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2.
Stem Cells Transl Med ; 10(5): 660-673, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400390

RESUMO

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.


Assuntos
Anti-Inflamatórios/uso terapêutico , Transplante de Células-Tronco Mesenquimais/métodos , Citocinas/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Cordão Umbilical/citologia
3.
Trials ; 22(1): 9, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407777

RESUMO

OBJECTIVES: 1. To assess the efficacy of Mesenchymal Stromal Cells (MSC) versus a control arm as described in the primary endpoint. 2. To evaluate the effects of MSC on the secondary efficacy endpoints. 3. To evaluate the safety and tolerability profiles of MSC. 4. To study soluble and cellular biomarkers that might be involved in the course of the disease and the response to the investigational product. TRIAL DESIGN: A double-blind, randomized, controlled, trial to evaluate the efficacy and safety of MSC intravenous administration in patients with COVID-induced Acute Respiratory Distress Syndrome (ARDS) compared to a control arm. PARTICIPANTS: The trial is being conducted at a third level hospital, Hospital Universitario Puerta de Hierro, in Majadahonda, Madrid (Spain). Inclusion criteria 1. Informed consent prior to performing study procedures (witnessed oral consent with written consent by representatives will be accepted to avoid paper handling). Written consent by patient or representatives will be obtained whenever possible. 2. Adult patients ≥18 years of age at the time of enrolment. 3. Laboratory-confirmed SARS-CoV-2 infection as determined by Polymerase Chain Reaction (PCR), in oropharyngeal swabs or any other relevant specimen obtained during the course of the disease. Alternative tests (e.g., rapid antigen tests) are also acceptable as laboratory confirmation if their specificity has been accepted by the Sponsor. 4. Moderate to severe ARDS (PaO2/FiO2 ratio equal or less than 200 mmHg) for less than 96 hours at the time of randomization. 5. Patients requiring invasive ventilation are eligible within 72 hours from intubation. 6. Eligible for ICU admission, according to the clinical team. Exclusion criteria 1. Imminent and unavoidable progression to death within 24 hours, irrespective of the provision of treatments (in the opinion of the clinical team). 2. "Do Not Attempt Resuscitation" order in place. 3. Any end-stage organ disease or condition, which in the investigator's opinion, makes the patient an unsuitable candidate for treatment. 4. History of a moderate/severe lung disorder requiring home-based oxygen therapy. 5. Patient requiring Extracorporeal Membrane Oxygenation (ECMO), haemodialysis or hemofiltration at the time of treatment administration. 6. Current diagnosis of pulmonary embolism. 7. Active neoplasm, except carcinoma in situ or basalioma. 8. Known allergy to the products involved in the allogeneic MSC production process. 9. Current pregnancy or lactation (women with childbearing potential should have a negative pregnancy test result at the time of study enrolment). 10. Current participation in a clinical trial with an experimental treatment for COVID-19 (the use of any off-label medicine according to local treatment protocols is not an exclusion criteria). 11. Any circumstances that in the investigator's opinion compromises the patient's ability to participate in the clinical trial. INTERVENTION AND COMPARATOR: - Experimental treatment arm: Allogeneic MSC (approximately 1 x 106 cells/kg). - Control arm: placebo solution (same composition as the experimental treatment, without the MSC). One single intravenous dose of the assigned treatment will be administered on Day 0 of the study. All trial participants will receive standard of care (SOC). In the context of the current worldwide pandemic, SOC can include medicines that are being used in clinical practice (e.g. lopinavir/ritonavir; hydroxy/chloroquine, tocilizumab, etc.), as well as those authorised for COVID (e.g., remdesivir). MAIN OUTCOMES: Primary endpoint: Change in the PaO2/FiO2 ratio from baseline to day 7 of treatment administration, or to the last available PaO2/FiO2 ratio if death occurs before day 7. Secondary endpoints: - All-cause mortality on days 7, 14, and 28 after treatment. - PaO2/FiO2 ratio at baseline and days 2, 4, 7, 14 and 28 after treatment. - Oxygen saturation (by standardized measurement) at baseline, daily until day 14, and on day 28 after treatment. - Time to PaO2/FiO2 ratio greater than 200 mmHg. - Subjects' clinical status on the WHO 7-point ordinal scale at baseline, daily until day 14, and on day 28 after treatment. - Time to an improvement of one category from admission on the WHO 7-point ordinal scale. - Percentage of patients that worsen at least one category on the WHO 7-point ordinal scale. - Percentage of patients that improve at least one category (maintained 48h) on the WHO 7-point ordinal scale. - Sequential Organ Failure Assessment (SOFA) scale at baseline and days 2, 4, 7, 14 and 28 after treatment. - Duration of hospitalization (days). - Duration of ICU stay (days). - Oxygen therapy-free days in the first 28 days after treatment. - Duration of supplemental oxygen. - Incidence of and duration of non-invasive and invasive mechanical ventilation in the first 28 days after treatment. - Mechanical ventilation-free days in the first 28 days after treatment. - Ventilation parameters. - Incidence of new onset pulmonary fibrosis at 3 and 12 months after treatment, based on CT scan and pulmonary function tests. - Survival at 3 and 12 months. - Cumulative incidence of Serious Adverse events (SAEs) and Grade 3 and 4 Adverse Events (AEs). - Cumulative incidence of Adverse Drug Reactions (ADR) in the experimental treatment arm. - Cumulative incidence of AEs of special interest. - Levels of analytical markers (C-Reactive Protein, lymphocyte and neutrophil counts, lymphocyte subpopulations, LDH, ferritin, D-dimer, coagulation tests and cytokines...) at baseline and days 2, 4, 7, 14 and 28 after treatment. - Other soluble and cellular biomarkers that might be involved in the course of the disease and the response to MSC. RANDOMISATION: The assignment to treatment will be carried out randomly and blinded, with a 1:1 allocation. Randomization will be done through a centralized system embedded in the electronic Case Report Form (CRF). BLINDING (MASKING): To ensure blinding, treatments will be prepared for administration at the Cell Production Unit and the administration of the treatment will be masked, not allowing the identification of the Investigational Medicinal Product (IMP). NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 20 participants are planned to be randomized, 10 to each treatment group. TRIAL STATUS: Protocol version: 1.2, dated October 14th, 2020 Start of recruitment: 01/10/2020 End of recruitment (estimated): December 2020. TRIAL REGISTRATION: EudraCT Number: 2020-002193-27 , registered on July 14th, 2020. NCT number: NCT04615429 , registered on November 4th, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/administração & dosagem , Transplante de Células-Tronco Mesenquimais/métodos , /terapia , Administração Intravenosa , Adulto , Biomarcadores/sangue , /diagnóstico , Ensaios Clínicos Fase II como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Método Duplo-Cego , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , /diagnóstico , /isolamento & purificação , Índice de Gravidade de Doença , Espanha , Padrão de Cuidado , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos
4.
Neurology ; 96(7): e1012-e1023, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33472925

RESUMO

OBJECTIVE: To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery. RESULTS: A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (p = 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index, p = 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events. CONCLUSIONS: IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT01716481.


Assuntos
/terapia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Resultado do Tratamento
5.
Tech Vasc Interv Radiol ; 23(4): 100704, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33308583

RESUMO

Biologics are a growing field that has shown immense promise for the treatment of musculoskeletal conditions both in orthopedic sports medicine and interventional pain management. These procedures utilize injection of supraphysiologic levels of platelets and growth factors to invoke the body's own inflammatory cascade to augment the healing of many bony and soft tissue conditions. While many patients improve with conservative care, there is a need to address the gap between those that improve with rehabilitation alone and those who ultimately require operative management. Orthobiologic procedures have the potential to fill this void. The purpose of this review is to summarize the basic science, evidence for use, and post-injection rehabilitation concepts of platelet-rich plasma (PRP) and mesenchymal stromal cells (MSCs) as they pertain to joints, tendons, ligaments, and the spine.


Assuntos
Transplante de Células-Tronco Mesenquimais , Doenças Musculoesqueléticas/terapia , Plasma Rico em Plaquetas , Animais , Medicina Baseada em Evidências , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/fisiopatologia , Resultado do Tratamento
6.
Drug Des Devel Ther ; 14: 3995-4001, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061304

RESUMO

The coronavirus disease 2019 (COVID-19) global pandemic continues and antiviral agents and vaccines are currently under investigation. Mesenchymal stem cell (MSC)-based therapy can be a suitable option for management of patients with COVID-19 at the urgent time of virus outbreak. Currently, MSCs are being explored against the novel infectious disease due to their therapeutic properties of anti-inflammation, immunomodulation and tissue repair and regeneration, albeit the precise mechanisms of MSC action toward COVID-19 remain unclear. To date, rigorous results from clinical trials using MSCs in human have been weakly positive. The pervasive uncertainty of using MSC therapeutic products as an effective combatant against COVID-19 requires rigorous resolution on several fronts, including MSC fate after infusion, safety issue, homing capability, and MSC resistance to the disease microenvironment. Focusing on these facets, a few important ones will be critically analyzed and addressed in this article for the development of safe and effective MSC-based therapies for COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/cirurgia , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/cirurgia , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Resultado do Tratamento
7.
NeuroRehabilitation ; 46(4): 613-615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538885

RESUMO

BACKGROUND: Even if there is sparse evidence of efficacy of stem cell administration for amyotrophic lateral sclerosis (ALS) in preclinical studies, the clinical use of cell-based therapy is yet to be defined. OBJECTIVE: To assess the efficacy, feasibility and safety of cell-based therapy in people with ALS/MND, compared with placebo or no treatment. METHODS: A Cochrane Review on the topic was summarized with comments. RESULTS: Two randomized controlled trials met the selection criteria, but only one provided data useful for the analysis. It compared autologous bone marrow-mesenchymal stem cells, combined with riluzole, to riluzole only, in 64 people with ALS. The ALS Functional Rating Scale-Revised score slightly improved 6 months after the intervention, though the change was not clinically meaningful. Respiratory function, overall survival and the risk of total adverse events or serious adverse events were not different in the two groups. CONCLUSIONS: The available evidence does not support the use of bone marrow-mesenchymal stem cells to treat people with ALS/MND.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Efeito Placebo , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Front Immunol ; 11: 1091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574263

RESUMO

Numerous clinical trials of mesenchymal stromal/stem cells (MSCs) as a new treatment for coronavirus-induced disease (COVID-19) have been registered recently, most of them based on intravenous (IV) infusion. There is no approved effective therapy for COVID-19, but MSC therapies have shown first promise in the treatment of acute respiratory distress syndrome (ARDS) pneumonia, inflammation, and sepsis, which are among the leading causes of mortality in COVID-19 patients. Many of the critically ill COVID-19 patients are in a hypercoagulable procoagulant state and at high risk for disseminated intravascular coagulation, thromboembolism, and thrombotic multi-organ failure, another cause of high fatality. It is not yet clear whether IV infusion is a safe and effective route of MSC delivery in COVID-19, since MSC-based products express variable levels of highly procoagulant tissue factor (TF/CD142), compromising the cells' hemocompatibility and safety profile. Of concern, IV infusions of poorly characterized MSC products with unchecked (high) TF/CD142 expression could trigger blood clotting in COVID-19 and other vulnerable patient populations and further promote the risk for thromboembolism. In contrast, well-characterized products with robust manufacturing procedures and optimized modes of clinical delivery hold great promise for ameliorating COVID-19 by exerting their beneficial immunomodulatory effects, inducing tissue repair and organ protection. While the need for MSC therapy in COVID-19 is apparent, integrating both innate and adaptive immune compatibility testing into the current guidelines for cell, tissue, and organ transplantation is critical for safe and effective therapies. It is paramount to only use well-characterized, safe MSCs even in the most urgent and experimental treatments. We here propose three steps to mitigate the risk for these vulnerable patients: (1) updated clinical guidelines for cell and tissue transplantation, (2) updated minimal criteria for characterization of cellular therapeutics, and (3) updated cell therapy routines reflecting specific patient needs.


Assuntos
Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Pneumonia Viral/terapia , Imunologia de Transplantes , Administração Intravenosa , Transtornos da Coagulação Sanguínea/etiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Guias como Assunto , Humanos , Injeções Intramusculares , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia
9.
Trials ; 21(1): 462, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493473

RESUMO

OBJECTIVES: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below. TRIAL DESIGN: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial. INTERVENTION AND COMPARATOR: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x106 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics. MAIN OUTCOMES: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO2/FiO2 ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality. RANDOMISATION: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC). TRIAL STATUS: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27th March 2020 and MHRA on 30th March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King's College London, Guys and St Thomas' Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). FULL PROTOCOL: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/cirurgia , Pulmão/virologia , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/cirurgia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Humanos , Pulmão/fisiopatologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Respiração Artificial , Índice de Gravidade de Doença , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Reino Unido
10.
Stem Cells Dev ; 29(12): 747-754, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32380908

RESUMO

This prospective nonrandomized open-label cohort study addresses the safety and efficacy of exosomes (ExoFlo™) derived from allogeneic bone marrow mesenchymal stem cells as treatment for severe COVID-19. During April 2020, ExoFlo was provided to 24 SARS-CoV-2 polymerase chain reaction-positive patients at a single hospital center, all of whom met criteria for severe COVID-19 as well as moderate-to-severe acute respiratory distress syndrome. Patients received a single 15 mL intravenous dose of ExoFlo and were evaluated for both safety and efficacy from days 1 to 14 post-treatment. All safety endpoints were met with no adverse events observed within 72 h of ExoFlo administration. A survival rate of 83% was observed. In total, 17 of 24 (71%) patients recovered, 3 of 24 (13%) patients remained critically ill though stable, and 4 of 24 (16%) patients expired for reasons unrelated to the treatment. Overall, after one treatment, patients' clinical status and oxygenation improved with an average pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) increase of 192% (P < 0.001). Laboratory values revealed significant improvements in absolute neutrophil count [mean reduction 32% (P value <0.001)] and lymphopenia with average CD3+, CD4+, and CD8+ lymphocyte counts increasing by 46% (P < 0.05), 45% (P < 0.05), and 46% (P < 0.001), respectively. Likewise, acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. In conclusion, owing to its safety profile, capacity to restore oxygenation, downregulate cytokine storm, and reconstitute immunity, ExoFlo is a promising therapeutic candidate for severe COVID-19. Future randomized controlled trials (RCTs) are needed to determine ExoFlo therapeutic potential.


Assuntos
Células da Medula Óssea/citologia , Infecções por Coronavirus/terapia , Estado Terminal/terapia , Exossomos/transplante , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Micropartículas Derivadas de Células/transplante , Estudos de Coortes , Infecções por Coronavirus/mortalidade , Estado Terminal/mortalidade , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/ultraestrutura , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença , Resultado do Tratamento
11.
J Transl Med ; 18(1): 203, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32423449

RESUMO

In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Animais , Ensaios Clínicos como Assunto , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pandemias
12.
Scand J Immunol ; 92(3): e12897, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32443180

RESUMO

Inflammatory bowel diseases (IBD) are a group of chronic recurrent gastrointestinal inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) and IBD unclassified. The pathogenesis may be related to the mucosal immune dysfunction in genetically susceptible hosts affected by environmental factors. Current therapeutic agents mainly include aminosalicylates, corticosteroids, immunosuppressive drugs and novel biological agents. The purpose of treatment is to suppress inflammation and prevent irreversible structural damage. However, long-term application of these drugs may lead to multiple adverse effects and is not always effective. Mesenchymal stem cells (MSCs) are multipotent progenitors with low immunogenicity, which can be obtained and expanded easily. They play an important role in regulating immune responses and repairing damaged tissues in vivo. Therefore, MSCs are considered to be a promising option for the treatment of IBD. Nonetheless, there are many factors that can reduce the efficacy of MSCs, such as gradual deterioration of functional stem cells with age, low recruitment and persistence in vivo and different routes of administration. In recent years, researchers have been able to improve the efficacy of MSCs by pretreatment, genetic modification or co-application with other substances, as well as using different tissue-derived cells, administration methods or doses. This article reviews these methods to provide references for more effective application of MSCs in the treatment of IBD in the future.


Assuntos
Doenças Inflamatórias Intestinais/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Biomarcadores , Terapia Combinada , Engenharia Genética , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Especificidade de Órgãos , Fenótipo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
13.
Stem Cells Transl Med ; 9(9): 1007-1022, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32472653

RESUMO

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2 /FiO2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , /terapia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Pulmão/fisiologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , /virologia
14.
Arch Dis Child Fetal Neonatal Ed ; 105(5): 563-568, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32253200

RESUMO

Recent decades have seen the rapid progress of neonatal intensive care, and the survival rates of the most preterm infants are improving. This improvement is associated with changing patterns of morbidity and new phenotypes of bronchopulmonary dysplasia and preterm brain injury are recognised. Inflammation and immaturity are known contributors to their pathogenesis. However, a new phenomenon, the exhaustion of progenitor cells is emerging as an important factor. Current therapeutic approaches do not adequately address these new mechanisms of injury. Cell therapy, that is the use of stem and stem-like cells, with its potential to both repair and prevent injury, offers a new approach to these challenging conditions. This review will examine the rationale for cell therapy in the extremely preterm infant, the preclinical and early clinical evidence to support its use in bronchopulmonary dysplasia and preterm brain injury. Finally, it will address the challenges in translating cell therapy from the laboratory to early clinical trials.


Assuntos
Lesões Encefálicas/terapia , Displasia Broncopulmonar/terapia , Transplante de Células/métodos , Lactente Extremamente Prematuro , Doenças do Prematuro/terapia , Animais , Transplante de Células/efeitos adversos , Protocolos Clínicos , Ensaios Clínicos como Assunto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Sangue Fetal , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Terapia Intensiva Neonatal/métodos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Fatores de Tempo
15.
Cytotherapy ; 22(6): 313-321, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32273232

RESUMO

BACKGROUND: Critical limb ischemia (CLI) is the most severe manifestation of peripheral vascular disease. Revascularization is the preferred therapy, but it is not achievable in 25%-40% of patients due to diffuse anatomic distribution of the disease or medical comorbidities. No-option CLI represents an unmet medical need. Mesenchymal stromal cells (MSCs) may provide salvage therapy through their angiogenic and tissue-trophic properties. This article reports a phase 1b clinical study examining the safety and feasibility of intramuscular transplantation of autologous bone-marrow MSCs for patients with no-option CLI. METHODS: Twelve patients were enrolled in the clinical trial, and nine proceeded to bone marrow aspiration and culture expansion of MSCs. RESULTS: A high rate of karyotype abnormality (>30%) was detected in the produced cell batches, resulting in failure of release for clinical administration. Four patients were treated with the investigational medicinal product (IMP), three with a low dose of 20 × 106 MSCs and one with a mid-dose of 40 × 106 MSCs. There were no serious adverse events related to trial interventions, including bone marrow aspiration, IMP injection or therapy. CONCLUSIONS: The results of this trial conclude that an autologous cell therapy approach with MSCs for critical limb ischemia is limited by the high rate of karyotype abnormalities.


Assuntos
Isquemia/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Doença Arterial Periférica/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação , Medula Óssea , Feminino , Humanos , Isquemia/cirurgia , Cariótipo , Perna (Membro)/irrigação sanguínea , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Doença Arterial Periférica/cirurgia , Terapia de Salvação , Transplante Autólogo , Resultado do Tratamento
16.
Plast Reconstr Surg ; 145(3): 827-841, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32097333

RESUMO

BACKGROUND: Autologous fat grafting is a dynamic modality used in plastic surgery as an adjunct to improve functional and aesthetic form. However, current practices in fat grafting for soft-tissue augmentation are plagued by tremendous variability in long-term graft retention, resulting in suboptimal outcomes and repetitive procedures. This systematic review identifies and critically appraises the evidence for various enrichment strategies that can be used to augment and improve the viability of fat grafts. METHODS: A comprehensive literature search of the Medline and PubMed databases was conducted for animal and human studies published through October of 2017 with multiple search terms related to adipose graft enrichment agents encompassing growth factors, platelet-rich plasma, adipose-derived and bone marrow stem cells, gene therapy, tissue engineering, and other strategies. Data on level of evidence, techniques, complications, and outcomes were collected. RESULTS: A total of 1382 articles were identified, of which 147 met inclusion criteria. The majority of enrichment strategies demonstrated positive benefit for fat graft survival, particularly with growth factors and adipose-derived stem cell enrichment. Platelet-rich plasma and adipose-derived stem cells had the strongest evidence to support efficacy in human studies and may demonstrate a dose-dependent effect. CONCLUSIONS: Improved understanding of enrichment strategies contributing to fat graft survival can help to optimize safety and outcomes. Controlled clinical studies are lacking, and future studies should examine factors influencing graft survival through controlled clinical trials in order to establish safety and to obtain consistent outcomes.


Assuntos
Tecido Adiposo/transplante , Contorno Corporal/métodos , Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Tecido Adiposo/citologia , Animais , Autoenxertos/fisiologia , Contorno Corporal/efeitos adversos , Estética , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Modelos Animais , Plasma Rico em Plaquetas/fisiologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Resultado do Tratamento
17.
Expert Opin Biol Ther ; 20(2): 125-140, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31701782

RESUMO

Introduction: The acute respiratory distress syndrome (ARDS) is a devastating clinical condition common in patients with respiratory failure. Based largely on numerous preclinical studies and recent Phase I/II clinical trials, administration of stem cells, specifically mesenchymal stem or stromal cells (MSC), as a therapeutic for acute lung injury (ALI) holds great promise. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that stem cell-derived conditioned medium (CM) and/or extracellular vesicles (EV) might constitute compelling alternatives.Areas covered: The current review focuses on the preclinical studies testing MSC CM and/or EV as treatment for ALI and other inflammatory lung diseases.Expert opinion: Clinical application of MSC or their secreted CM may be limited by the cost of growing enough cells, the logistic of MSC storage, and the lack of standardization of what constitutes MSC CM. However, the clinical application of MSC EV remains promising, primarily due to the ability of EV to maintain the functional phenotype of the parent cell as a therapeutic. However, utilization of MSC EV will also require large-scale production, the cost of which may be prohibitive unless the potency of the EV can be increased.


Assuntos
Lesão Pulmonar Aguda/terapia , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , /terapia , Animais , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Vesículas Extracelulares/fisiologia , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos
18.
Equine Vet J ; 52(1): 144-151, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31120574

RESUMO

BACKGROUND: Allogeneic bone marrow-derived mesenchymal stem cells (BMDMSCs) could provide multiple advantages over autologous BMDMSCs, including creating an 'off-the-shelf' treatment together with the ability to control for donor variation. OBJECTIVES: The objective of the study was to compare the clinical and synovial fluid response of the normal equine joint to autologous and pooled-allogeneic BMDMSCs while controlling for individual variation and joint variations in response to intra-articular injections. We hypothesised that, by controlling for individual animal and joint variation, we could identify differences between allogeneic vs. autologous BMDMSCs in noninflamed joints. STUDY DESIGN: Randomised-controlled experiment. METHODS: Bone marrow was harvested from eight horses. Autologous BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. For allogeneic BMDMSC treatments, four horses' BMDMSCs were culture expanded, pooled, cryopreserved and thawed immediately prior to use. Ten million (autologous or pooled-allogeneic) BMDMSCs were administered into contralateral forelimb metacarpophalangeal joints so that every autologous and allogeneic injection could be compared within the same animal. Clinical parameters included subjective lameness, objective lameness (Lameness Locator™), response to flexion, joint circumference and joint effusion. Arthrocentesis was performed for assessment of the nucleated cell count, differential cell count, total protein, and synovial concentrations of prostaglandin E2 (PGE2) and c-reactive protein (CRP). All parameters were measured at baseline, 6, 12, 24, 72, 168 and 336 h post-injection. RESULTS: No difference was detected in any parameters between forelimb metacarpophalangeal joints administered autologous or pooled-allogeneic BMDMSCs. MAIN LIMITATIONS: This study did not attempt to measure efficacy of BMDMSCs for musculoskeletal disease and should be followed by properly controlled efficacy trials. CONCLUSIONS: The study did not identify any clinical or cytological differences in the normal joint response to allogeneic or autologous BMDMSCs. A larger study to prove equivalence is warranted as allogeneic BMDMSCs may be a feasible alternative to autologous BMDMSCs.


Assuntos
Células da Medula Óssea , Cavalos , Transplante de Células-Tronco Mesenquimais/veterinária , Células-Tronco Mesenquimais/fisiologia , Animais , Biomarcadores/química , Injeções Intra-Articulares , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Líquido Sinovial , Transplante Autólogo , Transplante Homólogo
19.
Arch Orthop Trauma Surg ; 140(7): 853-868, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31456015

RESUMO

PURPOSE: According to the World Health organization (WHO), more than 10% in people older than 60 years suffer from osteoarthritis (OA). Over the last years, there has been an increased interest around regenerative medicine, especially regarding stem cell treatments and related applications. We hypothesize that stem cell therapies can represent a feasible option for idiopathic knee OA, delaying or even avoiding the joint replacement. To emphasize the potential of percutaneous injections of mesenchymal stem cells for knee OA, a comprehensive systematic review of the literature was conducted. MATERIAL AND METHODS: Two independent authors (FM, GC) performed the literature search. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). The main databases were accessed: Pubmed, Embase, Google Scholar, Cochrane Systematic Reviews, Scopus, AMED. For this systematic review, all articles treating percutaneous injections of mesenchymal stem cells for knee OA were considered. Because of the rapid advancements promoted by the scientific progress on stem cell expansion and processing, only articles published within the last five years were included. Solely articles reporting the outcomes of interest across 6- and 12-month follow-up were recruited for eligibility. We included only studies reporting quantitative data under the outcomes of interest. We referred for the quality assessment to the Coleman Methodology Score (CMS). The statistical analysis was performed with Review Manager Software 5.3 (The Nordic Cochrane Centre, Copenhagen). RESULTS: A total of 18 studies were enrolled in the present study, comprising 1069 treated knees. The mean age of the samples was 57.39 ± 7.37 years. 72% of the included studies harvested the stem cells from the iliac crest (bone marrow-derived MSCs), the remaining 28% from the adipose tissue (adipose-derived MSCs). The mean visual analogic scale improved from 18.37 to 30.98 and 36.91 at 6- and 12-month follow-up, respectively. The mean WOMAC score improved from 25.66 to 25.23 and 15.60 at 6- and 12-month follow-up, respectively. The mean walking distance improved from 71.90 to 152.22 and 316.72 at 6- and 12-month follow-up, respectively. The mean Lequesne scale improved from 33.76 to 12.90 at 12-month follow-up. The KOOS score improved from 41.07 to 8.47% and 18.94 at 6- and 12-month follow-up. All the KOOS subscales improved significantly from the baseline. A total of 136 (12.7%) local complications were detected. CONCLUSION: According to the current evidences and the main findings of this systematic review, we reported that MSC infiltrations for knee OA can represent a feasible option, leading to an overall remarkable improvement of all clinical and functional considered outcomes, regardless of the cell source. Patients treated at earlier-degeneration stages reported statistically significant greater outcomes. The pain and function scores were improved considerably, thus, leading to a significant improvement of patient participation in recreational activities and quality of life.


Assuntos
Transplante de Células-Tronco Mesenquimais , Osteoartrite do Joelho/cirurgia , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/estatística & dados numéricos , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Resultado do Tratamento
20.
J Orthop Surg Res ; 14(1): 441, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842921

RESUMO

INTRODUCTION: Patellar tendon overuse injuries are common in athletes. Imaging may show a change in tissue structure with tendon thickening and disruption of the intratendinous substance. We wish to test the hypothesis that both autologous bone marrow expanded mesenchymal stem cells and autologous leukocyte-poor platelet-rich plasma (LP-PRP) implanted into the area of the disrupted tendinopathic patellar tendon will restore function, but tendon regeneration tissue will only be observed in the subjects treated with autologous bone marrow expanded mesenchymal stem cells. METHODS AND ANALYSIS: This is a single-centre, pilot phase I/II, double-blinded clinical trial with randomisation with active control. Twenty patients with a diagnosis of patellar tendinopathy with imaging changes (tendon thickening and disruption of the intratendinous substance at the proximal portion of the patellar tendon) will be randomised in a 1:1 ratio to receive a local injection of either bone-marrow autologous mesenchymal stem cells (MSC), isolated and cultured under GMP at The Institute of Biology and Molecular Genetics (IBGM) (Spain) or P-PRP. The study will have two aims: first, to ascertain whether a clinically relevant improvement after 3, 6 and 12 months according to the visual analogue scale (VAS), Victorian Institute of Sport Assessment for patellar tendons (VISA-P) and dynamometry scales (DYN) will be achieved; and second, to ascertain whether the proposed intervention will restore tendon structure as determined by ultrasonography (US), Doppler ultrasonography (DUS), and innovative MRI and ultrasound techniques: Magnetic Resonance T2 FAT SAT (UTE, Ultrashort Echo TE) sequence and Ultrasound Tissue Characterization (UTC). Patients who are randomised to the P-PRP treatment group but do not achieve a satisfactory primary endpoint after 6 months will be offered treatment with MSC. TRIAL REGISTRATION: NCT03454737.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Ligamento Patelar , Tendinopatia/terapia , Adolescente , Adulto , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Método Duplo-Cego , Humanos , Imagem por Ressonância Magnética , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Medição da Dor/métodos , Ligamento Patelar/diagnóstico por imagem , Seleção de Pacientes , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Tendinopatia/diagnóstico por imagem , Resultado do Tratamento , Ultrassonografia , Adulto Jovem
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