An innovative cell-based transplantation therapy for an immature permanent tooth in an adult: a case report.

BACKGROUND: Immature teeth with necrotic pulps present multiple challenges to clinicians. In such cases, regenerative endodontic procedures (REPs) may be a favorable strategy. Cells, biomaterial scaffolds, and signaling molecules are three key elements of REPs. Autologous human dental pulp cells (hDPCs) play an important role in pulp regeneration. In addition, autologous platelet concentrates (APCs) have recently been demonstrated as effective biomaterial scaffolds in regenerative dentistry, whereas the latest generation of APCs-concentrated growth factor (CGF), especially liquid phase CGF (LPCGF)-has rarely been reported in REPs. CASE PRESENTATION: A 31-year-old woman presented to our clinic with the chief complaint of occlusion discomfort in the left mandibular posterior region for the past 5 years. Tooth #35 showed no pulp vitality and had a periodontal lesion, and radiographic examination revealed that the tooth exhibited extensive periapical radiolucency with an immature apex and thin dentin walls. REP was implemented via transplantation of autologous hDPCs with the aid of LPCGF. The periodontal lesion was managed with simultaneous periodontal surgery. After the treatment, the tooth was free of any clinical symptoms and showed positive results in thermal and electric pulp tests at 6- and 12-month follow-ups. At 12-month follow-up, radiographic evidence and three-dimensional models, which were reconstructed using Mimics software based on cone-beam computed tomography, synergistically confirmed bone augmentation and continued root development, indicating complete disappearance of the periapical radiolucency, slight lengthening of the root, evident thickening of the canal walls, and closure of the apex. CONCLUSION: hDPCs combined with LPCGF represents an innovative and effective strategy for cell-based regenerative endodontics.

Avoiding Graft Failure: Lessons Learned from the Stability Trial.

The Stability Study was a multicenter, pragmatic, parallel groups, randomized clinical trial comparing hamstring tendon autograft anterior cruciate ligament reconstruction with or without the addition of lateral extra-articular tenodesis in young patients at high risk of graft failure. Having recruited 618 patients with a 5% loss to follow up, we were able to demonstrate a clinically and statistically significant reduction in clinical failure and graft rupture at 2 years postoperative. No differences in patient-reported outcomes (PROs) were demonstrated between groups; however, patients who experienced an adverse event had significantly worse PROs than those who did not.

AUTOTRANSPLANTATION OF TEETH WITH OPEN APICES MAY RESULT IN HIGH SURVIVAL RATES BUT EVIDENCE IS LIMITED.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Tooth autotransplantation: an umbrella review. Tan BL, Tong HJ, Narashimhan S, Banihani A, Nazzal H, Duggal MS. Dent Traumatol 2023;39(Suppl 1):2-29. SOURCE OF FUNDING: Open access funding provided by the Qatar National Library TYPE OF STUDY/DESIGN: Umbrella review.

Comparison of allo-SCT, auto-SCT and chemotherapy for the treatment of patients with low- or intermediate-risk acute myeloid leukemia: a network meta-analysis.

BACKGROUND: The therapeutic status of allogeneic stem cell transplantation (allo-SCT) as a post-remission treatment for patients with high-risk acute myeloid leukemia (AML) was well-accepted. However, the optimal treatment for patients with low/favorable- or intermediate-risk AML who achieve complete remission has remained controversial. Therefore, we conducted a network meta-analysis to discuss this disputed problem. METHODS: We compared the effects of treatment strategies including allo-SCT, autologous stem cell transplantation (auto-SCT) and consolidation chemotherapy (CT) for patients with low/favorable- or intermediate-risk AML. The pooled HRs and 95% CIs for overall survival and disease-free survival were estimated with Stata12 and R software. Thirty clinical studies with 6682 patients were included in the meta-analysis. RESULTS: The results indicated that the treatment outcome of allo-SCT was the best, followed by auto-SCT, and CT was likely the worst in the total AML patients. In patients with low/favorable-risk AML, the treatment outcome of auto-SCT was likely ranked first, followed by allo-SCT, and CT was the worst. In patients with intermediate-risk AML, the treatment outcome of haploidentical stem cell transplantation (haplo-SCT) was the best, followed by allo-SCT (excluding haplo-SCT), and auto-SCT and CT were the worst. However, the median age of the haplo-SCT group was much younger than that of the control group, which may be one of the reasons for the better prognosis of the haplo-SCT group. CONCLUSIONS: Patients with low/favorable- and intermediate-risk (non-high-risk) AML should prioritize allo-SCT if they are eligible for transplantation, and auto-SCT is optional. However, in the subgroup analysis, auto-SCT was the optimal treatment choice for patients with low/favorable-risk AML, and allo-SCT was the priority selection for patients with intermediate-risk AML, especially young patients. These findings could provide references for clinical practice.

Matrix-Induced Autologous Chondrocyte Implantation Versus Autologous Chondrocyte Implantation of the Knee A Retrospective Comparison.

OBJECTIVE: The purpose of this study was to compare the short-term clinical outcomes of matrix-induced autologous chondrocyte implantation (MACI) to those seen following traditional autologous chondrocyte implantation (ACI) in the management of symptomatic cartilage lesions of the knee. METHODS: This was a retrospective cohort study of patients who underwent either ACI or MACI from January 2011 to March 2018. Patients with a minimum postoperative follow-up of 18 months were contacted. Demographic information, intraoperative findings, and patient-reported functional outcomes scores were collected. Comparisons were made between the two cell-based cartilage repair techniques. RESULTS: Fifty-six patients were included in the study (39 ACI, 17 MACI). Visual analog scale (VAS) for pain scores improved significantly in both groups, with MACI patients demonstrating significantly lower postoperative pain scores compared to those treated with ACI. In the ACI group, there was a decrease in the Tegner Activity score compared to the preoperative baseline, while no significant difference was seen between pre- and postoperative activity levels in the MACI group. Patients were generally satisfied with the outcome of their procedures, and there was no significant difference in satisfaction between groups. No patients re-quired additional surgery during the follow-up period. CONCLUSION: Both ACI and MACI demonstrated good short-term postoperative clinical results with improved pain and activity levels compared to the preoperative baseline. Patients treated with the MACI technique demonstrated greater reductions in pain scores compared to ACI, and while ACI resulted in a decrease in levels of postoperative activity, activity levels for MACI remained stable.

Autologous fat transplantation prior to permanent expander implant breast reconstruction enhances the outcome after two years: a randomized controlled trial.

Radiotherapy is important in breast cancer treatment. A side effect of the treatment is fibrosis that decreases the possibility for a successful breast reconstruction with expanders and with high patient satisfaction with the result. The most common option for mastectomized, irradiated women wishing for a breast reconstruction is autologous tissue transplantation. However, some patients are not suitable for flap surgery. Fifty mastectomized and irradiated women were included in a randomized controlled trial. They underwent breast reconstruction with expanders and were allocated 1:1 to either receive pre-treatment with autologous fat transplantation (AFT) or not. Primary outcomes were frequency of reoperations and complications. Secondary outcomes were number of days in hospital, number of outpatient visits to surgeon or nurse and patient reported outcome as reported with Breast Q. Follow-up time was 2 years. Fifty-two per cent of the intervention group and 68% of the controls underwent reoperations (p = 0.611). Thirty-two per cent of the intervention group and 52% of the controls had complications (p = 0.347). The median number of consultations with the nurse was four in the intervention group and six in the control group (p = 0.002). The AFT patients were significantly more satisfied with their breasts and psychosocial well-being after 2 years. They also had higher increase in satisfaction with breasts, psychosocial well-being, and sexual well-being when comparing baseline with 2 years postoperatively. This randomized controlled trial indicates benefits of AFT prior to breast reconstruction with expanders, especially on patient reported outcome even if the study sample is small.

Timing of Autologous Tissue Breast Reconstruction Does Not Affect Free Flap Failure.

ABSTRACT: This study aimed to determine whether there is a difference in free flap failure based on the decision to undergo immediate versus delayed autologous tissue breast reconstruction after mastectomy. The National Surgical Quality Improvement Program database was queried for breast free flap procedures performed between 2015 and 2020. This study demonstrates that the decision to undergo immediate versus delayed autologous tissue breast reconstruction does not have a significant association with free flap failure. This remains true regardless of whether patients undergo unilateral mastectomy with reconstruction or whether patients choose to also undergo contralateral prophylactic mastectomy with reconstruction.

Intra-Articular Application of Autologous, Fat-Derived Orthobiologics in the Treatment of Knee Osteoarthritis: A Systematic Review.

The aim of this study was to review the current literature regarding the effects of intra-articularly applied, fat-derived orthobiologics (FDO) in the treatment of primary knee osteoarthritis over a mid-term follow-up period. A systematic literature search was conducted on the online databases of Scopus, PubMed, Ovid MEDLINE, and Cochrane Library. Studies investigating intra-articularly applied FDO with a minimum number of 10 knee osteoarthritis patients, a follow-up period of at least 2 years, and at least 1 reported functional parameter (pain level or Patient-Reported Outcome Measures) were included. Exclusion criteria encompassed focal chondral defects and techniques including additional arthroscopic bone marrow stimulation. In 28 of 29 studies, FDO showed a subjective improvement in symptoms (pain and Patient-Reported Outcome Measures) up to a maximum follow-up of 7.2 years. Radiographic cartilage regeneration up to 3 years postoperatively, as well as macroscopic cartilage regeneration investigated via second-look arthroscopy, may corroborate the favorable clinical findings in patients with knee osteoarthritis. The methodological heterogeneity in FDO treatments leads to variations in cell composition and represents a limitation in the current state of knowledge. However, this systematic review suggests that FDO injection leads to beneficial mid-term results including symptom reduction and preservation of the affected joint in knee osteoarthritis patients.

Multiple conjunctival autografts from the contralateral eye for management of recurrent symblepharon in eyes with unilateral chemical burn.

We present two cases which underwent complex ocular surface reconstruction to achieve a stable ocular surface. Conjunctival autograft (CAG) procedure was required more than once, in addition to simple limbal epithelial transplantation to address extensive symblepharon in the eyes with total unilateral limbal stem cell deficiency secondary to acid ocular burns. These cases demonstrate that multiple CAGs may be harvested from the contralateral unaffected eye to correct recurrent symblepharon without any donor site complications if the correct surgical technique is adopted.

Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.

Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).

Reconstruction of the Medial Malleolus With Iliac Crest Autograft After Traumatic Loss: A Case Report.

CASE: A 19-year-old woman sustained an open ankle fracture with complete destruction of the left medial malleolus and significant soft-tissue loss. After temporizing external fixation and coverage with a rotational posterior tibial artery perforator flap, the medial malleolus was reconstructed with an autologous iliac crest bone graft and direct repair of the deltoid ligament. The patient achieved excellent improvement in functional outcomes at 21 months with adequate restoration of ankle motion. CONCLUSION: This case shows reconstruction of the medial malleolus with autologous iliac crest bone graft after traumatic loss can be a viable treatment option for young patients.

Safety and efficacy of autologous adipose tissue-derived stem cell transplantation in aging-related low-grade inflammation patients: a single-group, open-label, phase I clinical trial.

BACKGROUND: Inflamm-aging is associated with the rate of aging and is significantly related to diseases such as Alzheimer's disease, Parkinson's disease, atherosclerosis, heart disease, and age-related degenerative diseases such as type II diabetes and osteoporosis. This study aims to evaluate the safety and efficiency of autologous adipose tissue-derived mesenchymal stem cell (AD-MSC) transplantation in aging-related low-grade inflammation patients. METHODS: This study is a single-group, open-label, phase I clinical trial in which patients treated with 2 infusions (100 million cells i.v) of autologous AD-MSCs were initially evaluated in 12 inflamm-aging patients who concurrently had highly proinflammatory cytokines and 2 of the following 3 diseases: diabetes, dyslipidemia, and obesity. The treatment effects were evaluated based on plasma cytokines. RESULTS: During the study's follow-up period, no adverse effects were observed in AD-MSC injection patients. Compared to baseline (D-44), the inflammatory cytokines IL-1α, IL-1ß, IL-8, IL-6, and TNF-α were significantly reduced after 180 days (D180) of MSC infusion. IL-4/IL-10 at 90 days (D90) and IL-2/IL-10 at D180 increased, reversing the imbalance between proinflammatory and inflammatory ratios in the patients. CONCLUSION: AD-MSCs represent a potential intervention to prevent age-related inflammation in patients. TRIAL REGISTRATION: ClinicalTrials.gov number is NCT05827757, first registered on 13th Oct 2020.

Editorial: First Regulatory Approval for Adoptive Cell Therapy with Autologous Tumor-Infiltrating Lymphocytes (TILs) - Lifileucel (Amtagvi).

On February 16, 2024, the US Food and Drug Agency (FDA) granted accelerated approval to lifileucel (Amtagvi), an adoptive immune cell therapy with autologous ex vivo-expanded tumor-infiltrating lymphocytes (TILs) for adult patients with advanced or unresectable melanoma progressing after treatment with immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF/MEK inhibitors. The clinical studies supporting this regulatory approval have highlighted the complexity of the treatment manufacturing process and the requirements for patient selection, a pretreatment lymphodepletion regimen, followed by a single infusion of lifileucel (Amtagvi), and up to six treatments with high-dose IL-2, with the potential for adverse events at each stage of treatment. In early 2024, expert consensus guidelines were published on best practices and patient management for adoptive cell therapy with autologous, ex vivo-expanded TILs, and an international TIL Working Group was formed in anticipation of further regulatory approvals bringing these treatments to the clinic. This editorial aims to provide an update on the importance of a first approval for adoptive cell therapy with autologous, ex vivo-expanded TILs and the challenges of implementing a complex, time-consuming, and potentially costly immunotherapy.

Surgical outcomes of robotic versus conventional autologous breast reconstruction: a systematic review and meta-analysis.

Breast reconstruction is an integral part of breast cancer management. Conventional techniques of flap harvesting for autologous breast reconstruction are associated with considerable complications. Robotic surgery has enabled a new spectrum of minimally invasive breast surgeries. The current systematic review and meta-analysis study was designed to retrieve the surgical and clinical outcomes of robotic versus conventional techniques for autologous breast reconstruction. An extensive systematic literature review was performed from inception to 25 April 2023. All clinical studies comparing the outcomes of robotic and conventional autologous breast reconstruction were included for meta-analysis. The present meta-analysis included seven articles consisting of 783 patients. Of them, 263 patients received robotic breast reconstruction, while 520 patients received conventional technique. Of note, 477 patients received latissimus dorsi flap (LDF) and 306 were subjected to deep inferior epigastric artery perforator (DIEP) flap. There was a significantly prolonged duration of surgery (MD 58.36;95% CI 32.05,84.67;P < 0.001) and duration of anaesthesia (MD 47;95% CI 16.23,77.77;P = 0.003) among patients who underwent robotic surgery. There was a similar risk of complications between robotic and conventional surgeries. The mean level of pain intensity was significantly lower among patients who received robotic breast surgery (MD- 0.28;95% CI - 0.73,0.17; P = 0.22). There was prolonged length of hospitalization among patients with conventional DIEP flap surgery (MD- 0.59;95% CI - 1.13,- 0.05;P = 0.03). The present meta-analysis highlighted the feasibility, safety, and effectiveness of robotic autologous breast reconstruction. This included the successful harvesting of LDF and DIEP flap with acceptable surgical and functional outcomes.

[Current Standards in the Treatment of Hodgkin Lymphoma]. / Aktuelle Standards in der Behandlung des Hodgkin Lymphoms.

This review discusses current trends in the treatment of Hodgkin lymphoma, focusing on optimizing therapy outcomes while minimizing toxicity. We summarize advances made by the incorporation of Brentuximab Vedotin into first line therapy for advanced stage Hodgkin lymphoma. Similarly, the incorporation of checkpoint-inhibition into first-line therapy holds great promise and early results suggest superior efficacy with reduced toxicity. In relapsed or refractory Hodgkin lymphoma, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation remains the standard approach. However, the remarkable efficacy of checkpoint inhibition in this setting has the potential to redefine treatment paradigms and obviate the need for HD-ASCT in select patients. Finally, we discuss the evolving landscape of nodular lymphocyte predominant Hodgkin lymphoma and reclassification to nodular lymphocyte predominant B-cell lymphoma, with increasing recognition of its distinct characteristics and treatment strategies.

Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma.

Background: There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. Methods: A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. Results: With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. Conclusion: ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Optimizing autologous stem cell collections for patients with multiple myeloma receiving G-CSF and Plerixafor: A single center project.

BACKGROUND: Increasing indications for cellular therapy collections have stressed our healthcare system, with autologous collections having a longer than desired wait time until apheresis collection. This quality improvement initiative was undertaken to accommodate more patients within existing resources. STUDY DESIGN AND METHODS: Patients with multiple myeloma who underwent autologous peripheral blood stem cell collection from October 2022 to April 2023 were included. Demographic, mobilization, laboratory, and apheresis data were retrospectively collected from the medical record. RESULTS: This cohort included 120 patients (49.2% male), with a median age of 60 years. All received G-CSF and 95% received pre-emptive Plerixafor approximately 18 hours pre-collection. Most (79%) had collection goals of at least 8 × 106/kg CD34 cells, with 63% over 70 years old having this high collection goal (despite 20 years of institutional data showing <1% over 70 years old have a second transplant). With collection efficiencies of 55.9%, 44% of patients achieved their collection goal in a single day apheresis collection. A platelet count <150 × 103/µL on the day of collection was a predictor for poor mobilization; among 27 patients with a low baseline platelet count, 17 did not achieve the collection goal and 2 failed to collect a transplantable dose. CONCLUSIONS: With minor collection goal adjustments, 15% of all collection appointments could have been avoided over this 6-month period. Other strategies to accommodate more patients include mobilization modifications (Plerixafor timing or substituting a longer acting drug), utilizing platelet counts to predict mobilization, and modifying apheresis collection volumes or schedule templates.

Autotransplantation of an inverse impacted dilacerated incisor: a case report with 11-year follow-up.

BACKGROUND: Dilaceration can lead to impaction of maxillary incisors, resulting in both aesthetic and functional problems. This case report presents the multidisciplinary approach to managing an inverse impacted dilacerated left lateral incisor in a 9-year-old male patient. CASE REPORT: The orthodontic alignment of the remaining three incisors was achieved within six months. After using the diode laser to remove the gingiva covering the right lateral incisor during alignment process, a lingual button was bonded. The primary left canine and the impacted permanent left lateral incisor were extracted by raising the full-thickness mucoperiosteal flap, followed by the transplantation of the dilacerated lateral incisor into its correct position, splinted to the adjacent central incisors using composite resin. Root canal treatment was performed after the apical plug was created with mineral trioxide aggregate. The composite splint was removed after three weeks, and a new bracket was bonded to the left lateral incisor. It was left passively for 18 months until the permanent canines started to erupt. Light orthodontic forces were then applied for six months, and a passive eruption was expected over three months to properly position the canines within the dental arch. After an 11-year follow-up, the incisor displayed no clinical symptoms, although radiographic examination revealed external resorption in the long-term. CONCLUSION: This case demonstrates the successful and fast autotransplantation of an immature inverse impacted dilacerated incisor, highlighting the long-term clinical success and favorable aesthetic outcomes.

Efficacy and safety of autologous or allogeneic mesenchymal stromal cells from adult adipose tissue expanded and combined with tricalcium phosphate biomaterial for the surgical treatment of atrophic nonunion of long bones: a phase II clinical trial.

BACKGROUND: Autologous bone grafting is the standard treatment for the surgical management of atrophic nonunion of long bones. Other solutions, such as bone marrow mesenchymal stem cells (BM-MSC) combined with phospho-calcium material, have also been used. Here we evaluate the safety and early efficacy of a novel procedure using autologous or allogenic adipose tissue mesenchymal stromal cells (AT-MSC) seeded in a patented tricalcium phosphate-based biomaterial for the treatment of bone regeneration in cases of atrophic nonunion. METHODS: This was a prospective, multicentric, open-label, phase 2 clinical trial of patients with atrophic nonunion of long bones. Biografts of autologous or allogenic AT-MSC combined with a phosphate substrate were manufactured prior to the surgical procedures. The primary efficacy was measured 6 months after surgery, but patients were followed for 12 months after surgery and a further year out of the scope of the study. All adverse events were recorded. This cohort was compared with a historical cohort of 14 cases treated by the same research team with autologous BM-MSC. RESULTS: A total of 12 patients with atrophic nonunion of long bones were included. The mean (SD) age was 41.2 (12.1) years and 66.7% were men. Bone healing was achieved in 10 of the 12 cases (83%) treated with the AT-MSC biografts, a percentage of healing similar (11 of the 14 cases, 79%) to that achieved in patients treated with autologous BM-MSC. Overall, two adverse events, in the same patient, were considered related to the procedure. CONCLUSIONS: The results of this study suggest that AT-MSC biografts are safe for the treatment of bone regeneration in cases of atrophic nonunion and reach high healing rates. TRIAL REGISTRATION: Study registered with EUDRA-CT (2013-000930-37) and ClinicalTrials.gov (NCT02483364).