Current regenerative strategies for alveolar bone and periodontal tissues are effective and well adopted. These are mainly based on the use of a combination of synthetic/natural scaffolds and bioactive agents, obviating the incorporation of cells. However, there are some inherent limitations associated with traditional techniques, and we hypothesized that the use of cell-based therapies as part of comprehensive regenerative protocols may help overcome these hurdles to enhance clinical outcomes. We conducted a systematic review of human controlled clinical trials investigating the clinical and/or histological effect of the use of cell-based therapies for alveolar bone and periodontal regeneration and explored the translational potential of the different cell-based strategies identified in the included trials. A total of 16 studies (11 randomized controlled trials, 5 controlled clinical trials) were included for data synthesis and qualitative analysis with meta-analyses performed when appropriate. The results suggest a clinical benefit from the use of cell therapy. Improved outcomes were shown for alveolar ridge preservation, lateral ridge augmentation, and periodontal regeneration. However, there was insufficient evidence to identify best-performing treatment modalities amongst the different cell-based techniques. In light of the clinical and histological outcomes, we identify extraction socket and challenging lateral and vertical bone defects requiring bone block grafts as strong candidates for the adjuvant application of mesenchymal stem cells. Given the complexity, invasiveness, and costs associated with techniques that include "substantial manipulation" of tissues and cells, their additional clinical benefit when compared with "minimal manipulation" must be elucidated in future trials. Stem Cells Translational Medicine 2019;8:1286&1295.

Secretome and extracellular vesicles (EVs) are considered a promising option to exploit mesenchymal stem cells' (MSCs) properties to address knee osteoarthritis (OA). The aim of this systematic review was to analyze both the in vitro and in vivo literature, in order to understand the potential of secretome and EVs as a minimally invasive injective biological approach. A systematic review of the literature was performed on PubMed, Embase, and Web of Science databases up to 31 August 2019. Twenty studies were analyzed; nine in vitro, nine in vitro and in vivo, and two in vivo. The analysis showed an increasing interest in this emerging field, with overall positive findings. Promising in vitro results were documented in terms of enhanced cell proliferation, reduction of inflammation, and down-regulation of catabolic pathways while promoting anabolic processes. The positive in vitro findings were confirmed in vivo, with studies showing positive effects on cartilage, subchondral bone, and synovial tissues in both OA and osteochondral models. However, several aspects remain to be clarified, such as the different effects induced by EVs and secretome, which is the most suitable cell source and production protocol, and the identification of patients who may benefit more from this new biological approach for knee OA treatment.

Mesenchymal stromal cells (MSCs) and secretome are promising therapies for pulmonary arterial hypertension (PAH). This meta-analysis aimed to provide a precise estimate and compare the therapeutic efficacy of MSC and secretome in PAH. We searched six databases (CINAHL, Cochrane, Ovid Medline, PubMed, Science Direct and Scopus) until December 2018 using search terms related to MSCs, secretome and PAH. Twenty-three studies were included for the meta-analysis. The effect size of pulmonary hemodynamics and right ventricular hypertrophy markers was estimated using random effects model. MSCs and secretome significantly improved pulmonary hemodynamics and right ventricular hypertrophy compared to control. Comparison between MSCs and secretome indicate no significant difference in reducing right ventricular systolic pressure (RVSP) and medial wall thickening (MWT). However, treatment of PAH with secretome significantly improved mean pulmonary arterial pressure (mPAP) (p = 0.018) and right ventricular/left ventricular + septum (RV/LV+S) (p = 0.017) better than MSCs. Meta-regression shows that cell type (p = 0.034) is a predictor of MSCs to reduce RVSP in PAH. Similarly, the effect of secretome on MWT was significantly (p = 0.011) better at 4 weeks compared to 2 weeks of intervention. The overall risk of bias ranges from low to moderate; however, some of the essential elements required in reports of animal trials were not reported. There was evidence of publication bias for RV/LV+S and MWT, but not RVSP. This meta-analysis provides evidence of the therapeutic benefits of MSCs and secretome in PAH and the effect of secretome was similar or superior to MSCs.

There is controversy about the role of scaffolds as an adjunctive therapy to mesenchymal stem cell (MSC) transplantation in spinal cord injury (SCI). Thus, the authors aimed to design a meta-analysis on preclinical evidence to evaluate the effectiveness of combination therapy of scaffold + MSC transplantation in comparison with scaffolds alone and MSCs alone in improving motor dysfunction in SCI.

Inflammation plays an important role in the pathogenesis of many lung diseases. Preclinical studies suggest that mesenchymal stromal cell (MSC) conditioned media (CdM) can attenuate inflammation. Our aim was threefold: (1) summarize the existing animal literature evaluating CdM as a therapeutic agent for pediatric/adult lung disease, (2) quantify the effects of CdM on inflammation, and (3) compare inflammatory effects of CdM to MSCs.

There may be the potential to improve stroke recovery with mesenchymal stem cells (MSCs); however, questions about the efficacy and safety of this treatment remain. To address these issues and inform future studies, we performed a preclinical and clinical systematic review of MSC therapy for subacute and chronic ischemic stroke. MEDLINE, Embase, the Cochrane Register of Controlled Trials, and PubMed were searched. For the clinical review, interventional and observational studies of MSC therapy in ischemic stroke patients were included. For the preclinical review, interventional studies of MSC therapy using in vivo animal models of subacute or chronic stroke were included. Measures of safety and efficacy were assessed. Eleven clinical and 76 preclinical studies were included. Preclinically, MSC therapy was associated with significant benefits for multiple measures of motor and neurological function. Clinically, MSC therapy appeared to be safe, with no increase in adverse events reported (with the exception of self-limited fever immediately following injection). However, the efficacy of treatment was less apparent, with significant heterogeneity in both study design and effect size being observed. Additionally, in the only randomized phase II study to date, efficacy of MSC therapy was not observed. Preclinically, MSC therapy demonstrated considerable efficacy. Although MSC therapy demonstrated safety in the clinical setting, efficacy has yet to be determined. Future studies will need to address the discordance in the continuity of evidence as MSC therapy has been translated from "bench-to-bedside".

Novel therapeutic modalities have been proposed for the treatment and management of erectile dysfunction (ED). Stem cell therapy (SCT) is the injection of mesenchymal stem cells or stromal vascular fractions from adipose and other tissue sources. Although SCT has been studied and reported in multiple rodent trials, few human clinical trials exist.

Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood.

To evaluate the reported literature on the use of stem cells or growth factors for post extraction treatment of the alveolar bone.

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.

Our goal was to understand the impact of regenerative therapies on the functional capacity of skeletal muscle following volumetric muscle loss (VML) injury. An extensive database search (e.g., PubMed, Cochrane Library, and ClinicalTrials.gov) was conducted up through January 2019 to evaluate the following: "In humans or animals with VML injury, is treatment better than no treatment at recovering functional capacity?" Study eligibility criteria required studies to have both an untreated and at least one treated VML injury group. From 2312 study reports, 44 studies met the inclusion criteria. Quantitative functional capacity data (absolute and/or normalized strength) or proportional measures (histological analysis quantifying viable muscle tissue, mitochondrial function, and/or exhaustive treadmill running) were extracted for use. While both human and animal studies were included in the searches, only animal studies met the eligibility criteria. Using a random-effects model, Hedges' g was used as the effect size (ES) and calculated such that a positive ES indicated treatment efficacy. The overall ES was 0.75 (95% confidence interval: 0.53-0.96; p < 0.0000001), indicating that the treatments, on average, resulted in a significant improvement in functional capacity. From network meta-analyses, it was determined that an acellular biomaterial combined with stem and/or progenitor cells had the greatest treatment effectiveness. The findings indicate that various treatments in animal models of VML improve the functional capacity of muscle compared to leaving the injury untreated; however, the ∼16% beneficial effect is small. Our results suggest that current regenerative therapy paradigms require further maturation to achieve clinically meaningful improvements in the functional capacity of the muscle. Impact Statement Our most salient findings are that (1) various treatment approaches used in animal models of volumetric muscle loss (VML) injury improve functional capacity compared to leaving the injury untreated and (2) an acellular biomaterial in combination with cellular components was the most effective treatment to improve functional capacity following VML injury to date. The nature of our findings has substantial implications for regenerative medicine, biomedical engineering, and rehabilitative techniques currently being evaluated and developed for VML injury repair, and are pivotal to the progression of the regenerative medicine effort aimed at restoring maximal function to traumatized and disabled limbs.

Current techniques for breast reconstruction include an autologous-tissue flap or an implant-based procedure, although both can impose further morbidity. This systematic review aims to explore the existing literature on breast reconstruction using a tissue engineering approach; conducted with the databases Medline and Embase. A total of 28 articles were included, mainly comprising of level-5 evidence with in vitro and animal studies focusing on utilizing scaffolds to support the migration and growth of new tissue; scaffolds can be either biological or synthetic. Biological scaffolds were composed of collagen or a decellularized tissue matrix scaffold. Synthetic scaffolds were primarily composed of polymers with customisable designs, adjusting the internal morphology and pore size. Implanting cells, including adipose-derived stem cells, with combined use of basic fibroblast growth factor has been studied in an attempt to enhance tissue regeneration. Lately, a level-4 evidence human case series was reported; successfully regenerating 210 mL of tissue using an arterio-venous pedicled fat flap within a tissue engineering chamber implanted on the chest wall. Further research is required to evaluate whether the use of cells and other growth factors could adjust the composition of regenerated tissue and improve vascularity; the latter a major limiting factor for creating larger volumes of tissue.

This review describes the use of the comet assay for assessment of DNA damage in human colon cells. We screened 98 papers, which employed human colon -derived cells to analyse DNA damage induced by different insults with the comet assay. In most cases tumour cell lines were used, and only a few studies were performed with primary colon cells. The comet assay was mostly applied to test chemotherapeutics and natural products. We could not find a clear difference between the susceptibility of cell lines to genotoxic insults and they were all suitable for comet assay experiments. Further comparisons between cell lines, and with primary cells and stem cells would be desirable to understand the relevance of the established cell lines as model for the human target tissue better.

Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a substantial issue in neonatal intensive care units worldwide. Current therapies to prevent or treat GMH-IVH are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, and/or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies.

Objective: To identify any change in quality of life (QoL) caused by chemotherapy-induced toxicities, such as hearing loss and tinnitus, to provide information in order to improve services and aid clinicians in their decision-making. Design: This systematic review followed the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The search terms were cancer, platinum-based chemotherapy, ototoxicity and "quality of life". Titles and abstracts, followed by full texts, were screened by two independent researchers. The relevant data were extracted and quality analysis was performed using the NIH Quality Assessment Tool. Study sample: About 308 titles and abstracts were screened, and 27 full-text articles were screened. Ten articles representing 11 studies were included in the review. Study design included cross-sectional studies, randomised control trials and longitudinal studies. Results: Diagnostic criteria consisted of audiograms, questionnaires and patient complaints. The study quality ranged from 21.43% to 85.71%. Overall results found that those treated with cisplatin had more hearing loss and tinnitus than those treated with other therapies. Furthermore, those with hearing loss and tinnitus were more likely to have a lower QoL. Conclusions: There is an urgent need to standardise diagnostics when investigating ototoxicity and its effect on QoL, particularly for research into risk factors, prevention and management.

There is currently no definitive treatment for the painful scar. Autologous adipose tissue grafting (AATG) as a treatment option for scars has become increasingly popular and there is now an abundance of evidence in the literature that supports its application. Some studies suggest that human adipose tissue is a rich source of multipotent mesenchymal stromal cells. To our knowledge, there is currently no systematic literature review to date that examines the effectiveness of AATG for reducing pain in scars. Our novel systematic review aims to examine clinical studies on the use of AATG in the treatment of the painful scar.

The aim of this study was to compare tissue-engineered bone using mesenchymal stem cells (MSCs) and conventional bone grafts in terms of histomorphometric outcome, bone gained, and implant failure in the atrophic maxilla.

Beta-hydroxy-beta-methylbutyrate (HMB) has been used extensively as a dietary supplement for athletes and physically active people. HMB is a leucine metabolite, which is one of three branched chain amino acids. HMB plays multiple roles in the human body of which most important ones include protein metabolism, insulin activity and skeletal muscle hypertrophy. The ergogenic effects of HMB supplementation are related to the enhancement of sarcolemma integrity, inhibition of protein degradation (ubiquitin pathway), decreased cell apoptosis, increased protein synthesis (mTOR pathway), stimulation of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and enhancement of muscle stem cells proliferation and differentiation. HMB supplementation has been carried out with various groups of athletes. In endurance and martial arts athletes, HMB supplementation revealed positive effects on specific aerobic capacity variables. Positive results were also disclosed in resistance trained athletes, where changes in strength, body fat and muscle mass as well as anaerobic performance and power output were observed. The purpose of this review was to present the main mechanisms of HMB action, especially related to muscle protein synthesis and degradation, and ergogenic effects on different types of sports and physical activities.

The aim of the systematic review was to analyze the use of mesenchymal stem cells (MSC) and biomaterial for periodontal regeneration from preclinical animal models and human. Electronic databases were searched and additional hand-search in leading journals was performed. The research strategy was achieved according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The including criteria were as follows: MSC, biomaterial, in vivo studies, with histologic and radiologic analysis and written in English. The risk of bias was assessed for individual studies. A total of 50 articles were selected and investigated in the systematic review. These results indicate that MSC and scaffold provide beneficial effects on periodontal regeneration, with no adverse effects of such interventions. Future studies need to identify the suitable association of MSC and biomaterial and to characterize the type of new cementum and the organization of the periodontal ligament fiber regeneration.

Background: Dimethyl sulfoxide (DMSO) has been used for medical treatment and as a pharmacological agent in humans since the 1960s. Today, DMSO is used mostly for cryopreservation of stem cells, treatment of interstitial cystitis, and as a penetrating vehicle for various drugs. Many adverse reactions have been described in relation to the use of DMSO, but to our knowledge, no overview of the existing literature has been made. Our aim was to conduct a systematic review describing the adverse reactions observed in humans in relation to the use of DMSO. Methods: This systematic review was reported according to the PRISMA-harms (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines. The primary outcome was any adverse reactions occurring in humans in relation to the use of DMSO. We included all original studies that reported adverse events due to the administration of DMSO, and that had a population of five or more. Results: We included a total of 109 studies. Gastrointestinal and skin reactions were the commonest reported adverse reactions to DMSO. Most reactions were transient without need for intervention. A relationship between the dose of DMSO given and the occurrence of adverse reactions was seen. Conclusions: DMSO may cause a variety of adverse reactions that are mostly transient and mild. The dose of DMSO plays an important role in the occurrence of adverse reactions. DMSO seems to be safe to use in small doses. Registration: PROSPERO CRD42018096117.