicola

AU - Rouard, Helène

AU - Sensebé, Luc

AU - Gonzalo-Daganzo, Rosa M

AU - Giordano, Rosaria

AU - Padilla-Eguiluz, Norma

AU - García-Rey, Eduardo

AU - Cordero-Ampuero, José

AU - Rubio-Suárez, Juan Carlos

AU - Stanovici, Julien

AU - Ehrnthaller, Christian

AU - Huber-Lang, Markus

AU - Flouzat-Lachaniette, Charles Henri

AU - Chevallier, Nathalie

AU - Donati, Davide Maria

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 - 2018/3/19

Y1 - 2018/3/19

N2 - BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis.METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority.FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging).INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic.FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

AB - BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis.METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority.FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging).INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic.FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

KW - ATMP

KW - Bioceramic

KW - Bone tissue engineering

KW - Clinical trial

KW - Expanded autologous BM-hMSC

KW - Non-union

U2 - 10.1016/j.biomaterials.2018.03.033

DO - 10.1016/j.biomaterials.2018.03.033

M3 - Article

C2 - 29598897

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -