Effects of Therapy with Fibrin Glue combined with Mesenchymal Stem Cells (MSCs) on Bone Regeneration: A Systematic Review
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.
A novel approach for knee osteoarthritis using high molecular weight hyaluronic acid conjugated to plasma fibrinogen - interim findings of a double-blind clinical study
OBJECTIVE Osteoarthritis (OA) is a widespread degenerative joint disease leading to progressive loss of function and pain. Available treatments do not provide long-term relief or improvement. This study aimed to assess the safety and efficacy of a novel intra articular supplement, made of high molecular-weight hyaluronic acid (HA) uniquely conjugated to either purified (RegenoGel) or autologous plasma-derived fibrinogen (RegenoGel-OSP), as a long-term treatment for knee OA. METHODS Sixty-seven consecutive participants (mean age 67.26 ± 7 years) with symptomatic OA were randomly assigned to receive intraarticular injections of either RegenoGel, RegenoGel-OSP or saline solution (placebo). The active treatment groups received a second, repeat injection of the corresponding treatment at the 3-month evaluation, at which time, the placebo group was divided into two subgroups, one receiving RegenoGel and the other receiving RegenoGel-OSP. The OA symptoms were assessed by VAS, WOMAC, and IKDC questionnaires at baseline and at 1, 3, 4, and 6 months following the first injection. OA-related quality of life was evaluated by the SF-12 survey. RESULTS Our preliminary data suggests that both fibrin-HA formulations have positive effects on OA symptoms for all assessed parameters with the most prominent trend for reduction in OA-associated pain. Pooled data analysis of RegenoGel and RegenoGel-OSP shows significantly improved VAS scores compared to placebo at three months after the first injection, and sustained for another three months after the second injection. Both RegenoGel, RegenoGel-OSP had an excellent safety profile. CONCLUSIONS Interim analysis results indicate that RegenoGel and RegenoGel-OSP are safe and are potentially effective for at least six months in alleviating pain and symptoms of knee OA.
Autologous Interleukin 1 Receptor Antagonist Blood-Derived Products for Knee Osteoarthritis: A Systematic Review
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2019;35(7):2211-2221
PURPOSE To systematically review the available clinical data regarding the use of autologous IL-1 receptor antagonist blood products (AILBPs) and their validity as an alternative intra-articular (IA) therapy for symptomatic knee osteoarthritis (OA). METHODS The PubMed, MEDLINE, Embase, and Cochrane Library databases were searched from inception to June 2018. All randomized controlled trials (RCTs) and noncomparative studies that evaluated the clinical efficacy of AILBPs (i.e., autologous protein solution and autologous conditioned serum) for knee OA were included. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index. The secondary outcomes measured were the Knee Injury and Osteoarthritis Outcome Score, visual analog scale score, Short Form 36 (SF-36) score, radiographic scores, and adverse events, which were qualitatively analyzed. RESULTS We included 8 studies, comprising 3 RCTs (Level II) and 5 noncomparative studies (Level IV), with a total of 592 patients (mean age, 56.4 years; 49.7% male patients). The RCTs represented high methodologic quality, whereas the noncomparative studies represented moderate to good quality. With AILBPs, 2 of 4 studies (50%) showed improvements in the Knee Injury and Osteoarthritis Outcome Score symptom and sport subscales, 5 of 7 studies (71%) achieved improvements in the Western Ontario and McMaster Universities Osteoarthritis Index score, and 4 of 5 studies (80%) attained improvements in the visual analog scale pain score from baseline to final follow-up. Most adverse events associated with AILBPs were mild to moderate in severity and were primarily localized to the injection site. CONCLUSIONS Limited evidence substantiates that AILBPs are a safe and tolerable IA injection therapy that may improve pain parameters and functionality for mild to moderate knee OA patients and may be an effective adjunct for those unresponsive to traditional IA therapies. LEVEL OF EVIDENCE Level IV, systematic review of Level II through IV studies.
Interventions for dysphagia in long-term, progressive muscle disease
The Cochrane Database of Systematic Reviews. 2016;((2)):CD004303.
BACKGROUND Normal swallowing function is divided into oral, pharyngeal, and oesophageal phases. The anatomy and physiology of the oral cavity facilitates an oral preparatory phase of swallowing, in which food and liquid are pushed towards the pharynx by the tongue. During pharyngeal and oesophageal phases of swallowing, food and liquid are moved from the pharynx to the stomach via the oesophagus. Our understanding of swallowing function in health and disease has informed our understanding of how muscle weakness can disrupt swallowing in people with muscle disease. As a common complication of long-term, progressive muscle disease, there is a clear need to evaluate the current interventions for managing swallowing difficulties (dysphagia). This is an update of a review first published in 2004. OBJECTIVES To assess the effects of interventions for dysphagia in people with long-term, progressive muscle disease. SEARCH METHODS On 11 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, LILACS, and CINAHL. We checked references in the identified trials for additional randomised and quasi-randomised controlled trials. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform on 12 January 2016 for ongoing or completed but unpublished clinical trials. SELECTION CRITERIA We included randomised and quasi-randomised controlled trials that assessed the effect of interventions for managing dysphagia in adults and children with long-term, progressive muscle disease, compared to other interventions, placebo, no intervention, or standard care. Quasi-randomised controlled trials are trials that used a quasi-random method of allocation, such as date of birth, alternation, or case record number. Review authors previously excluded trials involving people with muscle conditions of a known inflammatory or toxic aetiology. In this review update, we decided to include trials of people with sporadic inclusion body myositis (IBM) on the basis that it presents as a long-term, progressive muscle disease with uncertain degenerative and inflammatory aetiology and is typically refractory to treatment. DATA COLLECTION AND ANALYSIS We applied standard Cochrane methodological procedures. MAIN RESULTS There were no randomised controlled trials (RCTs) that reported results in terms of the review's primary outcome of interest, weight gain or maintenance. However, we identified one RCT that assessed the effect of intravenous immunoglobulin on swallowing function in people with IBM. The trial authors did not specify the number of study participants who had dysphagia. There was also incomplete reporting of findings from videofluoroscopic investigations, which was one of the review's secondary outcome measures. The study did report reductions in the time taken to swallow, as measured using ultrasound. No serious adverse events occurred during the study, although data for the follow-up period were lacking. It was also unclear whether the non-serious adverse events reported occurred in the treatment group or the placebo group. We assessed this study as having a high risk of bias and uncertain confidence intervals for the review outcomes, which limited the overall quality of the evidence. Using GRADE criteria, we downgraded the quality of the evidence from this RCT to 'low' for efficacy in treating dysphagia, due to limitations in study design and implementation, and indirectness in terms of the population and outcome measures. Similarly, we assessed the quality of the evidence for adverse events as 'low'. From our search for RCTs, we identified two other non-randomised studies, which reported the effects of long-term intravenous immunoglobulin therapy in adults with IBM and lip-strengthening exercises in children with myotonic dystrophy type 1. Headaches affected two participants treated with long-term intravenous immunoglobulin therapy, who received a tailored dose reduction; there
Platelet-rich plasma as a treatment for patellar tendinopathy: a double-blind, randomized controlled trial
American Journal of Sports Medicine. 2014;42((3):):610-8.
BACKGROUND Previous studies have shown improvement in patellar tendinopathy symptoms after platelet-rich plasma (PRP) injections, but no randomized controlled trial has compared PRP with dry needling (DN) for this condition. PURPOSE To compare clinical outcomes in patellar tendinopathy after a single ultrasound-guided, leukocyte-rich PRP injection versus DN. STUDY DESIGN Randomized controlled trial; Level of evidence, 1. METHODS A total of 23 patients with patellar tendinopathy on examination and MRI who had failed nonoperative treatment were enrolled and randomized to receive ultrasound-guided DN alone (DN group; n = 13) or with injection of leukocyte-rich PRP (PRP group; n = 10), along with standardized eccentric exercises. Patients and the physician providing follow-up care were blinded. Participants completed patient-reported outcome surveys before and at 3, 6, 9, 12, and >26 weeks after treatment during follow-up visits. The primary outcome measure was the Victorian Institute of Sports Assessment (VISA) score for patellar tendinopathy at 12 weeks, and secondary measures included the visual analog scale (VAS) for pain, Tegner activity scale, Lysholm knee scale, and Short Form (SF-12) questionnaire at 12 and >26 weeks. Results were analyzed using 2-tailed paired and unpaired t tests. Patients who were dissatisfied at 12 weeks were allowed to cross over into a separate unblinded arm. RESULTS At 12 weeks after treatment, VISA scores improved by a mean + standard deviation of 5.2 + 12.5 points (P = .20) in the DN group (n = 12) and by 25.4 + 23.2 points (P = .01) in the PRP group (n = 9); at >26 weeks, the scores improved by 33.2 + 14.0 points (P = .001) in the DN group (n = 9) and by 28.9 + 25.2 points (P = .01) in the PRP group (n = 7). The PRP group had improved significantly more than the DN group at 12 weeks (P = .02), but the difference between groups was not significant at >26 weeks (P = .66). Lysholm scores were not significantly different between groups at 12 weeks (P = .81), but the DN group had improved significantly more than the PRP group at >26 weeks (P = .006). At 12 weeks, 3 patients in the DN group failed treatment and subsequently crossed over into the PRP group. These patients were excluded from the primary >26-week analysis. There were no treatment failures in the PRP group. No adverse events were reported. Recruitment was stopped because interim analysis demonstrated statistically significant and clinically important results. CONCLUSION A therapeutic regimen of standardized eccentric exercise and ultrasound-guided leukocyte-rich PRP injection with DN accelerates the recovery from patellar tendinopathy relative to exercise and ultrasound-guided DN alone, but the apparent benefit of PRP dissipates over time.
Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis
Cochrane Database of Systematic Reviews. 2012;8:CD003643.
BACKGROUND Idiopathic inflammatory myopathies are chronic diseases with significant mortality and morbidity. Whilst immunosuppressive and immunomodulatory therapies are frequently used, the optimal therapeutic regimen remains unclear. This is an update of a review first published in 2005. OBJECTIVES To assess the effects of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis. SEARCH METHODS We searched the Cochrane Neuromuscular Disease Group Specialized Register (August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3 2011), MEDLINE (January 1966 to August 2011), EMBASE (January 1980 to August 2011) and clinicaltrials.gov (August 2011). We checked the bibliographies of identified trials and wrote to disease experts. SELECTION CRITERIA We included all randomised controlled trials (RCTs) or quasi-RCTs involving participants with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter, or definite, probable or mild/early by the criteria of Dalakas. In participants without a classical rash of dermatomyositis, inclusion body myositis should have been excluded by muscle biopsy. We considered any immunosuppressant or immunomodulatory treatment. The two primary outcomes were the change in a function or disability scale measured as the proportion of participants improving one grade, two grades etc, predefined based on the scales used in the studies after at least six months, and a 15% or greater improvement in muscle strength compared with baseline after at least six months. Other outcomes were: the International Myositis Assessment and Clinical Studies Group (IMACS) definition of improvement, number of relapses and time to relapse, remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. DATA COLLECTION AND ANALYSIS Two authors independently selected papers, extracted data and assessed risk of bias in included studies. They collected adverse event data from the included studies. MAIN RESULTS The review authors identified fourteen 14 relevant RCTs. They excluded four trials.The 10 included studies, four of which have been added in this update, included a total of 258 participants. Six studies compared an immunosuppressant or immunomodulator with placebo control, and four studies compared two immunosuppressant regimes with each other. Most of the studies were small (the largest had 62 participants) and many of the reports contained insufficient information to assess risk of bias.Amongst the six studies comparing immunosuppressant with placebo, one study, investigating intravenous immunoglobulin (IVIg), showed statistically significant improvement in scores of muscle strength in the IVIg group over three months. Another study investigating etanercept showed some evidence of a steroid sparing effect, a secondary outcome in this review, but no improvement in other assessed outcomes. The other four randomised placebo-controlled trials assessed either plasma exchange and leukapheresis, eculizumab, infliximab or azathioprine against placebo and all produced negative results.Three of the four studies comparing two immunosuppressant regimes (azathioprine with methotrexate, ciclosporin with methotrexate, and intramuscular methotrexate with oral methotrexate plus azathioprine) showed no statistically significant difference in efficacy between the treatment regimes. The fourth study comparing pulsed oral dexamethasone with daily oral prednisolone and found that the dexamethasone regime had a shorter median time to relapse but fewer side effects.Immunosuppressants were associated with significant side effects. AUTHORS' CONCLUSIONS This systematic review highlights the lack of high quality RCTs that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.
Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review
Clinical Rheumatology. 2012;31((5):):801-6.
The objectives of this study are to review and summarize published information on the use, effectiveness, and adverse effects of intravenous immunoglobulin (IVIG) in patients with polymyositis (PM) or dermatomyositis (DM) and to search MEDLINE and CNKI (Chinese) databases from 1985 to 2011 to retrieve clinical research articles concerning IVIG in adult patients with PM/DM. Of the 14 articles selected, two were randomized controlled trials, nine prospective open studies, and three retrospective studies with a total of 308 adult patients. IVIG has been used successfully in the treatment of PM/DM. The standard dose is 2 g/kg, given in two to five individual daily doses. The course of IVIG treatment is usually 3~6 months. IVIG therapy seemed rarely employed as first-line therapy in PM/DM. In a double-blind study conducted in patients with refractory DM, IVIG combined with corticosteroid significantly improved muscle strength and decreased serum creatine kinase level, compared with placebo. The beneficial effect of IVIG in refractory, flare-up, rapidly progressive, or severe PM/DM has been documented in many open-label trials. IVIG was shown to be effective in most of PM/DM patients with lung involvement and esophageal involvement. In some patients, IVIG can lower the corticosteroid dose required for maintenance, demonstrating the most effective steroid-sparing effect. Adverse effects were generally tolerable. IVIG is effective in the treatment of adult patients with PM/DM and appears to be relatively well tolerated and safe. IVIG may be a good choice especially in patients with refractory, flare-up, rapidly progressive, or severe PM/DM, and can be tried in patients with a contraindication for corticosteroid.
Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis
BMC Pediatrics. 2012;12:29
BACKGROUND Treatment of juvenile idiopathic arthritis (JIA) with disease-modifying antirheumatic drugs (DMARDs) may improve outcomes compared to conventional therapy (e.g., non-steroidal anti-inflammatory drugs, intra-articular corticosteroids). The purpose of this systematic review was to evaluate the comparative effectiveness and safety of DMARDs versus conventional therapy and versus other DMARDs. RESULTS A systematic evidence review of 156 reports identified in MEDLINE, EMBASE, and by hand searches. There is some evidence that methotrexate is superior to conventional therapy. Among children who have responded to a biologic DMARD, randomized discontinuation trials suggest that continued treatment decreases the risk of having a flare. However, these studies evaluated DMARDs with different mechanisms of action (abatacept, adalimumab, anakinra, etanercept, intravenous immunoglobulin, tocilizumab) and used varying comparators and follow-up periods. Rates of serious adverse events are similar between DMARDs and placebo in published trials. This review identified 11 incident cases of cancer among several thousand children treated with one or more DMARD. CONCLUSIONS Few data are available to evaluate the comparative effectiveness of either specific DMARDs or general classes of DMARDs. However, based on the overall number, quality, and consistency of studies, there is moderate strength of evidence to support that DMARDs improve JIA-associated symptoms. Limited data suggest that short-term risk of cancer is low.
A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM
OBJECTIVE To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (s-IBM). BACKGROUND In a previous controlled trial in s-IBM, IVIg did not significantly improve strength in spite of modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with IVIg prompted another controlled trial. METHODS Thirty-six patients with biopsy-proven IBM were randomized to receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing; and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers. RESULTS Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or 4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p < 0.0001), denoting a steroid effect. CONCLUSION IVIg combined with prednisone for a 3-month period was not effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of clinical significance.
Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study
We randomized 19 patients with inclusion-body myositis (IBM) to a double-blind, placebo-controlled, crossover study using monthly infusions of 2 g/kg intravenous immunoglobulin (IVIg) or placebo for 3 months. Patients crossed over to the alternate treatment after a washout period. We evaluated responses at baseline and at the end of each treatment period using expanded (0-10) MRC scales, the Maximum Voluntary Isometric Contraction (MVIC) method, symptom and disability scores, and quantitative swallowing studies. We calculated the differences in scores between IVIg and placebo from baseline to end of treatment. Of the 19 patients, 9 (mean age, 61.2 years; mean disease duration, 5.6 years) were randomized to IVIg and 10 (mean age, 66.1 years; mean disease duration, 7.4 years) to placebo. During IVIg the patients gained a mean of 4.2 (-16 to +39.8) MRC points, and during placebo lost 2.7 (-10 to +8) points (p < 0.1). These gains were not significant. Similar results were obtained with the MRC and MVIC scores when the patients crossed to the alternate treatment. Six patients had a functionally important improvement by more than 10 MRC points that declined when crossed over to placebo. Limb-by-limb analysis demonstrated that during IVIg the muscle strength in 39% of the lower extremity limbs significantly increased compared with placebo (p < 0.05), while a simultaneous decrease in 28% of other limbs was detected. The clinical importance of these minor gains is unclear. The duration of swallowing functions measured in seconds with ultrasound improved statistically in the IVIg-randomized patients (p < 0.05) compared with placebo. Although the study did not establish efficacy of IVIg, possibly because of the small sample size, the drug induced functionally important improvement in 6 (28%) of the 19 patients. Whether the modest gains noted in certain muscle groups justify the high cost of trying IVIg in IBM patients at a given stage of the disease remains unclear.