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Effects of Therapy with Fibrin Glue combined with Mesenchymal Stem Cells (MSCs) on Bone Regeneration: A Systematic Review
Ortiz AC, Fideles SOM, Pomini KT, Reis CHB, Bueno CRS, Pereira Esbm, Rossi JO, Novais PC, Pilon JPG, Rosa Junior GM, et al
Cells. 2021;10(9)
Abstract
Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized cell lines. Fibrin sealant or fibrin glue is a natural polymer involved in the coagulation process. Fibrin glue provides a temporary structure that favors angiogenesis, extracellular matrix deposition and cell-matrix interactions. Additionally, fibrin glue maintains the local and paracrine functions of MSCs, providing tissue regeneration through less invasive clinical procedures. Thus, the objective of this systematic review was to assess the potential of fibrin glue combined with MSCs in bone or cartilage regeneration. The bibliographic search was performed in the PubMed/MEDLINE, LILACS and Embase databases, using the descriptors ("fibrin sealant" OR "fibrin glue") AND "stem cells" AND "bone regeneration", considering articles published until 2021. In this case, 12 preclinical and five clinical studies were selected to compose this review, according to the eligibility criteria. In preclinical studies, fibrin glue loaded with MSCs, alone or associated with bone substitute, significantly favored bone defects regeneration compared to scaffold without cells. Similarly, fibrin glue loaded with MSCs presented considerable potential to regenerate joint cartilage injuries and multiple bone fractures, with significant improvement in clinical parameters and absence of postoperative complications. Therefore, there is clear evidence in the literature that fibrin glue loaded with MSCs, alone or combined with bone substitute, is a promising strategy for treating lesions in bone or cartilaginous tissue.
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2.
A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures
Durdevic D, Vlahovic T, Pehar S, Miklic D, Oppermann H, Bordukalo-Niksic T, Gavrankapetanovic I, Jamakosmanovic M, Milosevic M, Martinovic S, et al
Bone. 2020;:115551
Abstract
Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 hours following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P=0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
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3.
Tranexamic acid administration for anatomic and reverse total shoulder arthroplasty: a systematic review and meta-analysis
Box, H. N., Tisano, B. S., Khazzam, M.
JSES open access. 2018;2(1):28-33
Abstract
Background: Tranexamic acid (TXA) has been shown to reduce perioperative blood loss and risk of blood transfusion. Evidence establishing its efficacy in total shoulder arthroplasty (TSA) is limited. The current study evaluated the effect of TXA on perioperative blood loss and transfusion risk after TSA. Methods: A systematic review and meta-analysis of TXA administration for TSA was performed, and 6 studies with a total of 680 patients were found. Data on change in hemoglobin, drain output, total blood loss, and transfusion were extracted. Meta-analysis was performed with stratification into reverse and anatomic TSA subgroups. Results: TXA administration was associated with decreased change in hemoglobin (-0.63 g/dL; 95% CI, -0.87 to -0.39 g/dL; P < .00001), drain output (-112.05 mL; 95% CI, -182.29 to -41.81 mL; P < .0001), and total blood loss (-231.87 mL; 95% CI, -334.23 to -129.48 mL; P < .00001) after reverse TSA. There was a trend toward reduction in transfusion rate after reverse TSA (-4%; 95% CI, -8% to 0%; P = .06). TXA administration was associated with reduced drain output after anatomic TSA (-123.07 mL; 95% CI, -163.93 to -82.20 mL; P < 0.00001). TXA administration was not associated with decreased transfusion rate after anatomic TSA. Data to evaluate the effect of TXA on change in hemoglobin and total blood loss after anatomic TSA were insufficient. Conclusions: Routine administration of TXA reduces perioperative blood loss and may reduce the risk of transfusion after reverse TSA. Future studies are needed to further characterize its effect on the risk of transfusion after reverse TSA and efficacy in anatomic TSA.
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4.
Tranexamic acid reduces blood loss after primary shoulder arthroplasty: a double-blind, placebo-controlled, prospective, randomized controlled trial
Cvetanovich GL, Fillingham YA, O'Brien M, Forsythe B, Cole BJ, Verma NN, Romeo AA, Nicholson GP
JSES open access. 2018;2(1):23-27
Abstract
Background: Tranexamic acid (TXA) is an antifibrinolytic that has been shown to decrease blood loss and transfusion rates after hip and knee arthroplasty, with only limited evidence to support its use in shoulder arthroplasty. This study was conducted to determine whether intravenous (IV) TXA is more effective than placebo in reducing blood loss after primary total shoulder arthroplasty (TSA). Methods: In this prospective, double-blind, placebo-controlled, randomized clinical trial, patients undergoing primary anatomic and reverse TSA were randomized to receive 1 g of intravenous TXA or a placebo of an equivalent volume of intravenous normal saline administered 10 minutes before the incision. The primary outcome measurement was calculated postoperative blood loss. Secondary outcomes included transfusion rates, weight of hemoglobin loss, hospital length of stay, and thromboembolic events. Results: The study enrolled 110 patients, 2 of whom were excluded because they did not have a postoperative hemoglobin measurement, and the remaining 108 patients (52 for TXA, 56 for placebo) were analyzed. There were no significant differences between TXA and placebo groups in preoperative characteristics. For the primary outcome, the TXA group had significantly lower postoperative blood loss of 1100.9 +/- 367.4 mL compared with 1274.5 +/- 460.0 mL for the placebo group (P = .03). For secondary outcomes, TXA had lower weight of hemoglobin loss compared with placebo (152.2 +/- 57.3 g vs. 178.0 +/- 65.8 g; P = .03). No patients in the TXA or placebo groups required a transfusion. Conclusions: Intravenous TXA reduced blood loss after primary TSA compared with placebo.
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5.
Local corticosteroid versus autologous blood injections in lateral epicondylitis: meta-analysis of randomized controlled trials
Sirico F, Ricca F, Di Meglio F, Nurzynska D, Castaldo C, Spera R, Montagnani S
European Journal of Physical and Rehabilitation Medicine. 2016;53((3):):483-491.
Abstract
BACKGROUND Lateral epicondylitis is a common painful elbow disorder. Several approaches to treatment have been proposed, with a local injection of corticosteroids being the most frequently used. Recent insights into the pathophysiology encouraged the introduction of autologous blood injections as an alternative treatment method. AIM: The aim of this meta-analysis is to summarize quantitatively the evidence regarding the efficacy of corticosteroids and autologous blood injections for treatment of pain in lateral epicondylitis. DESIGN Meta-analysis. SETTING Outpatient treatment. POPULATION Studies were considered eligible based on the following inclusion criteria: adult human, diagnosis of lateral epicondylitis, randomized controlled trials comparing corticosteroids versus autologous blood injections, pain assessment. Exclusion criteria were previous surgery for lateral epicondylitis or for other elbow disorders, concurrent treatment with drugs or physiotherapy, diagnosis of musculoskeletal systemic disorder. METHODS A systematic search of literature was performed according to PRISMA statement. Effect size of each included study was calculated and analyzed in a random-effects model. RESULTS Four studies, enrolling total of 218 patients (139 females and 79 males), were included in quantitative analysis. At 2 weeks there was a trend towards a reduction of VAS score in the corticosteroid group (WMD = 2.12 [95% CI: 4.38 to 0.14], P=0.07). No significant differences were recorded in the medium-term (4-12 weeks; WMD = 0.85 [95% CI: -0.44 to 2.15], P= 0.19) and long-term (24 weeks; WMD = 0.63 [95% CI: -2.40 to 3.66], P= 0.68) follow-up. CONCLUSIONS Few high-quality trials compare the efficacy of corticosteroid and autologous blood injections in the control of pain related to lateral epicondylitis. Available data indicate that corticosteroids tend to reduce VAS score in short-term follow-up, although these data are not statistically significant. No differences were recorded in the medium and long term. CLINICAL REHABILITATION IMPACT Contrary to popular opinion among medical professionals, and despite pathophysiological cues, the currently available data offer no support for the effectiveness of autologous blood injections in medium- and long- term follow-up. Further studies are necessary to establish which treatment has more impact on pain in lateral epicondylitis. These data could be then used as a basis for practical guidelines and new protocols of treatment.
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6.
Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis
Marti-Carvajal AJ, Agreda-Perez LH, Sola I, Simancas-Racines D
Cochrane Database of Systematic Reviews. 2013;2:CD000332.
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that mainly affects the small joints of the hands and feet. Erythropoiesis-stimulating agents have been used to treat anemia, one of the extra-articular manifestations of RA. Although anemia is less of a problem now because of the reduction in inflammation due to disease-modifying antirheumatic drugs (DMARDs), it could still be an issue in countries where DMARDs are not yet accessible. OBJECTIVES We assessed the clinical benefits and harms of erythropoiesis-stimulating agents for anemia in rheumatoid arthritis. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (1948 to 7 August 2012), OVID EMBASE (1980 to 7 August 2012), LILACS (1982 to 7 August 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles. We did not apply any language restrictions. SELECTION CRITERIA We included randomized controlled trials (RCTs) in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia. We considered health-related quality of life, fatigue and safety as the primary outcomes. DATA COLLECTION AND ANALYSIS Two authors independently performed trial selection, risk of bias assessment, and data extraction. We estimated difference in means with 95% confidence intervals (CIs) for continuous outcomes. We estimated risk ratios with 95% CIs for binary outcomes. MAIN RESULTS We included three RCTs with a total of 133 participants. All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo. All RCTs assessed health-related quality of life. All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry. Two trials administered EPO by a subcutaneous route while the other used an intravenous route.We decided not to pool results from trials, due to inconsistencies in the reporting of results.Health-related quality of life: subcutaneous EPO - one trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (P = 0.027) on a VAS scale (0 to 10)). The other shorter term trials (12 weeks with subcutaneous EPO and eight weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.Change in hemoglobin: both trials of subcutaneous EPO showed a statistically significant difference in increasing hemoglobin levels; (i) at 52 weeks (one trial, 70 patients), intervention hemoglobin level (median 134, interquartile range 110 to 158 g/litre) compared with the placebo group level (median 112, interquartile range; 86 to 128 g/litre) (P = 0.0001); (ii) at 12 weeks (one trial, 24 patients) compared with placebo (difference in means 8.00, 95% CI 7.43 to 8.57). Intravenous EPO at eight weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means 4.69, 95% CI -0.17 to 9.55; P = 0.06).Information on withdrawals due to adverse events was not reported in two trials, and one trial found no serious adverse events leading to withdrawals. None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue. AUTHORS' CONCLUSIONS We found conflicting evidence for erythropoiesis-stimulating agents to increase quality of life and hemoglobin level by treating anemia in patients with rheumatoid arthritis. However, this conclusion is based on randomized controlled trials with a high risk of bias, and relies on trials assessing human recombinant erythropoietin (EPO). The safety profile of EPO is unclear. Future trials assessing erythropoiesis-stimulating agents fo
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7.
Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial
Peeters HR, Jongen-Lavrencic M, Vreugdenhil G, Swaak AJ
Annals of the Rheumatic Diseases. 1996;55((10):):739-44.
Abstract
OBJECTIVE To study whether recombinant human erythropoietin (r-hu-Epo) improves anaemia and reduces disease activity in patients with rheumatoid arthritis and anaemia of chronic disease (ACD). METHODS A 52 week placebo controlled randomised double blind trial with r-hu-Epo was performed in 70 patients with active rheumatoid arthritis and ACD. Thirty four patients were treated with 240 U kg-1 r-hu-Epo subcutaneously, initially three doses weekly, while 36 patients received placebo. RESULTS A significant increase of haemoglobin from a median of 112 to 135 g litre-1 occurred in the Epo group within six weeks and could be sustained with reduced doses (median 240 U kg-1 once weekly). Sustained benefit compared to placebo was also apparent by six weeks for disease activity, as indicated by the Paulus 20% response rate. Of patients in the Epo group, 32% eventually showed a Paulus 20% response, compared to 8% of the placebo group (P = 0.016). Significant differences in favour of the Epo group were also observed in the secondary disease activity measures Ritchie index, number of swollen joints, pain score, ESR, and patients' global assessment of disease activity. C reactive protein concentrations did not change significantly. CONCLUSIONS Treatment of ACD in rheumatoid arthritis with r-hu-Epo is effective in restoring normal haemoglobin levels and also exerts a beneficial effect on disease activity.