From OT Europe

Bone regeneration trial under way to identify nonunion solutions

Editor’s Note: This article by Enrique Gómez Barrena, MD, Vice Chairman Education Committee – Basic Research Group of EFORT, is the first in a series of articles in Orthopedics Today Europe about the Basic Research Group’s activities.

Regenerative medicine is in the scope of many orthopaedic surgeons and patients as a promising field where unsolved issues of bone, joint and soft tissue reconstruction may find new treatments.

From 2007 and as per European Union directive, tissue engineering is considered an advanced therapy because engineered cells or tissues undergo substantial manipulation or are used in the recipient in a different function.

Enrique Gómez Barrena, MD
Enrique Gómez-Barrena

In the development of regenerative medicine solutions, many advanced medicinal therapy medicinal products (AMTPs) are under development through preclinical and clinical research. Specific regulations apply to the manufacturer under quality standards, traceability, pharmacovigilance and special authorization. All of these are required to grant an approval for clinical use in the future.

Clinical trials are required to prove the safety and efficacy of any new AMTP. Mesenchymal stem cells (MSCs) are among the most promising AMTPs as significant preclinical research has proven safety and efficacy in the animal model to regenerate bone, cartilage or other tissues. Until comparative, multicentered, multinational, well-powered randomized clinical trials (RCTs) are completed, no matter how appealing MSCs are, these will not become an approved treatment for our patients.

Significant debate exists about the origin of stem cells (bone marrow, adipose tissue, umbilical cord or other). It is also unclear how many cells are required, from the thousands obtained with bone marrow concentration to the millions that require cell expansion in certified facilities under good manufacturing practices (GMPs). Finally, cell delivery, distribution, viability and activity (from regeneration to cell recruitment or immunomodulation), are still unclear aspects.

Research projects

The European Union has launched different calls to support strong research projects in the FP7 and Horizon 2020 (H2020) programs to develop regenerative medicine solutions also in the orthopaedic field. Particularly, bone regeneration has been a major research aim as certain scenarios may not obtain bone healing without biological enhancement and tissue-engineered solutions may foster bone regeneration in those situations, such as complex fractures evolving to atrophic or recalcitrant nonunions, bone defects, osteonecrosis, and can be associated with a high societal cost.

While the clinical alternative has been bone autograft, limitations include previous harvesting, scarce bone stock, persistent pain, patient refusal, scar, late recovery or limping and gait abnormalities associated with pain. Culture-expanded autologous MSCs combined with biomaterial granules have been claimed as a solid regenerative medicine alternative to autologous bone grafting, although current data are limited.

Bone regenerative medicine used in a trial
Bone regenerative medicine used in a trial to administer a combination of expanded MSCs delivered in a syringe and biomaterial in granules is shown.

Image: Gómez-Barrena E

In a recent EU-FP7 project named REBORNE (Regenerating bone defects using new biomedical engineering approaches) that was developed from 2010 to 2015 under the coordination of Prof. Pierre Layrolle from INSERM Nantes (France), preclinical research allowed researchers to define a combination of commercial biphasic calcium phosphate (BCP) and highly expanded autologous MSCs derived from the patient’s bone marrow. Quality studies on the preparation and transportation of the cell product to the treating hospitals also confirmed cell product feasibility. REBORNE launched two safety and feasibility clinical trials in orthopaedics to obtain bone regeneration in long bone nonunions (EudraCT 2011-005441-13) and symptomatic pre-collapse femoral head osteonecrosis (EudraCT 2012-002010-39), with promising results (Figure).

ORTHOUNION

The tremendous work required to prepare the preclinical and early clinical information to support a solution developed and applied in hospitals from France, Germany, Italy and Spain, would not at this stage provide sufficient evidence to grant the approval of the biomaterial and cell combination for clinical use. In this context, a new H2020 project named ORTHOUNION (orthopedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonunions) was launched in 2017 and runs until 2021.

That project is coordinated by Hospital La Paz and UAM, Madrid (Spain). The overall objective of ORTHOUNION is to obtain evidence on the efficacy of the REBORNE-developed AMTP for bone regeneration through a multicentered, multinational, randomized controlled trial of autologous, expanded, bone marrow-derived MScs with biomaterial vs. iliac crest autograft to heal nonunions after long bone fractures in the humerus, femur or tibia.

To launch such an ambitious trial, 20 hospitals across Europe will be participating in Spain, France (national coordinator is Prof. Philippe Rosset from Tours), Italy (national coordinator is Prof. Nicola Baldini from Bologna) and Germany (national coordinator is Prof. Florian Gebhard from Ulm). In the event of positive results, these would further support the progress of bone regenerative medicine toward clinical application. In case of negative results, these would inform on the limitations to obtain clinical benefits from this technology with this previously proven medicinal product. Whether positive or negative, the results of this and other trials may be valuable to define the real potential of this innovative field of regenerative medicine.

Disclosure: Gómez-Barrena reports he is Work Package leader for FP7-REBORNE (Academic partner) and Coordinator for H2020-ORTHOUNION (Academic partner).

Editor’s Note: This article by Enrique Gómez Barrena, MD, Vice Chairman Education Committee – Basic Research Group of EFORT, is the first in a series of articles in Orthopedics Today Europe about the Basic Research Group’s activities.

Regenerative medicine is in the scope of many orthopaedic surgeons and patients as a promising field where unsolved issues of bone, joint and soft tissue reconstruction may find new treatments.

From 2007 and as per European Union directive, tissue engineering is considered an advanced therapy because engineered cells or tissues undergo substantial manipulation or are used in the recipient in a different function.

Enrique Gómez Barrena, MD
Enrique Gómez-Barrena

In the development of regenerative medicine solutions, many advanced medicinal therapy medicinal products (AMTPs) are under development through preclinical and clinical research. Specific regulations apply to the manufacturer under quality standards, traceability, pharmacovigilance and special authorization. All of these are required to grant an approval for clinical use in the future.

Clinical trials are required to prove the safety and efficacy of any new AMTP. Mesenchymal stem cells (MSCs) are among the most promising AMTPs as significant preclinical research has proven safety and efficacy in the animal model to regenerate bone, cartilage or other tissues. Until comparative, multicentered, multinational, well-powered randomized clinical trials (RCTs) are completed, no matter how appealing MSCs are, these will not become an approved treatment for our patients.

Significant debate exists about the origin of stem cells (bone marrow, adipose tissue, umbilical cord or other). It is also unclear how many cells are required, from the thousands obtained with bone marrow concentration to the millions that require cell expansion in certified facilities under good manufacturing practices (GMPs). Finally, cell delivery, distribution, viability and activity (from regeneration to cell recruitment or immunomodulation), are still unclear aspects.

Research projects

The European Union has launched different calls to support strong research projects in the FP7 and Horizon 2020 (H2020) programs to develop regenerative medicine solutions also in the orthopaedic field. Particularly, bone regeneration has been a major research aim as certain scenarios may not obtain bone healing without biological enhancement and tissue-engineered solutions may foster bone regeneration in those situations, such as complex fractures evolving to atrophic or recalcitrant nonunions, bone defects, osteonecrosis, and can be associated with a high societal cost.

While the clinical alternative has been bone autograft, limitations include previous harvesting, scarce bone stock, persistent pain, patient refusal, scar, late recovery or limping and gait abnormalities associated with pain. Culture-expanded autologous MSCs combined with biomaterial granules have been claimed as a solid regenerative medicine alternative to autologous bone grafting, although current data are limited.

Bone regenerative medicine used in a trial
Bone regenerative medicine used in a trial to administer a combination of expanded MSCs delivered in a syringe and biomaterial in granules is shown.

Image: Gómez-Barrena E

In a recent EU-FP7 project named REBORNE (Regenerating bone defects using new biomedical engineering approaches) that was developed from 2010 to 2015 under the coordination of Prof. Pierre Layrolle from INSERM Nantes (France), preclinical research allowed researchers to define a combination of commercial biphasic calcium phosphate (BCP) and highly expanded autologous MSCs derived from the patient’s bone marrow. Quality studies on the preparation and transportation of the cell product to the treating hospitals also confirmed cell product feasibility. REBORNE launched two safety and feasibility clinical trials in orthopaedics to obtain bone regeneration in long bone nonunions (EudraCT 2011-005441-13) and symptomatic pre-collapse femoral head osteonecrosis (EudraCT 2012-002010-39), with promising results (Figure).

ORTHOUNION

The tremendous work required to prepare the preclinical and early clinical information to support a solution developed and applied in hospitals from France, Germany, Italy and Spain, would not at this stage provide sufficient evidence to grant the approval of the biomaterial and cell combination for clinical use. In this context, a new H2020 project named ORTHOUNION (orthopedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonunions) was launched in 2017 and runs until 2021.

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That project is coordinated by Hospital La Paz and UAM, Madrid (Spain). The overall objective of ORTHOUNION is to obtain evidence on the efficacy of the REBORNE-developed AMTP for bone regeneration through a multicentered, multinational, randomized controlled trial of autologous, expanded, bone marrow-derived MScs with biomaterial vs. iliac crest autograft to heal nonunions after long bone fractures in the humerus, femur or tibia.

To launch such an ambitious trial, 20 hospitals across Europe will be participating in Spain, France (national coordinator is Prof. Philippe Rosset from Tours), Italy (national coordinator is Prof. Nicola Baldini from Bologna) and Germany (national coordinator is Prof. Florian Gebhard from Ulm). In the event of positive results, these would further support the progress of bone regenerative medicine toward clinical application. In case of negative results, these would inform on the limitations to obtain clinical benefits from this technology with this previously proven medicinal product. Whether positive or negative, the results of this and other trials may be valuable to define the real potential of this innovative field of regenerative medicine.

Disclosure: Gómez-Barrena reports he is Work Package leader for FP7-REBORNE (Academic partner) and Coordinator for H2020-ORTHOUNION (Academic partner).