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Silk fibroin (SF) is a biocompatible natural protein with excellent mechanical characteristics. SF-based biomaterials can be structured using a number of techniques, allowing the tuning of materials for specific biomedical applications. In this study, SF films, porous membranes, and electrospun membranes were produced using solvent-casting, salt-leaching, and electrospinning methodologies, respectively. SF-based materials were subjected to physicochemical and biological characterizations to determine their suitability for tissue regeneration applications. Mechanical analysis showed stress-strain curves of brittle materials in films and porous membranes, while electrospun membranes featured stress-strain curves typical of ductile materials. All samples showed similar chemical composition, melting transition, hydrophobic behavior, and low cytotoxicity levels, regardless of their architecture. Finally, all of the SF-based materials promote the proliferation of human umbilical vein endothelial cells (HUVECs). These findings demonstrate the different relationship between HUVEC behavior and the SF sample's topography, which can be taken advantage of for the design of vascular implants.
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Fibroínas , Humanos , Fibroínas/química , Andamios del Tejido/química , Materiales Biocompatibles/química , Células Endoteliales de la Vena Umbilical Humana , Porosidad , Seda/química , Ingeniería de TejidosRESUMEN
Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.
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Infarto del Miocardio , Taquicardia Ventricular , Animales , Cicatriz/patología , Corazón , Infarto del Miocardio/patología , Miocardio/patología , Células Madre/patología , Porcinos , Taquicardia Ventricular/patologíaRESUMEN
BACKGROUND: Acute myocardial infarction (AMI) is one of the most deleterious conditions leading to cardiovascular diseases and mortality. The importance of an early and accurate diagnosis assures immediate medical treatments, which are fundamental to reduce mortality and improve prognoses. AMI is associated to an inflammatory response which includes the increase of circulating inflammatory cytokines, chemokines and immune cell activation. This study aimed to identify which are the very early immune-related biomarkers that may be used as predictors of myocardial infarction severity. In order to mimic the pathophysiological events involved in human myocardial infarction, a temporary occlusion (90 min) of the mid-left anterior descending coronary artery was performed in a swine animal model. RESULTS: Lymphocyte subsets analysis in peripheral blood revealed significant alterations in CD4+/CD8+ ratio and naïve and effector/memory T cell percentages at 1 h post-myocardial infarction. Changes in TH1/TH2-related cytokine, monocyte and neutrophil markers gene expression were observed in peripheral blood lymphocytes, as well. Additionally, significant correlations between cardiac parameters (cardiac enzymes, left ventricular ejection fraction and % infarct) and blood-derived parameters (cytokine expression and lymphocyte subset distribution) were found. CONCLUSIONS: Peripheral blood lymphocyte alterations are easily and swiftly detectable, so they may be good biomarkers for a very early prognosis and to predict myocardial infarction severity.
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Inflamación/veterinaria , Infarto del Miocardio/veterinaria , Enfermedades de los Porcinos/diagnóstico , Animales , Biomarcadores/sangre , Relación CD4-CD8/veterinaria , Forma MB de la Creatina-Quinasa/sangre , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo/veterinaria , Pruebas de Función Cardíaca , Inflamación/sangre , Inflamación/diagnóstico , Subgrupos Linfocitarios , Linfocitos/metabolismo , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Porcinos , Enfermedades de los Porcinos/sangre , Troponina I/sangreRESUMEN
BACKGROUND: The optimal timing of cardiac stem cells administration is still unclear. We assessed the safety of same-day and delayed (one week) delivery and the possible influence of the timing on the therapeutic outcomes of allogeneic porcine cardiac stem cells administration after acute myocardial infarction in a closed-chest ischemia-reperfusion model. METHODS: Female swine surviving 90 min occlusion of the mid left anterior descending coronary artery received an intracoronary injection of 25x10(6) porcine cardiac stem cells either two hours (n = 5, D0) or 7 days (n = 6, D7) after reperfusion. Controls received intracoronary injection of vehicle on day 7 (n = 6, CON). Safety was defined in terms of absence of major cardiac events, changes to the ECG during injection, post-administration coronary flow assessed using the TIMI scale and cardiac troponin I determination after the intervention. Cardiac Magnetic Resonance was performed for morphological and functional assessment prior to infarction, before injection (D7 and CON groups only), at one and 10 weeks. Samples were taken from the infarct and transition areas for pathological examination. RESULTS: No major adverse cardiac events were seen during injection in any group. Animals receiving the therapy on the same day of infarction (D0 group) showed mild transient ST changes during injection (n = 4) and, in one case, slightly compromised coronary flow (TIMI 2). Cardiac function parameters and infarct sizes were not significantly different between groups, with a trend towards higher ejection fraction in the treated groups. Ventricular volumes indexed to body surface area increased over time in control animals, and decreased by the end of the study in animals receiving the therapy, significantly so when comparing End Diastolic Volume between CON and D7 groups (CON: 121.70 ml/m(2) ± 26.09 ml/m(2), D7: 98.71 ml/m(2) ± 8.30 ml/m(2), p = 0.037). The treated groups showed less organization of the collagenous scar, and a significantly (p = 0.019) higher amount of larger, more mature vessels at the infarct border. CONCLUSIONS: The intracoronary injection of 25x10(6) allogeneic cardiac stem cells is generally safe, both early and 7 days after experimental infarction, and alleviates myocardial dysfunction, with a greater limitation of left ventricular remodeling when performed at one week.
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Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Miocitos Cardíacos/citología , Trasplante de Células Madre , Células Madre/citología , Remodelación Ventricular , Animales , Femenino , Pruebas de Función Cardíaca , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Imagen por Resonancia Magnética , Infarto del Miocardio/patología , Líquido Pericárdico , Sus scrofa , Factores de Tiempo , Trasplante Homólogo , Troponina/metabolismo , Cromosoma Y/metabolismoRESUMEN
BACKGROUND: Despite recent advances, myocardial infarction (MI) remains the leading cause of death worldwide. Pre-clinical animal models that closely mimic human MI are pivotal for a quick translation of research and swine have similarities in anatomy and physiology. Here, we compared coronary surgical ligation versus coil embolization MI models in swine. METHODS: Fifteen animals were randomly distributed to undergo surgical ligation (n=7) or coil embolization (n=8). We evaluated infarct size, scar fibrosis, inflammation, myocardial vascularization, and cardiac function by magnetic resonance imaging (MRI). RESULTS: Thirty-five days after MI, there were no differences between the models in infarct size (P=0.53), left ventricular (LV) ejection fraction (P=0.19), LV end systolic volume (P=0.22), LV end diastolic volume (P=0.84), and cardiac output (P=0.89). Histologically, cardiac scars did not differ and the collagen content, collagen type I (I), collagen type III (III), and the I/III ratio were similar in both groups. Inflammation was assessed using specific anti-CD3 and anti-CD25 antibodies. There was similar activation of inflammation throughout the heart after coil embolization (P=0.78); while, there were more activated lymphocytes in the infarcted myocardium in the surgical occlusion model (P=0.02). Less myocardial vascularization in the infarction areas compared with the border and remote zones only in coil embolization animals was observed (P=0.004 and P=0.014, respectively). CONCLUSIONS: Our results support that surgical occlusion and coil embolization MI models generate similar infarct size, cardiac function impairment, and myocardial fibrosis; although, inflammation and myocardial vascularization levels were closer to those found in humans when coil embolization was performed.
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Modelos Animales de Enfermedad , Infarto del Miocardio/terapia , Animales , Femenino , Corazón/fisiopatología , Imagen por Resonancia Magnética , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/cirugía , PorcinosRESUMEN
Lymphedema presents significant challenges to patients' quality of life, prompting the exploration of innovative treatments, such as collagen scaffolds, aimed at treating and reducing the risk of lymphedema. We aimed to evaluate the preventive and therapeutic efficacy and the lymphangiogenic potential of implanted aligned nanofibrillar collagen scaffolds (BioBridgeTM) following the induction of secondary lymphedema in a rabbit model. Thirty rabbits were divided into treatment (G1), prevention (G2), and control (G3) groups. Secondary lymphedema was induced in all groups. BioBridgeTM implantation was performed in G2 and G1 on days 0 and 60, respectively. Follow-ups included hindlimb circumference measurements and indocyanine green lymphography at 0, 60, and 90 days. None of the study rabbits exhibited dermal backflow on day 0 before surgery. At 60 days, the incidence rates of dermal backflow in G1, G2, and G3 were 100%, 44.4%, and 90%, respectively. Furthermore, at 90 days, the incidence rates were 22.2%, 44.4%, and 90%, respectively. New linear lymphatic observation was seen in rabbits with resolved dermal backflow. The findings of this study demonstrated the capacity of BioBridgeTM scaffolds to induce new lymphatic vessel formation and reduce dermal backflow in secondary lymphedema in a rabbit model.
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ARTICLES DISCUSSED: Blanco-Blázquez, V. et al. Swine models of aneurysmal diseases for training and research. Journal of Visualized Experiments. (181), e63616 (2022). Constantin, I., Tabaran, A. F. Dissection techniques and histological sampling of the heart in large animal models for cardiovascular diseases. Journal of Visualized Experiments. (184), e63809 (2022). Hao, Y. et al. Transcatheter pulmonary valve replacement from autologous pericardium with a self-expandable nitinol stent in an adult sheep model. Journal of Visualized Experiments. (184), e63661 (2022). Martínez-Falguera, D. et al. Myocardial infarction by percutaneous embolization coil deployment in a swine model. Journal of Visualized Experiments. (177), e63172 (2021). Tubeeckx, M. R. L. et al. Sterile pericarditis in aachener minipigs as a model for atrial myopathy and atrial fibrillation. Journal of Visualized Experiments. (175), e63094 (2021).
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Enfermedades Cardiovasculares , Infarto del Miocardio , Animales , Ovinos , Porcinos , Enfermedades Cardiovasculares/terapia , Porcinos Enanos , Atrios Cardíacos , Modelos AnimalesRESUMEN
BACKGROUND: The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. METHODS: Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90âmin and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (nâ=â14) or standard therapy alone (nâ=â13). The pigs were treated for 30âdays and underwent two cardiac magnetic resonance (CMR) scans at 72âh and 30âdays. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). RESULTS: In the hearts explanted after 31âdays, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); Pâ=â0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (Pâ=â0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. CONCLUSION: Colchicine therapy for 1âmonth after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling.
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Cicatriz , Infarto del Miocardio , Porcinos , Humanos , Animales , Cicatriz/patología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Imagen por Resonancia Magnética , Fibrosis , Remodelación VentricularRESUMEN
Therapy microencapsulation allows minimally invasive, safe, and effective administration. Hepatocyte growth factor (HGF) has angiogenic, anti-inflammatory, anti-apoptotic, and anti-fibrotic properties. Our objective was to evaluate the cardiac safety and effectiveness of intracoronary (IC) administration of HGF-loaded extended release microspheres in an acute myocardial infarction (AMI) swine model. An IC infusion of 5 × 106 HGF-loaded microspheres (MS+HGF, n = 7), 5 × 106 placebo microspheres (MS, n = 7), or saline (SAL, n = 7) was performed two days after AMI. TIMI flow and Troponin I (TnI) values were assessed pre- and post-treatment. Cardiac function was evaluated with magnetic resonance imaging (cMR) before injection and at 10 weeks. Plasma cytokines were determined to evaluate the inflammatory profile and hearts were subjected to histopathological evaluation. Post-treatment coronary flow was impaired in five animals (MS+HGF and MS group) without significant increases in TnI. One animal (MS group) died during treatment. There were no significant differences between groups in cMR parameters at any time (p > 0.05). No statistically significant changes were found between groups neither in cytokines nor in histological analyses. The IC administration of 5 × 106 HGF-loaded-microspheres 48 h post-AMI did not improve cardiac function, nor did it decrease inflammation or cardiac fibrosis in this experimental setting.
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Acute myocardial infarction (AMI) is the consequence of an acute interruption of myocardial blood flow delimiting an area with ischemic necrosis. The loss of cardiomyocytes initiates cardiac remodeling in the myocardium, leading to molecular changes in an attempt to recover myocardial function. The purpose of this study was to unravel the differences in the molecular profile between ischemic and remote myocardium after AMI in an experimental model. To mimic human myocardial infarction, healthy pigs were subjected to occlusion of the mid-left anterior descending coronary artery, and myocardial tissue was collected from ischemic and remote zones for omics techniques. Comparative transcriptome analysis of both areas was accurately validated by proteomic analysis, resulting in mitochondrion-related biological processes being the most impaired mechanisms in the infarcted area. Moreover, Immune system process-related genes were up-regulated in the remote tissue, mainly due to the increase of neutrophil migration in this area. These results provide valuable information regarding differentially expressed genes and their biological functions between ischemic and remote myocardium after AMI, which could be useful for establishing therapeutic targets for the development of new treatments.
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Tissue engineering is a promising methodology to produce advanced therapy medicinal products (ATMPs). We have developed personalized tissue engineered veins (P-TEV) as an alternative to autologous or synthetic vascular grafts utilized in reconstructive vein surgery. Our hypothesis is that individualization through reconditioning of a decellularized allogenic graft with autologous blood will prime the tissue for efficient recellularization, protect the graft from thrombosis, and decrease the risk of rejection. In this study, P-TEVs were transplanted to vena cava in pig, and the analysis of three veins after six months, six veins after 12 months and one vein after 14 months showed that all P-TEVs were fully patent, and the tissue was well recellularized and revascularized. To confirm that the ATMP product had the expected characteristics one year after transplantation, gene expression profiling of cells from P-TEV and native vena cava were analyzed and compared by qPCR and sequencing. The qPCR and bioinformatics analysis confirmed that the cells from the P-TEV were highly similar to the native cells, and we therefore conclude that P-TEV is functional and safe in large animals and have high potential for use as a clinical transplant graft.
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Ingeniería de Tejidos , Venas , Animales , Porcinos , Ingeniería de Tejidos/métodos , Venas/trasplante , Células Endoteliales , Perfilación de la Expresión GénicaRESUMEN
Large animal models, specifically swine, are widely used to research cardiovascular diseases and therapies, as well as for training purposes. This paper describes two different aneurysmal swine models that may help researchers to study new therapies for aneurysmal diseases. These aneurysmal models are created by surgically adding a pouch of tissue to carotid arteries in swine. When the model is used for research, the pouch must be autologous; for training purposes, a synthetic pouch suffices. First, the right external jugular vein (EJV) and right common carotid artery (CCA) must be surgically exposed. The EJV is ligated and a vein pouch fashioned from a short segment. This pouch is then sutured to an elliptical arteriotomy performed in the CCA. Animals must be kept heparinized during model creation, and local vasodilators may be used to decrease vasospasms. Once the suture is completed, correct blood flow should be inspected, checking for bleeding from the suture line and vessel patency. Finally, the surgical incision is closed by layers and an angiography performed to image the aneurysmal model. A simplification of this aneurysmal carotid model that decreases invasiveness and surgical time is the use of a synthetic, rather than venous, pouch. For this purpose, a pouch is tailored in advance with a segment of a polytetrafluoroethylene (PTFE) prosthesis, one end of which is sutured close using polypropylene vascular suture and sterilized prior to surgery. This "sac" is then attached to an arteriotomy performed in the CCA as described. Although these models do not reproduce many of the physiopathological events related to aneurysm formation, they are hemodynamically similar to the situation found in the clinical setting. Therefore, they can be used for research or training purposes, allowing physicians to learn and practice different endovascular techniques in animal models that are close to the human system.
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Aneurisma , Procedimientos Endovasculares , Aneurisma/diagnóstico por imagen , Aneurisma/cirugía , Animales , Arterias Carótidas/cirugía , Arteria Carótida Común/cirugía , Modelos Animales de Enfermedad , PorcinosRESUMEN
Tissue engineering (TE) aims to develop structures that improve or even replace the biological functions of tissues and organs. Mechanical properties, physical-chemical characteristics, biocompatibility, and biological performance of the materials are essential factors for their applicability in TE. Poly(vinylidene fluoride) (PVDF) is a thermoplastic polymer that exhibits good mechanical properties, high biocompatibility and excellent thermal properties. However, PVDF structuring, and the corresponding processing methods used for its preparation are known to significantly influence these characteristics. In this study, doctor blade, salt-leaching, and electrospinning processing methods were used to produce PVDF-based structures in the form of films, porous membranes, and fiber scaffolds, respectively. These PVDF scaffolds were subjected to a variety of characterizations and analyses, including physicochemical analysis, contact angle measurement, cytotoxicity assessment and cell proliferation. All prepared PVDF scaffolds are characterized by a mechanical response typical of ductile materials. PVDF films displayed mostly vibration modes for the a-phase, while the remaining PVDF samples were characterized by a higher content of electroactive ß-phase due the low temperature solvent evaporation during processing. No significant variations have been observed between the different PVDF membranes with respect to the melting transition. In addition, all analysed PVDF samples present a hydrophobic behavior. On the other hand, cytotoxicity assays confirm that cell viability is maintained independently of the architecture and processing method. Finally, all the PVDF samples promote human umbilical vein endothelial cells (HUVECs) proliferation, being higher on the PVDF film and electrospun randomly-oriented membranes. These findings demonstrated the importance of PVDF topography on HUVEC behavior, which can be used for the design of vascular implants.
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The arrhythmic substrate of ventricular tachycardias in many structural heart diseases is located in the epicardium, often resulting in poor outcomes with currently available therapies. Cardiosphere-derived cells (CDCs) have been shown to modify myocardial scarring. A total of 19 Large White pigs were infarcted by occlusion of the mid-left anterior descending coronary artery for 150 min. Baseline cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement sequences was obtained 4 weeks post-infarction and pigs were randomized to a treatment group (intrapericardial administration of 300,000 allogeneic CDCs/kg), (n = 10) and to a control group (n = 9). A second CMR and high-density endocardial electroanatomical mapping were performed at 16 weeks post-infarction. After the electrophysiological study, pigs were sacrificed and epicardial optical mapping and histological studies of the heterogeneous tissue of the endocardial and epicardial scars were performed. In comparison with control conditions, intrapericardial CDCs reduced the growth of epicardial dense scar and epicardial electrical heterogeneity. The relative differences in conduction velocity and action potential duration between healthy myocardium and heterogeneous tissue were significantly smaller in the CDC-treated group than in the control group. The lower electrical heterogeneity coincides with heterogeneous tissue with less fibrosis, better cardiomyocyte viability, and a greater quantity and better polarity of connexin 43. At the endocardial level, no differences were detected between groups. Intrapericardial CDCs produce anatomical and functional changes in the epicardial arrhythmic substrate, which could have an anti-arrhythmic effect.
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Acute myocardial infarction (AMI) is a manifestation of ischemic heart disease where the immune system plays an important role in the re-establishment of homeostasis. We hypothesize that the anti-inflammatory activity of secretomes from menstrual blood-derived mesenchymal stromal cells (S-MenSCs) and IFNγ/TNFα-primed MenSCs (S-MenSCs*) may be considered a therapeutic option for the treatment of AMI. To assess this hypothesis, we have evaluated the effect of S-MenSCs and S-MenSCs* on cardiac function parameters and the involvement of immune-related genes using a porcine model of AMI. Twelve pigs were randomly divided into three biogroups: AMI/Placebo, AMI/S-MenSCs, and AMI/S-MenSCs*. AMI models were generated using a closed chest coronary occlusion-reperfusion procedure and, after 72 h, the different treatments were intrapericardially administered. Cardiac function parameters were monitored by magnetic resonance imaging before and 7 days post-therapy. Transcriptomic analyses in the infarcted tissue identified 571 transcripts associated with the Gene Ontology term Immune response, of which 57 were differentially expressed when different biogroups were compared. Moreover, a prediction of the interactions between differentially expressed genes (DEGs) and miRNAs from secretomes revealed that some DEGs in the infarction area, such as STAT3, IGFR1, or BCL6 could be targeted by previously identified miRNAs in secretomes from MenSCs. In conclusion, the intrapericardial administration of secretome early after infarction has a significant impact on the expression of immune-related genes in the infarcted myocardium. This confirms the immunomodulatory potential of intrapericardially delivered secretomes and opens new therapeutic perspectives in myocardial infarction treatment.
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OBJECTIVE: The purpose of this study was to prospectively evaluate pathologic responses to transarterial prostatic embolization and its technical safety in a canine model. MATERIALS AND METHODS: Ten adult male beagle dogs were surgically castrated and given hormonal therapy for 4 months to induce prostatic hyperplasia. After three months of hormonal therapy, the dogs were randomly assigned to a transarterial prostatic embolization group (n = 7) or a control group (n = 3). Dogs in the transarterial prostatic embolization group were subjected to embolization with microspheres 300-500 µm in diameter. Four months after the study was begun, all dogs were sacrificed for pathologic study. Transrectal ultrasound and MRI were performed to evaluate pathologic responses. The data on prostate size acquired with transrectal ultrasound were processed for statistical analysis by paired Student t test. RESULTS: The canine prostatic hyperplasia model was successfully established in 10 dogs. The increase in mean prostate size being as great as 572% after 3 months of hormonal therapy. An intraprostatic cavity was detected 1 month after transarterial prostatic embolization in all seven dogs. Four dogs had significant shrinkage of the prostate, and the other three had an increase in prostate size. Imaging examinations and necropsy revealed a huge cavity occupying almost the entire prostate in the three dogs with increased prostate size. No complications associated with transarterial prostatic embolization were encountered. CONCLUSION: Transarterial prostatic embolization is a safe procedure that can induce prostatic infarction and ablate the prostate. The findings suggest the procedure has potential clinical applications in the care of patients with benign prostatic hyperplasia.
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Embolización Terapéutica/métodos , Hiperplasia Prostática/terapia , Angiografía , Animales , Modelos Animales de Enfermedad , Perros , Imagen por Resonancia Magnética , Masculino , Microesferas , Estudios Prospectivos , Hiperplasia Prostática/diagnóstico por imagen , Hiperplasia Prostática/patología , Distribución Aleatoria , Seguridad , UltrasonografíaRESUMEN
Pathologies related to the cardiovascular system are the leading causes of death worldwide. One of the main treatments is conventional surgery with autologous transplants. Although donor grafts are often unavailable, tissue-engineered vascular grafts (TEVGs) show promise for clinical treatments. A systematic review of the recent scientific literature was performed using PubMed (Medline) and Web of Science databases to provide an overview of the state-of-the-art in TEVG development. The use of TEVG in human patients remains quite restricted owing to the presence of vascular stenosis, existence of thrombi, and poor graft patency. A total of 92 original articles involving human patients and animal models were analyzed. A meta-analysis of the influence of the vascular graft diameter on the occurrence of thrombosis and graft patency was performed for the different models analyzed. Although there is no ideal animal model for TEVG research, the murine model is the most extensively used. Hybrid grafting, electrospinning, and cell seeding are currently the most promising technologies. The results showed that there is a tendency for thrombosis and non-patency in small-diameter grafts. TEVGs are under constant development, and research is oriented towards the search for safe devices.
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The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization. The aim of this study was to assess viability, safety and effectiveness of cardiosphere-derived cells (CDCs), their extracellular vesicles (EVs) or placebo administered via a mini-thoracotomy 72 h after experimental infarction in swine. The epicardial administration was completed successfully in all cases in a surgery time (knife-to-skin) below 30 min. No significant differences between groups were found in cardiac function parameters evaluated using magnetic resonance imaging before therapy and at the end of the study, despite a trend towards improved function in CDC-treated animals. Moreover, infarct size at 10 weeks was smaller in treated animals, albeit not significantly. Arrhythmia inducibility did not differ between groups. Pathological examination showed no differences, nor were there any pericardial adhesions evidenced in any case 10 weeks after surgery. These results show that the epicardial delivery of CDCs or their EVs is safe and technically easy 3 days after experimental myocardial infarction in swine, but it does not appear to have any beneficial effect on cardiac function. Our results do not support clinical translation of these therapies as implemented in this work.
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Vesículas Extracelulares , Infarto del Miocardio/terapia , Miocitos Cardíacos/citología , Animales , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Miocitos Cardíacos/trasplante , Pericardio/patología , Esferoides Celulares , Sus scrofa , Toracotomía , Trasplante AutólogoRESUMEN
Myocardial infarction is caused by an interruption of coronary blood flow, leading to one of the main death causes worldwide. Current therapeutic approaches are palliative and not able to solve the loss of cardiac tissue. Cardiosphere derived cells (CDCs) reduce scarring, and increase viable myocardium, with safety and adequate biodistribution, but show a low rate engraftment and survival after implantation. In order to solve the low retention, we propose the encapsulation of CDCs within three-dimensional alginate-poly-L-lysine-alginate matrix as therapy for cardiac regeneration. In this work, we demonstrate the encapsulation of CDCs in alginate matrix, with no decrease in viability over a month, and showing the preservation of CDCs phenotype, differentiation potential, gene expression profile and growth factor release after encapsulation, moving a step forward to clinical translation of CDCs therapy in regeneration in heart failure.
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Miocardio , Trasplante de Células Madre , Alginatos , Animales , Diferenciación Celular , Corazón , Miocitos Cardíacos , Porcinos , Distribución TisularRESUMEN
The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.