Authors: Enrique GómezBarrena Cristina Avendaño Solá Carmen Painatescu Bunu
Publish Date: 2014/04/15
Volume: 38, Issue: 9, Pages: 1803-1809
Abstract
Skeletal injuries requiring bone augmentation techniques are increasing in the context of avoiding or treating difficult cases with bone defects bone healing problems and bone regeneration limitations Musculoskeletal severe trauma osteoporosisrelated fractures and conditions where bone defect bone collapse or insufficient bone regeneration occur are prone to disability and serious complications Bone cell therapy has emerged as a promising technique to augment and promote bone regeneration Interest in the orthopaedic community is considerable although many aspects related to the research of this technique in specific indications may be insufficiently recognised by many orthopaedic surgeons Clinical trials are the ultimate research in real patients that may confirm or refute the value of this new therapy However before launching the required trials in bone cell therapy towards bone regeneration preclinical data is needed with the cell product to be implanted in patients to ensure safety and efficacy These preclinical studies support the endpoints that need to be evaluated in clinical trials Orthopaedic surgeons are the ultimate players that through their research would confirm in clinical trials the benefit of bone cell therapies To further foster this research the pathway to eventually obtain authorisation from the National Competent Authorities and Research Ethics Committees under the European regulation is reviewed and the experience of the REBORNE European project offers information and important clues about the current Voluntary Harmonization Procedure and other opportunities that need to be considered by surgeons and researchers on the topicBone healing augmentation through bone regeneration seeks to repair or replace damaged bone with the goal to fully restore structure and function While cellbased therapies are promising new therapeutic approaches their clinical application is still under discussion The burden of skeletal injuries and bone diseases that could benefit from regenerative medicine approaches includes not only bone defects of traumatic origin but also bone healing delays and nonunions osteonecrotic damage or other situations where bone regeneration is required but osteogenic potential is insufficientBy using mesenchymal stem cells MSCs good results have been reported for bone engineering in a number of early clinical studies 1 most of them investigatorinitiated trials with limited scope with respect to controls and outcome With the implementation of a new regulatory framework for advanced therapeutic medicinal products ATMPs in Europe both the characterization of the cells and combination products need to be more clearly defined Welldesigned clinical trials CT are expected to clarify the safety and efficacy issues with specific cell products in specific indicationsSignificant investment has been dedicated to bone regenerative medicine Although tremendous efforts have been conducted in basic research leading to the reinforcement of developmental bone cell biology knowledge very limited if any patient benefit has been clearly obtained uptodate The time of opportunities has come for clinical translation of these advancements and progress towards definite clinical applications might be the most genuine pathway to foster this research in the benefit of our patients The orthopaedic surgeon requires specific information about the state of the art on clinical applications of this therapy and ongoing research that will soon be ready to incorporate new solutions to the orthopaedic armamentarium Furthermore the practising surgeons need also to be aware of the opportunities and barriers to offer their patients the best care based on the best available scientific knowledge and how to develop the required evidence when insufficientThrough this review we will consider the orthopaedic bone injuries that could constitute opportunities for bone regeneration techniques the studies that are needed to establish a wellsupported bone cell therapy through the definition of safety feasibility and efficacy endpoints the role of investigatordriven clinical trials IDCT in advanced therapy medicinal products for bone and the current multinational regulatory pathway in Europe as followed by the REBORNE trials through a national approach and through the European voluntary harmonization procedureThe Bone and Joint Decade 5 6 has contributed to focus on the most prevalent and complex orthopaedic problems The conjoined efforts developed by researchers and clinicians institutions and countries have increased the awareness and the interest in the present and future solutions to these problems Particularly bone repair and healing advancements have been focused through the Bone and Joint Decade on the management of musculoskeletal trauma the reconstruction of osteoporosisrelated fractures and the high number of surgicallytreated spine disorders requiring fusion and refusionMusculoskeletal severe trauma requires structural support and bone healing enhancement particularly in complex cases to avoid or treat bone healing complications Especially traumatic bone defects associated with high energy fractures after traffic accidents are a devastating problem all over the world Thirteen bone injuries were among the 20 leading nonfatal injuries sustained after road traffic accidents worldwide in 2002 4 estimating 25 of total health expenditures in developed nations Furthermore a significant change in the rank order of disabilityadjusted years DALYs measuring loss of health from disability has been found from 1990 with traffic injuries being the ninth cause and potentially becoming the third cause in 2020 Disability frequently associates bone healing fracturerelated problems such as nonunion at a rough 5 –10 rate Delayed unions and nonunions after fracture may relate to biomechanical factors that can be solved through modifications of surgical technique but the bone capability to consolidate through regeneration may be compromised when insufficient osteogenic reaction is observed in the fracture callus and an atrophic nonunion may develop In those cases and provided vascular status and skin coverage are preserved or recovered biological potential for osteogenesis relying on osteoprogenitor cell lines determines adequate healing In the United Kingdom 850000 new fractures are seen in a year but the overall regional nonunion incidence rate has been reported in 189/100000 population/year 7
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