Periodic Reporting for period 1 - ORTHO-ALLO-UNION (ORTHOpaedic treatment with ALLOgenic combined ATMP in long bone fracture delayed UNION and non-union (ORTHO-ALLO-UNION).)
Reporting period: 2023-12-01 to 2025-05-31
Bone fracture with delay or failure to heal is a condition with a huge health impact. Although only a small proportion of long bone fractures evolve to non-union (5%), it is a first-magnitude problem due to the number of new annual fractures and increasing incidence of complex fractures with high risk of non-consolidation, need for repeated procedures, and years of patient disability. Bone autografts, autologous mesenchymal cells, or other complex interventions are used in this setting.
The aim of this project is the development of a universal therapy for fractures with delay or failure to heal, aiming to a simple and wide access to allogenic cell therapy combined with biomaterial, in a broad number of patients. Rather than considering ATMP only as a last solution in established non-union fractures, this project advocates that the indication should be moved to an earlier time point.
Patients will be treated with the combined ATMP as soon as the need for reoperation is identified due to delayed healing, with or without an added infectious component, to avoid long-term suffering for patients and their relatives and prevent progression to more severe non-unions, with high personal, social and economic costs. This approach is aligned with the real needs of patients and better fits with the usual practice in the EU, where reoperations are performed at 6 months or before in an attempt to accelerate bone healing and avoid complications. The project will establish a master cell bank for a wide allogenic production with donors' selection criteria of bone formation potential.
Necessary preclinical and clinical information to support the EU approval of a specific combined ATMP will be obtained.
Open access to scientific and regulatory information will be available for other EU medical device companies and cell therapy producers. In addition to direct clinical benefits to patients and healthcare providers, other developers of combined ATMP products will benefit.
The aim of this project is the development of a universal therapy for fractures with delay or failure to heal, aiming to a simple and wide access to allogenic cell therapy combined with biomaterial, in a broad number of patients. Rather than considering ATMP only as a last solution in established non-union fractures, this project advocates that the indication should be moved to an earlier time point.
Patients will be treated with the combined ATMP as soon as the need for reoperation is identified due to delayed healing, with or without an added infectious component, to avoid long-term suffering for patients and their relatives and prevent progression to more severe non-unions, with high personal, social and economic costs. This approach is aligned with the real needs of patients and better fits with the usual practice in the EU, where reoperations are performed at 6 months or before in an attempt to accelerate bone healing and avoid complications. The project will establish a master cell bank for a wide allogenic production with donors' selection criteria of bone formation potential.
Necessary preclinical and clinical information to support the EU approval of a specific combined ATMP will be obtained.
Open access to scientific and regulatory information will be available for other EU medical device companies and cell therapy producers. In addition to direct clinical benefits to patients and healthcare providers, other developers of combined ATMP products will benefit.
The OrthoAlloUnion consortium signed its project Grant Agreement on December 1, 2023, and received approval for a widening proposal involving the University of Aveiro (UAveiro#16) in January 2025. The Consortium Agreement was signed on February 12, 2024 (UAveiro#16 signed it retroactively from February 2, 2025).
In this initial periodic report, we set the bases for the OrthoAlloUnion clinical trial (WP2, WP3, WP6). Key activities included the development and production of essential study documents, namely the Study Protocol, Informed Consent Forms, and the Investigational Medicinal Product Dossier (IMPD). These documents were submitted for approval via the Clinical Trials Information System (CTIS) in April 2025, with authorization anticipated in the third quarter of 2025.
Furthermore, the COHORTHOUnion study has received approvals from three clinical centres located in Spain (La Paz Hospital) and Germany (ULM and Munich Hospitals), where it has successfully enrolled a total of 80 cases to date. The rest of the participant sites from France and Italy have already submitted the documentation for approval, and a response is expected by September 2025.
ULM#2 successfully established the allogeneic donor bank, which was approved by the ULM/IKT Ethics Committee in November 2023. So far, 41 potential donors have been screened, resulting in 19 individuals being accepted for Bone Marrow (BM) donation. Utilizing these 19 samples, they have created three Master Cell Banks-alike for the validation of quality control tests necessary for the IMPD. The final Master Cell Bank, intended for the production of the combined Advanced Therapy Medicinal Product (ATMP), is currently awaiting results from potency assays (UNIMORE#5).
Advances have also been made by EFS#4 in the development of quality controls for the ready-to-use combined ATMP, focusing on adhesion and viability quantification, as well as transport and storage conditions.
Preliminary results from INSERM#6 and Biomatlante#12 indicate that the 3D bone model is a feasible and promising system, demonstrating that the BCP scaffold effectively supported both the proliferation and differentiation of bone cells.
UAveiro joined the consortium in February 2025 as a widening country, through the Hop-on facility, proposing the bioengineering of in vitro mini-bone constructs cultured in a microfluidic Bone-on-Chip (BoC) system with an integrated inflammatory environment for novel biomaterial testing. For this purpose, UAveiro team aims to explore human proteins derived from perinatal tissues, specifically the placenta, to produce macroporous cryogels that mimic bone architecture and support both osteogenic and osteoclastogenic differentiation. The work carried out during the reporting period, under the scope of the ORTHOALLOUNION project, covered the first steps of the two tasks UAveiro is involved (Work Package 4, Tasks 4.6 and 4.7) leading to significant progress. Human-derived methacryloyl placenta (hPCMA) demonstrated to be a promising biomaterial to fabricate cryogels with varying protein concentrations (ranging from 0.5 to 1.5% (w/v)), which exhibited high porosity within an interconnected macroporous network (Deliverable D.4.12 Milestone M13). In parallel, preliminary experiments toward Deliverable D.4.11 were initiated, focusing on the optimization of placenta proteins modification with dopamine groups. Seeking the establishment and optimization of a microfluidic BoC device to support the integration of these cryogels, an open-top microfluidic chip and a perfusion holder were designed and fabricated (Deliverable D.4.13 Milestone M14). In-chip cryogel production was successfully achieved, and the system demonstrated effective perfusion capability with a dye solution - an essential accomplishment for the execution of the project. Overall, the planned activities were implemented smoothly, with no major challenges encountered. This progress marks a solid foundation for further developments toward the project’s objectives.
WP5 has been working on establishing the foundations for Communication, Dissemination, and Exploitation activities, supported by the expertise of PONS IP#13 in IPR aspects. The Dissemination, Communication, and Exploitation Committee has been established, in agreement with the consortium. The project's visual identity has been established, including the visibility of the funding authority. The project website has been created and is operational.
Overall, 24% of the actions were completed during this report, including the submission of 86% (13/15) of the planned deliverables. It was expected to achieve seven Milestones during the first reporting period; of these, three have been achieved, two were partially achieved, and two are pending.
In this initial periodic report, we set the bases for the OrthoAlloUnion clinical trial (WP2, WP3, WP6). Key activities included the development and production of essential study documents, namely the Study Protocol, Informed Consent Forms, and the Investigational Medicinal Product Dossier (IMPD). These documents were submitted for approval via the Clinical Trials Information System (CTIS) in April 2025, with authorization anticipated in the third quarter of 2025.
Furthermore, the COHORTHOUnion study has received approvals from three clinical centres located in Spain (La Paz Hospital) and Germany (ULM and Munich Hospitals), where it has successfully enrolled a total of 80 cases to date. The rest of the participant sites from France and Italy have already submitted the documentation for approval, and a response is expected by September 2025.
ULM#2 successfully established the allogeneic donor bank, which was approved by the ULM/IKT Ethics Committee in November 2023. So far, 41 potential donors have been screened, resulting in 19 individuals being accepted for Bone Marrow (BM) donation. Utilizing these 19 samples, they have created three Master Cell Banks-alike for the validation of quality control tests necessary for the IMPD. The final Master Cell Bank, intended for the production of the combined Advanced Therapy Medicinal Product (ATMP), is currently awaiting results from potency assays (UNIMORE#5).
Advances have also been made by EFS#4 in the development of quality controls for the ready-to-use combined ATMP, focusing on adhesion and viability quantification, as well as transport and storage conditions.
Preliminary results from INSERM#6 and Biomatlante#12 indicate that the 3D bone model is a feasible and promising system, demonstrating that the BCP scaffold effectively supported both the proliferation and differentiation of bone cells.
UAveiro joined the consortium in February 2025 as a widening country, through the Hop-on facility, proposing the bioengineering of in vitro mini-bone constructs cultured in a microfluidic Bone-on-Chip (BoC) system with an integrated inflammatory environment for novel biomaterial testing. For this purpose, UAveiro team aims to explore human proteins derived from perinatal tissues, specifically the placenta, to produce macroporous cryogels that mimic bone architecture and support both osteogenic and osteoclastogenic differentiation. The work carried out during the reporting period, under the scope of the ORTHOALLOUNION project, covered the first steps of the two tasks UAveiro is involved (Work Package 4, Tasks 4.6 and 4.7) leading to significant progress. Human-derived methacryloyl placenta (hPCMA) demonstrated to be a promising biomaterial to fabricate cryogels with varying protein concentrations (ranging from 0.5 to 1.5% (w/v)), which exhibited high porosity within an interconnected macroporous network (Deliverable D.4.12 Milestone M13). In parallel, preliminary experiments toward Deliverable D.4.11 were initiated, focusing on the optimization of placenta proteins modification with dopamine groups. Seeking the establishment and optimization of a microfluidic BoC device to support the integration of these cryogels, an open-top microfluidic chip and a perfusion holder were designed and fabricated (Deliverable D.4.13 Milestone M14). In-chip cryogel production was successfully achieved, and the system demonstrated effective perfusion capability with a dye solution - an essential accomplishment for the execution of the project. Overall, the planned activities were implemented smoothly, with no major challenges encountered. This progress marks a solid foundation for further developments toward the project’s objectives.
WP5 has been working on establishing the foundations for Communication, Dissemination, and Exploitation activities, supported by the expertise of PONS IP#13 in IPR aspects. The Dissemination, Communication, and Exploitation Committee has been established, in agreement with the consortium. The project's visual identity has been established, including the visibility of the funding authority. The project website has been created and is operational.
Overall, 24% of the actions were completed during this report, including the submission of 86% (13/15) of the planned deliverables. It was expected to achieve seven Milestones during the first reporting period; of these, three have been achieved, two were partially achieved, and two are pending.
The project will have an impact on the development of the combined ATMP by obtaining scientific evidence that supports the feasibility of the combined allogeneic treatment. Main results are still needed, but the proposed impact expressed in the grant agreement is still relevant.