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).

Biofilm on total joint replacement materials can be reduced through electromagnetic induction heating using a portable device.

BACKGROUND: Periprosthetic joint infection is a serious complication following joint replacement. The development of bacterial biofilms bestows antibiotic resistance and restricts treatment via implant retention surgery. Electromagnetic induction heating is a novel technique for antibacterial treatment of metallic surfaces that has demonstrated in-vitro efficacy. Previous studies have always employed stationary, non-portable devices. This study aims to assess the in-vitro efficacy of induction-heating disinfection of metallic surfaces using a new Portable Disinfection System based on Induction Heating. METHODS: Mature biofilms of three bacterial species: S. epidermidis ATCC 35,984, S. aureus ATCC 25,923, E. coli ATCC 25,922, were grown on 18 × 2 mm cylindrical coupons of Titanium-Aluminium-Vanadium (Ti6Al4V) or Cobalt-chromium-molybdenum (CoCrMo) alloys. Study intervention was induction-heating of the coupon surface up to 70ºC for 210s, performed using the Portable Disinfection System (PDSIH). Temperature was monitored using thermographic imaging. For each bacterial strain and each metallic alloy, experiments and controls were conducted in triplicate. Bacterial load was quantified through scraping and drop plate techniques. Data were evaluated using non-parametric Mann-Whitney U test for 2 group comparison. Statistical significance was fixed at p ≤ 0.05. RESULTS: All bacterial strains showed a statistically significant reduction of CFU per surface area in both materials. Bacterial load reduction amounted to 0.507 and 0.602 Log10 CFU/mL for S. aureus on Ti6Al4V and CoCrMo respectively, 5.937 and 3.500 Log10 CFU/mL for E. coli, and 1.222 and 0.372 Log10 CFU/mL for S. epidermidis. CONCLUSIONS: Electromagnetic induction heating using PDSIH is efficacious to reduce mature biofilms of S aureus, E coli and S epidermidis growing on metallic surfaces of Ti6Al4V and CoCrMo alloys.

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.

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.

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.

Biomarkers of bone healing induced by a regenerative approach based on expanded bone marrow-derived mesenchymal stromal cells.

BACKGROUND: Safety and feasibility of a regenerative strategy based on the use of culture-expanded mesenchymal stromal cells (MSCs) have been investigated in phase 2 trials for the treatment of nonunion and osteonecrosis of the femoral head (ONFH). As part of the clinical study, we aimed to evaluate if bone turnover markers (BTMs) could be useful for predicting the regenerative ability of the cell therapy product. MATERIALS AND METHODS: The bone defects of 39 patients (nonunion: n = 26; ONFH: n = 13) were treated with bone marrow-derived MSCs, expanded using a clinical-grade protocol and combined with biphasic calcium phosphate before implantation. Bone formation markers, bone-resorption markers and osteoclast regulatory proteins were measured before treatment (baseline) and after 12 and 24 weeks from surgery. At the same time-points, clinical and radiological controls were performed to evaluate the bone-healing progression. RESULTS: We found that C-Propeptide of Type I Procollagen (CICP) and C-terminal telopeptide of type-I collagen (CTX) varied significantly, not only over time, but also according to clinical results. In patients with a good outcome, CICP increased and CTX decreased, and this trend was observed in both nonunion and ONFH. Moreover, collagen biomarkers were able to discriminate healed patients from non-responsive patients with a good diagnostic accuracy. DISCUSSION: CICP and CTX could be valuable biomarkers for monitoring and predicting the regenerative ability of cell products used to stimulate the repair of refractory bone diseases. To be translated in a clinical setting, these results are under validation in a currently ongoing phase 3 clinical trial.

Preclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration.

The extended life expectancy and the raise of accidental trauma call for an increase of osteoarticular surgical procedures. Arthroplasty, the main clinical option to treat osteoarticular lesions, has limitations and drawbacks. In this manuscript, we test the preclinical safety of the innovative implant ARTiCAR for the treatment of osteoarticular lesions. Thanks to the combination of two advanced therapy medicinal products, a polymeric nanofibrous bone wound dressing and bone marrow-derived mesenchymal stem cells, the ARTiCAR promotes both subchondral bone and cartilage regeneration. In this work, the ARTiCAR shows 1) the feasibility in treating osteochondral defects in a large animal model, 2) the possibility to monitor non-invasively the healing process and 3) the overall safety in two animal models under GLP preclinical standards. Our data indicate the preclinical safety of ARTiCAR according to the international regulatory guidelines; the ARTiCAR could therefore undergo phase I clinical trial.

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.

BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

Arthroscopic Partial Meniscectomy for Painful Degenerative Meniscal Tears in the Presence of Knee Osteoarthritis in Patients Older than 50 Years of Age: Predictors of an Early (1 to 5 Years) Total Knee Replacement.

BACKGROUND: The role of arthroscopic partial meniscectomy (APM) for painful degenerative meniscal tears (PDMT) is currently controversial.To define the rate of early (1 to 5 years) conversion to total knee replacement (TKR) and their predictors after APM for PDMT in patients with knee osteoarthritis and more than 50 years of age. METHODS: Retrospective cohort study of patients more than 50 years of age with the diagnosis of PDMT, treated by means of APM. Patients were classified in two groups: Patients that required an early (between 1 and 5 years after APM) TKR (TKR group) after its failure and patients that did not require a TKR (non-TKR group). Patient demographics, general characteristics, Kellgren & Lawrence (KL) classification, Outerbridge classification, and other characteristics were analyzed. Postoperative variables were also analyzed: pain, use of walking aids and use of intra-articular injections (hyaluronic acid or corticosteroids) at 3, 6, and 12 months of follow-up. RESULTS: A total of 356 patients (356 APMs) were included. Forty-nine patients (13.7%) required an early (1.8 years on average) TKR and 307 did not. The main predictor of early TKR was the grade of the KL classification. After APM, the presence of pain and the need of walking aids also were predictors of an early TKR. CONCLUSION: In patients older than 50 years with PDMT, APM should be cautiously indicated in case of KL grade of 1 or more. Postoperative pain and prolonged need of walking aids were also predictors of an early (mean 1.8 years) TKR.

Substrate Microarchitecture Shapes the Paracrine Crosstalk of Stem Cells with Endothelial Cells and Osteoblasts.

We examined the hypothesis that substrate microarchitecture regulates the crosstalk between human mesenchymal stem cells (hMSC) and cell types involved in bone regeneration. Compared with polyester flat substrates having uniformly distributed homogenous pores (2D), three-dimensional polystyrene substrates with randomly oriented and interconnected pores of heterogeneous size (3D) stimulated the stromal secretion of IGF-1 while lessened the production of VEGFR-1, MCP-1 and IL-6. The medium conditioned by hMSC cultured in 3D substrates stimulated tube formation by human endothelial cells (hEC) to a higher extent than medium from 2D cultures. 3D co-cultures of hMSC and hEC contained higher secreted levels of IGF-1, EGF and FGF-2 than 2D co-cultures, resulting in increased hEC proliferation and migration. Substrate microarchitecture influenced the secretion of factors related to bone remodeling as the ratio RANKL to OPG, and the levels of M-CSF and IL-6 were higher in 3D co-cultures of hMSC and human osteoblasts (hOB) than in 2D co-cultures. Cytokine microenvironment in 3D co-cultures stimulated osteoblast matrix reorganization while demoted the late steps of osteoblastic maturation. Altogether, data in this study may unveil a new role of scaffold microarchitecture during bone regeneration, as modulator of the paracrine relationships that hMSC establish with hEC and hOB.

Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach.

In this clinical trial, we investigated if biochemical bone turnover markers (BTM) changed according to the progression of bone healing induced by autologous expanded MSC combined with a biphasic calcium phosphate in patients with delayed union or nonunion of long bone fractures. Bone formation markers, bone resorption markers, and osteoclast regulatory proteins were measured by enzymatic immunoassay before surgery and after 6, 12, and 24 weeks. A satisfactory bone healing was obtained in 23 out of 24 patients. Nine subjects reached a good consolidation already at 12 weeks, and they were considered as the "early consolidation" group. We found that bone-specific alkaline phosphatase (BAP), C-terminal propeptide of type I procollagen (PICP), and beta crosslaps collagen (CTX) changed after the regenerative treatment, BAP and CTX correlated to the imaging results collected at 12 and 24 weeks, and BAP variation along the healing course differed in patients who had an "early consolidation." A remarkable decrease in BAP and PICP was observed at all time points in a single patient who experienced a treatment failure, but the predictive value of BTM changes cannot be determined. Our findings suggest that BTM are promising tools for monitoring cell therapy efficacy in bone nonunions, but studies with larger patient numbers are required to confirm these preliminary results.

Tranexamic Acid in a Multimodal Blood Loss Prevention Protocol to Decrease Blood Loss in Revision Total Knee Arthroplasty: A Cohort Study.

PURPOSE: To clarify if blood loss and transfusion requirements can be decreased in revision knee surgery through a multimodal blood loss approach with tranexamic acid (TXA). PATIENTS AND METHODS: A retrospective study was designed in 87 knees (79 patients) that received a knee revision between 2007 and 2013. To avoid heterogeneity in the surgical technique, only revisions with one single implant system were included. A treatment series of 44 knees that received TXA and other techniques in a multimodal blood loss protocol was compared to a control series of 43 knees that received neither TXA nor the rest of the multimodal blood loss protocol. No differences in the complexity of surgeries or case severity were detected. RESULTS: A significant decrease was observed from 58% transfusion rate in the control group to 5% in the treated group. The postoperative haemoglobin drop was also significantly different. Although the use of a blood loss prevention approach including TXA was the most relevant factor in the transfusion risk (OR=15), longer surgical time also associated an increased risk of transfusion (OR=1.15). CONCLUSION: This study supports the use of a two-dose intravenous TXA under a multimodal blood loss prevention approach in revision knee replacement with significant reduction in the transfusion rate, postoperative blood loss and haemoglobin drop.

Mid-term comparative outcomes of autologous bone-marrow concentration to treat osteonecrosis of the femoral head in standard practice.

PURPOSE: To evaluate mid-term effectiveness of core decompression (CD) followed by injection of bone-marrow concentration (BMC) in osteonecrosis of the femoral head (ONFH) compared with CD alone. METHODS: We retrospectively studied 60 hips in 45 patients with ONFH Ficat I-II after a mean follow-up of 45 (range 24-171) months. Group A (19 hips) were treated with CD, and Group B (41 hips) with CD plus autologous BMC. Necrotic lesions were classified according to MRI findings in: (i) the lesion angle; and (ii) the relation of the necrotic area to the weight-bearing portion. Outcomes included clinical changes and radiographic femoral head collapse. Risk factors associated with radiological collapse were evaluated by Cox regression analysis. RESULTS: Postoperative Merlé D´Aubigne and Postel hip score was similar in both groups. Femoral head collapse was observed in 10/19 hips in Group A and 22/41 in Group B. At 24 months, the probability of not having a collapse was 56.4% (95% CI, 33.6%-79.1%) for Group A and 57.6% (95% CI, 41.7%-73.4%) for Group B (p = 0.47). The risk of collapse increased in hips with a lesion angle higher than 150° (p<0.02, hazard risk [HR] 4.073) in both groups. CONCLUSIONS: With the standard BMC technique performed without monitoring the number of progenitors in the concentrate, we are uncertain to observe a significant decrease in femoral head collapse compared to CD alone. Improved outcomes may require the monitoring of progenitor cells injected into the femoral head, particularly in large lesions.

Effect of different agents with potential antibiofilm activity on antimicrobial susceptibility of biofilms formed by Staphylococcus spp. isolated from implant-related infections.

An in vitro study aimed to evaluate the effect of N-acetyl cysteine (NAC) or sub-ICs of erythromycin on antimicrobial susceptibility of staphylococcal biofilms was performed. Staphylococcus aureus and Staphylococcus epidermidis strains were isolated from patients with prosthetic joint infections using a previously published sonication procedure. Conventional susceptibility studies were performed using microdilution according to the CLSI procedures. Biofilm susceptibility was performed using the Calgary methodology. The addition of NAC showed no effect with the S. aureus strains, and a strain-dependent effect with the S. epidermidis strains. No effect was detected with erythromycin for almost all tested strains.

Osteostatin-coated porous titanium can improve early bone regeneration of cortical bone defects in rats.

A promising bone graft substitute is porous titanium. Porous titanium, produced by selective laser melting (SLM), can be made as a completely open porous and load-bearing scaffold that facilitates bone regeneration through osteoconduction. In this study, the bone regenerative capacity of porous titanium is improved with a coating of osteostatin, an osteoinductive peptide that consists of the 107-111 domain of the parathyroid hormone (PTH)-related protein (PTHrP), and the effects of this osteostatin coating on bone regeneration were evaluated in vitro and in vivo. SLM-produced porous titanium received an alkali-acid-heat treatment and was coated with osteostatin through soaking in a 100 nM solution for 24 h or left uncoated. Osteostatin-coated scaffolds contained ∼0.1 µg peptide/g titanium, and in vitro 81% was released within 24 h. Human periosteum-derived osteoprogenitor cells cultured on osteostatin-coated scaffolds did not induce significant changes in osteogenic (alkaline phosphatase [ALP], collagen type 1 [Col1], osteocalcin [OCN], runt-related transcription factor 2 [Runx2]), or angiogenic (vascular endothelial growth factor [VEGF]) gene expression; however, it resulted in an upregulation of osteoprotegerin (OPG) gene expression after 24 h and a lower receptor activator of nuclear factor kappa-B ligand (RankL):OPG mRNA ratio. In vivo, osteostatin-coated, porous titanium implants increased bone regeneration in critical-sized cortical bone defects (p=0.005). Bone regeneration proceeded until 12 weeks, and femurs grafted with osteostatin-coated implants and uncoated implants recovered, respectively, 66% and 53% of the original femur torque strength (97±31 and 77±53 N·mm, not significant). In conclusion, the osteostatin coating improved bone regeneration of porous titanium. This effect was initiated after a short burst release and might be related to the observed in vitro upregulation of OPG gene expression by osteostatin in osteoprogenitor cells. Long-term beneficial effects of osteostatin-coated, porous titanium implants on bone regeneration or mechanical strength were not established here and may require optimization of the pace and dose of osteostatin release.