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Title of Journal: International Orthopaedics SICOT

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Abbravation: International Orthopaedics

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Springer Berlin Heidelberg

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DOI

10.1002/cem.2563

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ISSN

1432-5195

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Regulatory authorities and orthopaedic clinical tr

Authors: Enrique GómezBarrena Cristina Avendaño Solá Carmen Painatescu Bunu
Publish Date: 2014/04/15
Volume: 38, Issue: 9, Pages: 1803-1809
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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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  2. The use of an eccentric glenosphere compared with a concentric glenosphere in reverse total shoulder arthroplasty: two-year minimum follow-up results
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  4. Primary cementless hip arthroplasty as a potential risk factor for non-union after long-stem revision arthroplasty in periprosthetic femoral fractures
  5. Preparation, antibacterial properties and biocompatibility studies on vancomycin-poly(D,L)-lactic loaded plates
  6. Has the management of shoulder dislocation changed over time?
  7. Does an increase in modularity improve the outcomes of total shoulder replacement? Comparison across design generations
  8. Intertrochanteric osteotomy in young adults for sequelae of Legg-Calvé-Perthes’ disease—a long term follow-up
  9. Posterior lumbar interbody fusion versus posterolateral fusion in spondylolisthesis: a prospective controlled study in the Han nationality
  10. Antibiotic-loaded bone cement spacers in two-stage management of infected total knee arthroplasty
  11. Skeletal tissue regeneration: where can hydrogels play a role?
  12. Gait characteristics before hardware removal in patients operated upon for tibial plateau fractures
  13. Zoledronate reduces unwanted bone resorption in intercalary bone allografts
  14. Anchor suture fixation of distal pole fractures of patella: twenty seven cases and comparison to partial patellectomy
  15. A 5 to 8 year follow-up study of the Rotaglide mobile bearing total knee arthroplasty
  16. Wide resection of sacral chordoma via a posterior approach
  17. The influence of stem offset and neck shaft angles on the range of motion in total hip arthroplasty
  18. Marshall R. Urist and the discovery of bone morphogenetic proteins
  19. Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients
  20. Vascular endothelial growth factor gene silencing suppresses wear debris-induced inflammation
  21. Complications of definitive open reduction and internal fixation of pilon fractures of the distal tibia
  22. Tumour response of osteosarcoma to neoadjuvant chemotherapy evaluated by magnetic resonance imaging as prognostic factor for outcome
  23. Role of MRI in detecting early physeal changes due to acute osteoarticular infection around the knee joint: a pilot study
  24. Lengthening of short bones by distraction osteogenesis—results and complications
  25. Validity of published outcome data concerning Anatomic Graduated Component total knee arthroplasty: a structured literature review including arthroplasty register data
  26. Tibial lengthening over an intramedullary nail in patients with short stature or leg-length discrepancy: a comparative study
  27. Sacroiliac joint tuberculosis
  28. Delayed union of multifragmentary diaphyseal fractures after bridge-plate fixation
  29. Clinical and biological assessment of cemented titanium femoral stems: an 11-year experience
  30. Association of oestrogen receptor gene polymorphism with the long-term results of rotational acetabular osteotomy
  31. Surgical treatment of undisplaced femoral neck fractures in the elderly
  32. Modified sacrospinalis muscle pedicle bone graft for fusion of isthmic spondylolisthesis
  33. Design and application of Nickel-Titanium olecranon memory connector in treatment of olecranon fractures: a prospective randomized controlled trial
  34. Surgical treatment for young adult hip dysplasia: joint-preserving options
  35. Anatomical principles for minimally invasive reconstruction of the acromioclavicular joint with anchors
  36. The gait of patients with one resurfacing and one replacement hip: a single blinded controlled study
  37. Integrated care pathways in lower-limb arthroplasty: are they effective in reducing length of hospital stay?
  38. Percutaneous reduction and leverage fixation using K-wires in paediatric angulated radial neck fractures
  39. Distal tibia fractures: management and complications of 101 cases
  40. Surgical fixation of sternal fractures: locked plate fixation by low-profile titanium plates—surgical safety through depth limited drilling
  41. Bovine xenograft locking Puddu plate versus tricalcium phosphate spacer non-locking Puddu plate in opening-wedge high tibial osteotomy: a prospective double-cohort study
  42. Are abductor muscle quality and previous revision surgery predictors of constrained liner failure in hip arthroplasty?
  43. Mono versus polyaxial locking plates in distal femur fractures: a prospective randomized multicentre clinical trial
  44. Identification of prognostic factors for the nonoperative treatment of stiff shoulder
  45. Single-row versus double-row arthroscopic repair in the treatment of rotator cuff tears: a prospective randomized clinical study
  46. Post-discectomy syndrome treated with lumbar interbody fusion
  47. In-out-in technique for acetabular fractures: is it really good?
  48. Impaction bone grafting and a cemented cup after acetabular fracture
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  50. Comparison of tibial rotation in fixed and mobile bearing total knee arthroplasty using computer navigation
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  52. Modular megaprosthesis for distal femoral tumors
  53. Proximal humerus reconstruction after tumour resection: biological versus endoprosthetic reconstruction
  54. Factors predicting the failure of Bernese periacetabular osteotomy: a meta-regression analysis
  55. Acetabular rim lesions: arthroscopic assessment and clinical relevance
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  58. Osseointegration in hip prostheses: experimental study in sheep
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  60. Radiographic correlation of symptomatic and asymptomatic flexible flatfoot in young male adults
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  63. Pre-operative scoring system to determine the surgical strategy for periprosthetic hip infection
  64. GRADE outcomes or studies: how to use the GRADE approach correctly?
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  67. Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty
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  70. Comment on Korsten et al.: Operative or conservative treatment in patients with Rockwood type III acromioclavicular dislocation: a systematic review and update of current literature
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