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1.
J Mech Behav Biomed Mater ; 126: 105074, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35030471

RESUMO

After myocardial infarction (MI), adult mammals exhibit scar formation, adverse left ventricular (LV) remodeling, LV stiffening, and impaired contractility, ultimately resulting in heart failure. Neonatal mammals, however, are capable of natural heart regeneration after MI. We hypothesized that neonatal cardiac regeneration conserves native biaxial LV mechanics after MI. Wistar rat neonates (1 day old, n = 46) and adults (8-10 weeks old, n = 20) underwent sham surgery or permanent left anterior descending coronary artery ligation. At 6 weeks after neonatal MI, Masson's trichrome staining revealed negligible fibrosis. Echocardiography for the neonatal MI (n = 15) and sham rats (n = 14) revealed no differences in LV wall thickness or chamber diameter, and both groups had normal ejection fraction (72.7% vs 77.5%, respectively, p = 0.1946). Biaxial tensile testing revealed similar stress-strain curves along both the circumferential and longitudinal axes across a full range of physiologic stresses and strains. The circumferential modulus (267.9 kPa vs 274.2 kPa, p = 0.7847), longitudinal modulus (269.3 kPa vs 277.1 kPa, p = 0.7435), and maximum shear stress (3.30 kPa vs 3.95 kPa, p = 0.5418) did not differ significantly between the neonatal MI and sham groups, respectively. In contrast, transmural scars were observed at 4 weeks after adult MI. Adult MI hearts (n = 7) exhibited profound LV wall thinning (p < 0.0001), chamber dilation (p = 0.0246), and LV dysfunction (ejection fraction 45.4% vs 79.7%, p < 0.0001) compared to adult sham hearts (n = 7). Adult MI hearts were significantly stiffer than adult sham hearts in both the circumferential (321.5 kPa vs 180.0 kPa, p = 0.0111) and longitudinal axes (315.4 kPa vs 172.3 kPa, p = 0.0173), and also exhibited greater maximum shear stress (14.87 kPa vs 3.23 kPa, p = 0.0162). Our study is the first to show that native biaxial LV mechanics are conserved after neonatal heart regeneration following MI, thus adding biomechanical support for the therapeutic potential of cardiac regeneration in the treatment of ischemic heart disease.


Assuntos
Infarto do Miocárdio , Animais , Animais Recém-Nascidos , Fenômenos Biomecânicos , Cicatriz/patologia , Modelos Animais de Doenças , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ratos , Ratos Wistar , Remodelação Ventricular
2.
Chem Rev ; 121(18): 11385-11457, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-33938724

RESUMO

Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposes-they can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast during imaging, protect tissues or organs during radiotherapy, and improve the biocompatibility of medical implants. These capabilities make hydrogels useful for many distinct and pressing diseases and medical conditions and even for less conventional areas such as environmental engineering. In this review, we cover the major capabilities of hydrogels, with a focus on the novel benefits of injectable hydrogels, and how they relate to translational applications in medicine and the environment. We pay close attention to how the development of contemporary hydrogels requires extensive interdisciplinary collaboration to accomplish highly specific and complex biological tasks that range from cancer immunotherapy to tissue engineering to vaccination. We complement our discussion of preclinical and clinical development of hydrogels with mechanical design considerations needed for scaling injectable hydrogel technologies for clinical application. We anticipate that readers will gain a more complete picture of the expansive possibilities for hydrogels to make practical and impactful differences across numerous fields and biomedical applications.


Assuntos
Hidrogéis , Engenharia Tecidual , Próteses e Implantes
3.
Clin Transl Med ; 11(4): e387, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33931977

RESUMO

Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal announcements. Overall time-in-range (70-180 mg/dl) for AndroidAPS was 58% ± 5%, while time-in-range for Loop was 35% ± 5%. The effect of the algorithms on time-in-range differed between meals and overnight. During the overnight monitoring period, pigs had an average time-in-range of 90% ± 7% when on AndroidAPS compared to 22% ± 8% on Loop. Time-in-hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/-0.8)% in hypoglycemia compared to 10% (+3/-6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Infusão de Insulina , Algoritmos , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Feminino , Controle Glicêmico/métodos , Insulina/administração & dosagem , Insulina/uso terapêutico , Suínos
4.
Sci Transl Med ; 12(550)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611683

RESUMO

Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput-controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Animais , Glicemia , Excipientes , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes , Insulina Lispro , Suínos
5.
Microb Biotechnol ; 13(6): 1780-1792, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32476224

RESUMO

The cyanobacterium Synechococcus elongatus (SE) has been shown to rescue ischaemic heart muscle after myocardial infarction by photosynthetic oxygen production. Here, we investigated SE toxicity and hypothesized that systemic SE exposure does not elicit a significant immune response in rats. Wistar rats intravenously received SE (n = 12), sterile saline (n = 12) or E. coli lipopolysaccharide (LPS, n = 4), and a subset (8 SE, 8 saline) received a repeat injection 4 weeks later. At baseline, 4 h, 24 h, 48 h, 8 days and 4 weeks after injection, clinical assessments, blood cultures, blood counts, lymphocyte phenotypes, liver function tests, proinflammatory cytokines and immunoglobulins were assessed. Across all metrics, SE rats responded comparably to saline controls, displaying no clinically significant immune response. As expected, LPS rats exhibited severe immunological responses. Systemic SE administration does not induce sepsis or toxicity in rats, thereby supporting the safety of cyanobacteria-mammalian symbiotic therapeutics using this organism.


Assuntos
Escherichia coli , Synechococcus , Animais , Fotossíntese , Ratos , Ratos Wistar
6.
Nat Biomed Eng ; 4(5): 507-517, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32393892

RESUMO

Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Composição de Medicamentos , Glucagon/metabolismo , Insulina/uso terapêutico , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Difusão , Vias de Administração de Medicamentos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Imidazóis/química , Insulina/administração & dosagem , Insulina/farmacocinética , Insulina/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/administração & dosagem , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacocinética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Polietilenoglicóis/química , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Suínos
7.
Sci Rep ; 10(1): 7319, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355240

RESUMO

Neonatal mice exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). Cardiac biomechanics intricately affect long-term heart function, but whether regenerated cardiac muscle is biomechanically similar to native myocardium remains unknown. We hypothesized that neonatal heart regeneration preserves native left ventricular (LV) biomechanical properties after MI. C57BL/6J mice underwent sham surgery or left anterior descending coronary artery ligation at age P1 or P7. Echocardiography performed 4 weeks post-MI showed that P1 MI and sham mice (n = 22, each) had similar LV wall thickness, diameter, and ejection fraction (59.6% vs 60.7%, p = 0.6514). Compared to P7 shams (n = 20), P7 MI mice (n = 20) had significant LV wall thinning, chamber enlargement, and depressed ejection fraction (32.6% vs 61.8%, p < 0.0001). Afterward, the LV was explanted and pressurized ex vivo, and the multiaxial lenticular stress-strain relationship was tracked. While LV tissue modulus for P1 MI and sham mice were similar (341.9 kPa vs 363.4 kPa, p = 0.6140), the modulus for P7 MI mice was significantly greater than that for P7 shams (691.6 kPa vs 429.2 kPa, p = 0.0194). We conclude that, in neonatal mice, regenerated LV muscle has similar biomechanical properties as native LV myocardium.


Assuntos
Ventrículos do Coração/fisiopatologia , Coração/fisiologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Regeneração , Animais , Animais Recém-Nascidos , Fenômenos Biomecânicos , Proliferação de Células , Colágeno/química , Ecocardiografia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Estresse Mecânico , Remodelação Ventricular
8.
Cells ; 9(1)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963369

RESUMO

Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson's trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2'-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.


Assuntos
Infarto do Miocárdio/fisiopatologia , Regeneração , Animais , Animais Recém-Nascidos , Aurora Quinase B/metabolismo , Proliferação de Células , Cicatriz/patologia , Colágeno/metabolismo , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Fibrose , Antígeno Ki-67/metabolismo , Ligadura , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Miócitos Cardíacos/patologia , Ratos Wistar , Fatores de Tempo , Troponina/metabolismo
9.
Cytokine ; 127: 154974, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31978642

RESUMO

Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.


Assuntos
Hidrogéis/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Catéteres , Células Cultivadas , Modelos Animais de Doenças , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Ácido Hialurônico/administração & dosagem , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Ratos
10.
Proc Natl Acad Sci U S A ; 116(42): 20820-20827, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31570592

RESUMO

Polyphosphate fire retardants are a critical tactical resource for fighting fires in the wildland and in the wildland-urban interface. Yet, application of these retardants is limited to emergency suppression strategies because current formulations cannot retain fire retardants on target vegetation for extended periods of time through environmental exposure and weathering. New retardant formulations with persistent retention to target vegetation throughout the peak fire season would enable methodical, prophylactic treatment strategies of landscapes at high risk of wildfires through prolonged prevention of ignition and continual impediment to active flaming fronts. Here we develop a sprayable, environmentally benign viscoelastic fluid comprising biopolymers and colloidal silica to enhance adherence and retention of polyphosphate retardants on common wildfire-prone vegetation. These viscoelastic fluids exhibit appropriate wetting and rheological responses to enable robust retardant adherence to vegetation following spray application. Further, laboratory and pilot-scale burn studies establish that these materials drastically reduce ignition probability before and after simulated weathering events. Overall, these studies demonstrate how these materials actualize opportunities to shift the approach of retardant-based wildfire management from reactive suppression to proactive prevention at the source of ignitions.


Assuntos
Conservação dos Recursos Naturais/métodos , Retardadores de Chama/análise , Substâncias Viscoelásticas/química , Incêndios Florestais/prevenção & controle , Florestas , Polifosfatos/química , Estações do Ano , Árvores/química
11.
Nat Biomed Eng ; 3(8): 611-620, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391596

RESUMO

Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Hidrogéis/química , Pericárdio/cirurgia , Polímeros/química , Aderências Teciduais , Animais , Celulose Oxidada , Ácido Hialurônico , Hidrogéis/uso terapêutico , Masculino , Modelos Animais , Nanopartículas , Polímeros/uso terapêutico , Ratos , Ovinos
12.
J Mech Behav Biomed Mater ; 96: 165-171, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31035067

RESUMO

Adverse remodeling of the left ventricle (LV) after myocardial infarction (MI) results in abnormal tissue biomechanics and impaired cardiac function, often leading to heart failure. We hypothesized that intramyocardial delivery of engineered stromal cell-derived factor 1α analog (ESA), our previously-developed supra-efficient pro-angiogenic chemokine, preserves biaxial LV mechanical properties after MI. Male Wistar rats (n = 45) underwent sham surgery (n = 15) or permanent left anterior descending coronary artery ligation. Rats sustaining MI were randomized for intramyocardial injections of either saline (100 µL, n = 15) or ESA (6 µg/kg, n = 15), delivered at four standardized borderzone sites. After 4 weeks, echocardiography was performed, and the hearts were explanted. Tensile testing of the anterolateral LV wall was performed using a displacement-controlled biaxial load frame, and modulus was determined after constitutive modeling. At 4 weeks post-MI, compared to saline controls, ESA-treated hearts had greater wall thickness (1.68 ±â€¯0.05 mm vs 1.42 ±â€¯0.08 mm, p = 0.008), smaller end-diastolic LV internal dimension (6.88 ±â€¯0.29 mm vs 7.69 ±â€¯0.22 mm, p = 0.044), and improved ejection fraction (62.8 ±â€¯3.0% vs 49.4 ±â€¯4.5%, p = 0.014). Histologic analysis revealed significantly reduced infarct size for ESA-treated hearts compared to saline controls (29.4 ±â€¯2.9% vs 41.6 ±â€¯3.1%, p = 0.021). Infarcted hearts treated with ESA exhibited decreased modulus compared to those treated with saline in both the circumferential (211.5 ±â€¯6.9 kPa vs 264.3 ±â€¯12.5 kPa, p = 0.001) and longitudinal axes (194.5 ±â€¯6.5 kPa vs 258.1 ±â€¯14.4 kPa, p < 0.001). In both principal directions, ESA-treated infarcted hearts possessed similar tissue compliance as sham non-infarcted hearts. Overall, intramyocardial ESA therapy improves post-MI ventricular remodeling and function, reduces infarct size, and preserves native LV biaxial mechanical properties.


Assuntos
Quimiocina CXCL12/genética , Quimiocina CXCL12/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Fenômenos Mecânicos/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Engenharia de Proteínas , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Remodelação Ventricular/efeitos dos fármacos
13.
Adv Healthc Mater ; 8(5): e1801147, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714355

RESUMO

Hydrogels have emerged as a diverse class of biomaterials offering a broad range of biomedical applications. Specifically, injectable hydrogels are advantageous for minimally invasive delivery of various therapeutics and have great potential to treat a number of diseases. However, most current injectable hydrogels are limited by difficult and time-consuming fabrication techniques and are unable to be delivered through long, narrow catheters, preventing extensive clinical translation. Here, the development of an easily-scaled, catheter-injectable hydrogel utilizing a polymer-nanoparticle crosslinking mechanism is reported, which exhibits notable shear-thinning and self-healing behavior. Gelation of the hydrogel occurs immediately upon mixing the biochemically modified hyaluronic acid polymer with biodegradable nanoparticles and can be easily injected through a high-gauge syringe due to the dynamic nature of the strong, yet reversible crosslinks. Furthermore, the ability to deliver this novel hydrogel through a long, narrow, physiologically-relevant catheter affixed with a 28-G needle is highlighted, with hydrogel mechanics unchanged after delivery. Due to the composition of the gel, it is demonstrated that therapeutics can be differentially released with distinct elution profiles, allowing precise control over drug delivery. Finally, the cell-signaling and biocompatibility properties of this innovative hydrogel are demonstrated, revealing its wide range of therapeutic applications.


Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Animais , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Camundongos , Células NIH 3T3 , Polímeros/química , Ratos , Ratos Wistar , Engenharia Tecidual/métodos
14.
J Thorac Cardiovasc Surg ; 158(2): 392-403, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30745047

RESUMO

OBJECTIVE: The optimal conduit for valve-sparing aortic root replacement is still debated, with several conduit variations available, ranging from straight tubular grafts to Valsalva grafts. Benefits of neosinus reconstruction include enhanced flow profiles and improved hemodynamics. Curiously, however, some clinical data suggest that straight grafts may have greater long-term durability. In this study, we hypothesized that straight tubular grafts may help maintain the native cylindrical position of the aortic valve commissures radially, resulting in preserved leaflet coaptation, reduced stresses, and potentially improved valve performance. METHODS: Using 3D printing, a left heart simulator with a valve-sparing root replacement model and a physiologic coronary circulation was constructed. Aortic valves were dissected from fresh porcine hearts and reimplanted into either straight tubular grafts (n = 6) or Valsalva grafts (n = 6). Conduits were mounted into the heart simulator and hemodynamic, echocardiographic, and high-speed videometric data were collected. RESULTS: Hemodynamic parameters and coronary blood flow were similar between straight and Valsalva grafts, although the former were associated with lower regurgitant fractions, less peak intercommissural radial separation, preserved leaflet coaptation, decreased leaflet velocities, and lower relative leaflet forces compared with Valsalva grafts. CONCLUSIONS: Valsalva grafts and straight grafts perform equally well in terms of gross hemodyanics and coronary blood flow. Interestingly, however, the biomechanics of these 2 conduits differ considerably, with straight grafts providing increased radial commissural stability and leaflet coaptation. Further investigation into how these parameters influence clinical outcomes is warranted.


Assuntos
Aorta/cirurgia , Valva Aórtica/cirurgia , Impressão Tridimensional , Animais , Aorta/patologia , Aorta/fisiopatologia , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Fenômenos Biomecânicos , Circulação Coronária , Ecocardiografia Transesofagiana , Hemodinâmica , Modelos Anatômicos , Seio Aórtico/patologia , Seio Aórtico/fisiopatologia , Seio Aórtico/cirurgia , Suínos , Enxerto Vascular/métodos
15.
Macromol Biosci ; 19(1): e1800275, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30369048

RESUMO

Drug delivery and cell transplantation require minimally invasive deployment strategies such as injection through clinically relevant high-gauge needles. Supramolecular hydrogels comprising dodecyl-modified hydroxypropylmethylcellulose and poly(ethylene glycol)-block-poly(lactic acid) have been previously demonstrated for the delivery of drugs and proteins. Here, it is demonstrated that the rheological properties of these hydrogels allow for facile injectability, an increase of cell viability after injection when compared to cell viabilities of cells injected in phosphate-buffered saline, and homogeneous cell suspensions that do not settle. These hydrogels are injected at 1 mL min-1 with pressures less than 400 kPa, despite the solid-like properties of the gel when at rest. The cell viabilities immediately after injection are greater than 86% for adult human dermal fibroblasts, human umbilical vein cells, smooth muscle cells, and human mesenchymal stem cells. Cells are shown to remain suspended and proliferate in the hydrogel at the same rate as observed in cell media. The work expands on the versatility of these hydrogels and lays a foundation for the codelivery of drugs, proteins, and cells.


Assuntos
Sistemas de Liberação de Medicamentos , Hidrogéis , Teste de Materiais , Células-Tronco Mesenquimais/metabolismo , Nanopartículas/química , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/citologia , Poliésteres/química , Poliésteres/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia
16.
Cardiovasc Diabetol ; 16(1): 142, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096622

RESUMO

BACKGROUND: Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM. METHODS: Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle). RESULTS: SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group. CONCLUSIONS: Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Cardiomiopatias Diabéticas/prevenção & controle , Células Progenitoras Endoteliais/transplante , Microvasos , Miócitos de Músculo Liso/transplante , Engenharia Tecidual/métodos , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/fisiopatologia , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Microvasos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Roedores
17.
Sci Adv ; 3(6): e1603078, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28630913

RESUMO

Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.


Assuntos
Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Processos Fototróficos , Animais , Terapia Biológica , Cianobactérias , Metabolismo Energético , Testes de Função Cardíaca , Hipóxia/metabolismo , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/terapia , Miócitos Cardíacos/metabolismo , Fotossíntese , Ratos
18.
Proc Natl Acad Sci U S A ; 113(50): 14255-14260, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27911849

RESUMO

Hydrogels are a class of soft material that is exploited in many, often completely disparate, industrial applications, on account of their unique and tunable properties. Advances in soft material design are yielding next-generation moldable hydrogels that address engineering criteria in several industrial settings such as complex viscosity modifiers, hydraulic or injection fluids, and sprayable carriers. Industrial implementation of these viscoelastic materials requires extreme volumes of material, upwards of several hundred million gallons per year. Here, we demonstrate a paradigm for the scalable fabrication of self-assembled moldable hydrogels using rationally engineered, biomimetic polymer-nanoparticle interactions. Cellulose derivatives are linked together by selective adsorption to silica nanoparticles via dynamic and multivalent interactions. We show that the self-assembly process for gel formation is easily scaled in a linear fashion from 0.5 mL to over 15 L without alteration of the mechanical properties of the resultant materials. The facile and scalable preparation of these materials leveraging self-assembly of inexpensive, renewable, and environmentally benign starting materials, coupled with the tunability of their properties, make them amenable to a range of industrial applications. In particular, we demonstrate their utility as injectable materials for pipeline maintenance and product recovery in industrial food manufacturing as well as their use as sprayable carriers for robust application of fire retardants in preventing wildland fires.

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