Bone injuries represent an important world medical problem producing significant healthcare and societal expenditure. While most bone injuries are not severe and capable of healing through bone regeneration by natural callus formation with standard treatments, severe bone injuries may not heal, becoming a critical unmet clinical need. Severe bone injuries may associate with soft tissue injuries and impaired biological scenarios, frequently leading to consolidation problems after a fracture and eventually to recalcitrant non-unions. Functional capacity and quality of life in survivors of severe injuries often do not return to normal, even one year after trauma. Therefore, this proposal is oriented to prove the added value of bone regenerative medicine to heal bones with consolidation problems.
Non-unions, also known as pseudarthrosis, may occur in 5% of long-bone fractures that cannot heal properly after more than six months, with morbidity, prolonged hospitalization, and increased expenses. The most accepted standard augmentation to procure fracture and non-union healing consists of autologous bone grafting frequently obtained from the iliac crest (ICAG). ICAG is the best available biological option because it provides factors that are considered to guide bone regeneration and thus heal bone injuries, such as extracellular matrix (for osteoconduction), growth factors (modulating bone healing as per osteoinduction), and patient’s cells (leading to local osteogenesis). ICAG has drawbacks due to persistent pain, patient refusal, scar, late recovery, limping and gait abnormality associated with pain, and a limited amount of bone, all with a limited regeneration efficacy (success rate of about 74%) and high societal cost. Culture-expanded autologous MSCs combined with biphasic calcium phosphate (BCP) biomaterial granules have been claimed as a solid regenerative medicine alternative to autologous bone grafting in non-unions, although current data are limited.
The primary aim of ORTHOUNION is to prove the efficacy of an advanced therapy medicinal product (ATMP) in long bone non-unions developed after a bone fracture in a comparative, multicentre, multinational, randomized clinical trial (RCT). This advanced RCT may confirm previous encouraging results and provide high-level evidence. The importance of an evidence-based positive confirmation would be translating this ATMP towards clinical application as an efficacious therapeutic strategy for unmet clinical needs of significant complexity, such as unhealed severe traumatic injuries, while decreasing disability and improving quality of life in patients.
The secondary aim of the project is to pave the way for future clinical translation by defining exploitation strategies based on objective economic evaluations. This is reinforced by associated innovation to facilitate personalized medicine approaches with safe and efficacious but variable autologous cells.
The overall objective of ORTHOUNION is to obtain evidence on the efficacy of an ATMP for bone regeneration. In case of positive results, these would support the progress of bone regenerative medicine towards clinical application. In case of negative outcomes, these would inform the limitations of obtaining clinical benefits from this technology. Either positive or negative results may be highly valuable to define the future of the field.
