Long bone uninfected non-union: grafting techniques.

Long bone non-unions represent a serious clinical and socioeconomical problem due to the prolonged episodes, frequent sequelae, and variable treatment effectiveness. Bone grafts, classically involving the autologous iliac crest graft as the 'gold standard' bone graft, enhance bone regeneration and fracture healing incorporating osteoconductive and/or osteoinductive/osteogenic capacity to the non-union under treatment. Structural alternatives to autologous bone grafts include allografts and bone substitutes, expanding the available stock but loosing biological properties associated with cells in the graft. Biological alternatives to autologous bone grafts include bone marrow concentration from iliac crest aspiration, bone marrow aspiration from reaming of the diaphyseal medullary canal in the long bones, and isolated, expanded mesenchymal stem cells under investigation. When the combination with natural and synthetic bone substitutes allows for larger volumes of structural grafts, the enhancement of the biological regenerative properties through the incorporation of cells and their secretoma permits to foresee new bone grafting solutions and techniques.

Association between Bone Turnover Markers and Fracture Healing in Long Bone Non-Union: A Systematic Review.

Background: Fracture healing is a very complex and well-orchestrated regenerative process involving many cell types and molecular pathways. Despite the high efficiency of this process, unsatisfying healing outcomes, such as non-union, occur for approximately 5-10% of long bone fractures. Although there is an obvious need to identify markers to monitor the healing process and to predict a potential failure in callus formation to heal the fracture, circulating bone turnover markers' (BTMs) utility as biomarkers in association with radiographic and clinical examination still lacks evidence so far. Methods: A systematic review on the association between BTMs changes and fracture healing in long bone non-union was performed following PRISMA guidelines. The research papers were identified via the PubMed, Cochrane, Cinahl, Web of Science, Scopus, and Embase databases. Studies in which the failure of fracture healing was associated with osteoporosis or genetic disorders were not included. Results: A total of 172 studies were collected and, given the inclusion criteria, 14 manuscripts were included in this review. Changes in circulating BTMs levels were detected during the healing process and across groups (healed vs. non-union patients and healthy vs. patients with non-union). However, we found high heterogeneity in patients' characteristics (fracture site, gender, and age) and in sample scheduling, which made it impossible to perform a meta-analysis. Conclusions: Clinical findings and radiographic features remain the two important components of non-union diagnosis so far. We suggest improving blood sample standardization and clinical data collection in future research to lay the foundations for the effective use of BTMs as tools for diagnosing non-union.

Volume and location of bone regeneration after autologous expanded mesenchymal stromal cells in hip osteonecrosis : a pilot study.

AIMS: Successful cell therapy in hip osteonecrosis (ON) may help to avoid ON progression or total hip arthroplasty (THA), but the achieved bone regeneration is unclear. The aim of this study was to evaluate amount and location of bone regeneration obtained after surgical injection of expanded autologous mesenchymal stromal cells from the bone marrow (BM-hMSCs). METHODS: A total of 20 patients with small and medium-size symptomatic stage II femoral head ON treated with 140 million BM-hMSCs through percutaneous forage in the EudraCT 2012-002010-39 clinical trial were retrospectively evaluated through preoperative and postoperative (three and 12 months) MRI. Then, 3D reconstruction of the original lesion and the observed postoperative residual damage after bone regeneration were analyzed and compared per group based on treatment efficacy. RESULTS: The mean preoperative lesion volume was 18.7% (SD 10.2%) of the femoral head. This reduced to 11.6% (SD 7.5%) after three months (p = 0.015) and 3.7% (SD 3%) after one year (p < 0.001). Bone regeneration in healed cases represented a mean 81.2% (SD 13.8%) of the initial lesion volume at one year. Non-healed cases (n = 1 stage progression; n = 3 THAs) still showed bone regeneration but this did not effectively decrease the ON volume. A lesion size under mean 10% (SD 6%) of the femoral head at three months predicted no ON stage progression at one year. Regeneration in the lateral femoral head (C2 under Japanese Investigation Committee (JCI) classification) and in the central and posterior regions of the head was predominant in cases without ON progression. CONCLUSION: Bone regeneration was observed in osteonecrotic femoral heads three months after expanded autologous BM-hMSC injection, and the volume and location of regeneration indicated the success of the therapy.Cite this article: Bone Joint Res 2022;11(12):881-889.

Complications and surgical treatment after pathological fracture associated to HIV secondary disease. A case report.

Due to advances in retroviral treatment, human immunodeficiency virus (HIV)-related disease may become chronic and the patient survival has substantially increased. Osteoarticular disease in those patients include multifocal osteonecrosis and its complications. Pain and functional limitation may be due to these complications, frequently underdiagnosed, including pathological fractures. Its prompt management may require a different approach than osteosynthesis. We present a long-term chronic HIV patient with severe pain and limitation. A tibial plateau pathological fracture associated to multifocal osteonecrosis was identified and treated with osteonecrosis debridement and total knee arthroplasty (TKA). Acute periprosthetic joint infection developed and required debridement, antibiotic and implant retention. The contralateral knee, also with multiple osteonecrosis foci, was managed with early TKA. We highlight the importance of timely surgical reconstruction to avoid serious limitation and complications.

Extensor mechanism ruptures.

Native patellar tendon injuries are seen in younger patients compared to quadriceps tendon ruptures. Up to a third of the patients may have local (antecedent tendinopathy and cortisone injections) or systemic risk factors (obesity, diabetes, hyperparathyroidism, chronic renal failure, fluoroquinolone or statin use) of injury, these are more frequent in bilateral disruptions. Complete extensor mechanism disruptions should be repaired surgically. Although isolated primary repair has been reported to have good outcomes in younger patients with acute tears and good tendon quality, augmentation of the repair with autograft, allograft or synthetic material should be considered in patients with poor tendon quality, chronic tears or tendon defects. High rates of return to work/sports have been reported in native patellar and quadriceps tendon tears, with re-rupture rates <5%. Extensor mechanism disruptions in patients with a total knee arthroplasty are challenging due to older age, systemic co-morbidities and poor local conditions, resulting in inferior outcomes compared to native extensor mechanism injuries. Some form of augmentation with autograft, allograft or synthetics is advisable in all cases. Salvage procedures such as whole extensor mechanism allografts provide acceptable outcomes in multiply operated knees with extensive bone and soft tissue deficits.

Prevention of Periprosthetic Joint Infection in Total Hip and Knee Replacement: One European Consensus.

Periprosthetic joint infection (PJI) is a devastating complication in total hip and knee replacement. Its prevention is key to decrease the incidence and avoid some consequences that seriously impact patients and health systems. In view of the variety of recommendations and guidelines, we decided to conduct an expert, peer-reviewed European consensus analysis about the pre-, intra-, and postoperative prevention of PJI. A multinational group of practicing orthopedic experts developed a series of 47 consensus statements in 6 main groups of intervention, and a 2-stage Delphi approach was launched with a threshold for agreement at 75% and for very high agreement at more than 90%. A total of 306 orthopedic surgeon responses were gathered from 9 countries. Consensus was reached for 42/47 statements, 31/47 of which achieved a very high consensus. Many preoperative actions gathered strong consensus, although areas like the use of alcoholic chlorhexidine or the timing of hair removal did not attain strong consensus, despite available evidence. Intra- and postoperative actions showed more variability regarding incise drapes, skin suturing techniques, and wound follow-up. This study confirms an important consensus among orthopedic surgeons across Europe in many areas well known to contribute to the prevention of PJI; however, there are still grounds for improvement.

Both younger and elderly patients in pain are willing to undergo knee replacement despite the COVID-19 pandemic: a study on surgical waiting lists.

PURPOSE: To identify factors influencing patient's availability to re-schedule primary total knee replacement (TKR) or revision (RKR) surgery after the lockdown (March-May 2020) during the COVID-19 pandemic. METHODS: A prospective cohort study through a telephone survey was performed in 156 patients (143 for primary and 13 for revision) included in the TKR and RKR surgical waiting list before March 2020. Contact of each patient with COVID-19, stress and anxiety, perceived pain, and function were obtained in the interviews, and also the preference of each patient to have re-scheduled surgery (early or late). Finally, we registered their response (acceptance or refusal) when surgery was effectively re-scheduled. RESULTS: 88 out of 156 patients waiting for knee replacement (76/143 of those waiting for TKR, 12/13 of those waiting for RKR) declared themselves ready for surgery in less than 1 month. When re-scheduled, 115 patients underwent surgery and 41 refused. Significantly different preferences were found for age (more prone to surgery if under 65), revision surgery (more readily available), pain (7.9 ± 1.7/10 in NRS in those undergoing surgery, 5.6 ± 2.3/10 in those refusing, p = 0.000), or COVID-19 diagnosis, but not other close contact with COVID-19, comorbidities, stress, or anxiety. A logistic regression model confirmed that revision surgery (OR 9.33), perceived severe pain (OR 5.21), and age under 65 years (OR 5.82) were significantly associated with patient preference. The probability of patients over 65 to prefer early surgery reached 60% only with pain at or above 9/10. CONCLUSIONS: Surgical timing preferences for knee replacement vary between patients older than 65 years (immediate surgery only when pain is intense) and younger patients (immediate surgery no matter the amount of pain). Even if COVID-19 severely stroke our population, the need for knee replacement stood in the young population and even in the aged population at risk for COVID when pain was important.

One-Year, Efficacy and Safety Open Label Study, with a Single Injection of a New Hyaluronan for Knee OA: The SOYA Trial.

PURPOSE: To assess the efficacy and safety of a single injection of a new formulation of hyaluronic acid (MPS-HA2%) in patients with symptomatic knee osteoarthritis after 12 months' follow-up. PATIENTS AND METHODS: Prospective, single-arm, multicentre, open-label, 12-month follow-up study. Patients with Kellgren-Lawrence (KL) 2-3 and visual analogue scale (VAS) pain scores of ≥40-< 80 mm received a single injection of MPS-HA2%. The primary outcome was the reduction in VAS pain scores from baseline, and the secondary outcomes were the Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index, the minimum clinically important improvement (MCII), and patient and investigator global assessments (PGA, IGA) measured on 5-point Likert scale. Adverse events were recorded throughout the study for safety purposes. RESULTS: A total of 101 patients (mean age: 68 years; 74% female; and 78% overweight) were included. The mean reduction in pain at 12 months was 37.7%; the total WOMAC score improved by 36.5% and the pain, stiffness and physical function subscores returned improvements of 32.1%, 34.1% and 32.7%, respectively (p=0.0001 with respect to baseline). At 12 months, a statistically significant 62.2% of patients obtained an improvement equal to or greater than the MCII. The mean PGA score at baseline was 2.44 and 1.46 at 12 months (p<0.05), and the mean IGA scores at equivalent timepoints were 2.29 and 1.48 (p<0.05). Fourteen patients received a second injection at the 6-month follow-up visit. Eight patients reported a total of 12 treatment-related adverse events that were local, non-serious and of mild-to-moderate intensity. CONCLUSION: With just a single intra-articular injection, this not controlled trial suggests that MPS-HA2% is effective 12 months after the procedure in most cases. Patient tolerability and safety were both optimal (NCT03852914).

The contribution of the histopathological examination to the diagnosis of adverse local tissue reactions in arthroplasty.

The histopathological examination of the periprosthetic soft tissue and bone has contributed to the identification and description of the morphological features of adverse local tissue reactions (ALTR)/adverse reactions to metallic debris (ARMD). The need of a uniform vocabulary for all disciplines involved in the diagnosis and management of ALTR/ARMD and of clarification of the parameters used in the semi-quantitative scoring systems for their classification has been considered a pre-requisite for a meaningful interdisciplinary evaluation.This review of key terms used for ALTR/ARMD has resulted in the following outcomes: (a) pseudotumor is a descriptive term for ALTR/ARMD, classifiable in two main types according to its cellular composition defining its clinical course; (b) the substitution of the term metallosis with presence of metallic wear debris, since it cannot be used as a category of implant failure or histological diagnosis; (c) the term aseptic lymphocytic-dominated vasculitis- associated lesion (ALVAL) should be replaced due to the absence of a vasculitis with ALLTR/ALRMD for lymphocytic-predominant and AMLTR/AMRMD for macrophage-predominant reaction.This review of the histopathological classifications of ALTR/ARMD has resulted in the following outcomes: (a) distinction between cell death and tissue necrosis; (b) the association of corrosion metallic debris with adverse local lymphocytic reaction and tissue necrosis; (c) the importance of cell and particle debris for the viscosity and density of the lubricating synovial fluid; (d) a consensus classification of lymphocytic infiltrate in soft tissue and bone marrow; (e) evaluation of the macrophage infiltrate in soft tissues and bone marrow; (f) classification of macrophage induced osteolysis/aseptic loosening as a delayed type of ALTR/ARMD; (g) macrophage motility and migration as possible driving factor for osteolysis; (h) usefulness of the histopathological examination for the natural history of the adverse reactions, radiological correlation, post-marketing surveillance, and implant registries.The review of key terms used for the description and histopathological classification of ALTR/ARMD has resulted in a comprehensive, new standard for all disciplines involved in their diagnosis, clinical management, and long-term clinical follow-up. Cite this article: EFORT Open Rev 2021;6:399-419. DOI: 10.1302/2058-5241.6.210013.

An update about molecular biology techniques to detect orthopaedic implant-related infections.

Despite different criteria to diagnose a prosthetic joint infection (PJI), aetiological diagnosis of the causing microorganism remains essential to guide treatment.Molecular-biology-based PJI diagnosis is progressing (faster, higher specificity) in different techniques, from the experimental laboratory into clinical use.Multiplex polymerase chain reaction techniques (custom-made or commercial) provide satisfactory results in clinical series of cases, with specificity close to 100% and sensitivity over 70-80%.Next-generation metagenomics may increase sensitivity while maintaining high specificity.Molecular biology techniques may represent, in the next five years, a significant transformation of the currently available microbiological diagnosis in PJI. Cite this article: EFORT Open Rev 2021;6:93-100. DOI: 10.1302/2058-5241.6.200118.

Implantation of autologous Expanded Mesenchymal Stromal Cells in Hip Osteonecrosis through Percutaneous Forage: Evaluation of the Operative Technique.

Bone forage to treat early osteonecrosis of the femoral head (ONFH) has evolved as the channel to percutaneously deliver cell therapy into the femoral head. However, its efficacy is variable and the drivers towards higher efficacy are currently unknown. The aim of this study was to evaluate the forage technique and correlate it with the efficacy to heal ONFH in a multicentric, multinational clinical trial to implant autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSCs). METHODS: In the context of EudraCT 2012-002010-39, patients with small and medium-sized (mean volume = 13.3%, range: 5.4 to 32.2) ONFH stage II (Ficat, ARCO, Steinberg) C1 and C2 (Japanese Investigation Committee (JIC)) were treated with percutaneous forage and implantation of 140 million BM-hMSCs in a standardized manner. Postoperative hip radiographs (AP-anteroposterior and lateral), and MRI sections (coronal and transverse) were retrospectively evaluated in 22 patients to assess the femoral head drilling orientation in both planes, and its relation to the necrotic area. RESULTS: Treatment efficacy was similar in C1 and C2 (coronal plane) and in anterior to posterior (transverse plane) osteonecrotic lesions. The drill crossed the sclerotic rim in all cases. The forage was placed slightly valgus, at 139.3 ± 8.4 grades (range, 125.5-159.3) with higher dispersion (f = 2.6; p = 0.034) than the anatomical cervicodiaphyseal angle. Bonferroni's correlation between both angles was 0.50 (p = 0.028). More failures were seen with a varus drill positioning, aiming at the central area of the femoral head, outside the weight-bearing area (WBA) (p = 0.049). In the transverse plane, the anterior positioning of the drill did not result in better outcomes (p = 0.477). CONCLUSION: The forage drilling to deliver cells should be positioned within the WBA in the coronal plane, avoiding varus positioning, and central to anterior in the transverse plane. The efficacy of delivered MSCs to regenerate bone in ONFH could be influenced by the drilling direction. Standardization of this surgical technique is desirable.

Epidemiology of long bone non-unions in Spain.

Epidemiological and ecological studies on long bone non-unions (NU) are scarce, based on different populations and methodologies. The aim of this study was to produce a descriptive analysis of the femur, tibia, and humerus non-union epidemiology in Spain. Methods Data were obtained from the Minimum Basic Data (Conjunto Mínimo Básico de Datos, CMBD) Hospital Discharge Database of the Spanish Ministry of Health, according to the ICD9-CM coding for diagnoses and procedures, and from the National Institute of Statistics for population, generating secondary databases with the reported cases that included the code 733.82 in a disaggregated manner, by age (categorized in 5 intervals), gender, Spanish region, and calendar year (1997-2015). Percentage of non-unions related to fractures in the previous year, annual prevalence (expressed per 100,000 person-years) and period prevalence (expressed per 100,000 person-period) were calculated by age, gender, and Spanish regions. The Odds ratio (OR) was estimated with a confidence of 95% using a logistic regression model per anatomical site. Results A mean of 235,446 fractures in all locations were annually reported in Spain from 1997 to 2015. Regarding non-union of long bones (femur, tibia and humerus), a total of 37,053 cases were found, representing a yearly mean of 1,950 cases. The proportion of long bone fractures that evolved into a non-union was 4% (1.4% femur, 1.5% tibia, and 1% humerus). The mean annual prevalence rate of NU in Spain was estimated in 4.5 (3.7-4.9) cases per 100,000 persons-year. The overall NU prevalence in Spain was estimated in 86 cases per 100,000 persons. By the type of bone, the period prevalence (per 100,000 persons-period) of the femur NU was 31, of the tibia 33, and of the humerus 22. Conclusions This description of the epidemiology of long bone non-unions in Spain confirms that the overall non-union rate has been stable from 2000 to 2015, higher in the tibia and in the femur compared to the humerus. NU occurred more frequently in aged females than in males in the femur and the humerus, while the tibia non-unions were more frequent in males and younger age.

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up.

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year.

Frontiers in non-union research.

Multifactorial aetiology defines non-unions, with a biological and a mechanical distortion of the timeline of bone healing.Research on new advances to increase osteogenesis and promote non-union healing is strongly directed towards new forms of cell products.Basic science and research on non-union treatments is needed to compile preclinical data on new treatments.Bone marrow concentration and expanded mesenchymal stromal cells still require extensive clinical research to confirm efficacy in non-union treatment.Solid preclinical studies, precise cell product definition and preparation, and appropriate ethical and regulatory approvals are needed to assess new advanced therapy medicinal products. Cite this article: EFORT Open Rev 2020;5:574-583. DOI: 10.1302/2058-5241.5.190062.

Preoperative Correction of Anemia to Allow a 3000 ml Blood Loss Without Transfusion in a Jehovah's Witness Presenting for Explantation of an Infected Hip Joint Prosthesis: A Case Report.

A 70-year-old Jehovah's Witness was treated with iron carboxymaltose intravenously, recombinant human erythropoietin alpha subcutaneously, and vitamin B12 and folate orally for 9 weeks to raise hemoglobin (Hb) from 10.8 to 17.0 g/dL before explantation of an infected hip joint prosthesis. The target Hb was calculated from the following formula: Hbtarget = Hbfinal/(1 - ABL/EBV), where Hbtarget= Hb to achieve before surgery, Hbfinal = lowest Hb patient could tolerate taking into consideration his comorbidities (7 g/dL), ABL = volume of blood the surgeon estimated the patient would lose intra- and postoperatively (3000 mL), and EBV = estimated blood volume (75 mL/kg for an adult man). Spinal anesthesia was provided with a single shot hyperbaric bupivacaine and fentanyl. Acute hypervolemic hemodilution was achieved with lactated Ringer's solution and hydroxyethyl starch. To further minimize blood loss, controlled hypotension to a mean blood pressure of 55 mm Hg was achieved with a propofol infusion and tranexamic acid was administered. Surgical blood loss was estimated to be 2500 mL. Hb at the end of surgery was 13.3 g/dL; on postoperative day 5, 11.7 g/L. No blood products were utilized.

Defining the Most Effective Patient Blood Management Combined with Tranexamic Acid Regime in Primary Uncemented Total Hip Replacement Surgery.

The application of patient blood management (PBM) combined with tranexamic acid administration (TXA) results in decreased total blood loss volume (TVB) and transfusions in total hip replacements (THRs). Dosages, timing, and routes of administration of TXA are still under debate as all these aspects, as well as interpatient variations, may affect the efficacy of the protocol. This study aims to examine the effectiveness of timing and route of administration of TXA in combination with PBM by reducing the TBV following THR surgery. Consecutive primary uncemented THRs operated by a single surgical and anaesthetic team had the data prospectively collected and then retrospectively studied. Five treatment groups were formed, reflecting the progressive evolution of our protocol. Group 1 included patients managed with PBM alone (preoperative erythrocyte mass optimisation to at least 14 g/dL haemoglobin (Hb), hypotensive spinal anaesthesia and restrictive red blood cell transfusion criteria). Group 2 included patients with PBM and topical 3 g TXA diluted in normal saline to a total volume of 50 mL. Group 3 were patients with PBM and an IV dose of 20 mg/kg TXA at induction, followed by 20 mg/kg TXA as a continuous infusion for the duration of the operation. Group 4 consisted of patients managed as per Group 3 plus another 20 mg/kg TXA at three-hour post-procedure. Group 5 (combined): PBM and IV TXA as per Group 4 and topical TXA as per Group 2. A generalised linear model with the treatment group as an independent variable was modelled, using TBV as the dependent variable. The transfusion rate for all groups was 0%. TBV at 24 h, oscillated from 613.5 ± 337.63 mL in Group 1 to 376.29 ± 135.0 mL in Group 5. TBV at 48 h oscillated from 738.3 ± 367.3 mL (PBM group) to 434 ± 155.2 mL (PBM + combined group). The multivariate regression model confirmed a significant decrease of TBV in all groups with TXA compared with the PBM-only group. Overweight and preoperative Hb were confirmed to significantly influence TBV. The optimal regime to achieve the least TBV and a transfusion rate of 0% requires PBM and one loading 20 mg/kg dose of TXA, followed by continuous infusion of 20 mg/kg for the duration of the operation in uncemented THRs. Additional doses of TXA did not add a clear benefit.

Limiting spread of COVID-19 in an orthopaedic department-a perspective from Spain.

Besides national and international recommendations, orthopaedic departments face significant changes in daily activity and serious issues to maintain their standards in musculoskeletal care during the pandemic Covid-19 crisis that we are facing. This report retrospectively addresses measures that were progressively put in place to modify in a week time the activity of a busy orthopaedic department in a large tertiary university hospital in face of the pandemic. Surgical priorities and surgical outcomes are key aspects to consider. The experience may offer some insight to areas where the spread of the disease may be slower or delayed. Abrupt stop of scheduled surgery and clinics is useful to adapt an orthopaedic department to the overall hospital resource reorganization. Orthopaedic surgeons need to be aware of the risks to patients and personnel in view of underdiagnosed cases, which make pre-operative Covid-19 evaluation mandatory for all surgical cases.

Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions.

BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture. PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni). RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation. CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.

Validation of a long bone fracture non-union healing score after treatment with mesenchymal stromal cells combined to biomaterials.

The available scores to clinically evaluate fracture consolidation encounter difficulties to interpret progression towards consolidation in long-bone non-union, particularly when incorporating biomaterials in the surgical treatment. The aims of this study were to validate the REBORNE bone healing scale in tibia, humerus and femur non-unions treated by a combination of mesenchymal stromal cells (MSCs) and biomaterials, through the interclass correlation (ICC) among raters, and to define reliability and concordance in anteroposterior and lateral radiographs, compared to computed tomography (CT). METHODS: Twenty-six cases from the EudraCT 2011-005441-13 clinical trial underwent bone healing evaluation, if at least 3 out of 4 cortical views clearly identified. Three senior orthopaedic surgeons evaluated radiographs and CTs at 3 and 6 months FU. All cases included preoperative imaging and radiographs at 12 months. The 4-stage scale score was obtained from each cortical view in orthogonal radiographs or CTs. A score of 0.6875 (11/16) was set as a threshold for bone healing. Statistically, ICC evaluated agreement among raters. Cronbach's alpha coefficient tested reliability. Lin's concordance correlation coefficients (CCC) were estimated between mean CT scores and mean radiographic scores. Bland and Altman graphs provided the limits of agreement between both imaging techniques. Sensitivity and specificity were assessed in radiographs (against CT), and the Area Under the Receiver Operating Characteristics (ROC) Curve was estimated. The probability to predict bone consolidation with REBORNE scores obtained from radiographs was modelled. RESULTS: An ICC of 0.88 and 0.91 (CT and radiographs) confirmed agreement in the REBORNE score for non-union bone healing, with an inter-rater reliability of 0.92 and 0.95. Scores through the radiographic evaluation were found equivalent to the CTs at 6 months FU. A CCC of 0.79 was detected against CT. The radiographic scores in the REBORNE bone healing scale correctly classified bone consolidation in 77%, with an accuracy of 83% based on ROC curves. CONCLUSIONS: The REBORNE score measured with CT or radiographic images was reliable among raters at a follow-up time above 6 months for long bone non-union fractures. The REBORNE scale measured with radiographs proved valid to assess consolidation against CT measurements.

Complications in Total Joint Arthroplasties.

Total joint arthroplasties (TJA) are today considered highly successful operations [...].