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OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (nâ¯=â¯44 SAVM; nâ¯=â¯46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.
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Insuficiência Cardíaca , Nervos Esplâncnicos , Volume Sistólico , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/terapia , Volume Sistólico/fisiologia , Método Duplo-Cego , Nervos Esplâncnicos/cirurgia , Masculino , Feminino , Estudos Prospectivos , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Idoso , Pessoa de Meia-Idade , Técnicas de Ablação/métodos , SeguimentosRESUMO
BACKGROUND: The MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) has demonstrated that the HeartMate 3 (HM3) pump is associated with reduced strokes compared with the HeartMate II (HMII) device. We now perform a comprehensive analysis of stroke events to evaluate their longitudinal occurrence, clinical correlates, patterns, and impact on outcome across the 2-year duration of support. METHODS: MOMENTUM 3 is a randomized controlled trial of the HM3 centrifugal-flow pump versus the HMII axial-flow pump in patients with advanced heart failure, regardless of the intended goal of support (bridge to transplantation or destination therapy). Baseline and postimplantation clinical correlates of stroke events were assessed with multivariable analyses. Longitudinal patterns, including device association, type of stroke (hemorrhagic versus ischemic), changing severity of impairment assessed with the modified Rankin Scale (disabling [modified Rankin Scale score >3] versus nondisabling [modified Rankin Scale score ≤3]) over time, and association with outcome, were determined. RESULTS: In 361 patients with the intended implant (189 HM3 and 172 HMII), 65 strokes (40 ischemic strokes and 25 hemorrhagic strokes) occurred in 52 patients at a median of 131 (range, 1-733) days. No difference in stroke rate was noted between 0 and 180 days of follow-up between devices. However, stroke incidence in the long-term period (181-730 days after left ventricular assist device) was 3.3 times lower for the HM3 group (HM3: 0.04 versus HMII: 0.13 events per patient-year; odds ratio, 0.23; 95% CI, 0.08-0.63; P=0.01). Treatment with the HM3 pump was the only independent predictor of lower stroke events. We found no direct association of blood pressure or antithrombotic regimens with observed stroke rates. A stroke event significantly lowered 2-year postimplantation survival regardless of subtype or initial severity of neurological impairment compared with patients without a stroke (43±12% for hemorrhagic stroke, 57±9% for ischemic stroke, 51±11% for disabling, and 51±11% for nondisabling compared with 85±2% 2-year survival for patients without stroke). CONCLUSIONS: The HM3 pump is associated with a marked reduction in stroke rates compared with the HMII device, with benefits observed in the long-term period (>6 months). The occurrence of stroke of any type (hemorrhagic and ischemic) or of any functional severity (disabling and nondisabling) is predictive of a poor 2-year clinical outcome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02224755.
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Isquemia Encefálica/prevenção & controle , Insuficiência Cardíaca/terapia , Coração Auxiliar , Hemorragias Intracranianas/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/mortalidade , Isquemia Encefálica/fisiopatologia , Avaliação da Deficiência , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hemorragias Intracranianas/diagnóstico , Hemorragias Intracranianas/mortalidade , Hemorragias Intracranianas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Desenho de Prótese , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Função Ventricular EsquerdaRESUMO
BACKGROUND: Correction of valvular disease is often undertaken during left ventricular assist device (LVAD) implantation with uncertain benefit. We analyzed clinical outcomes with HeartMate 3 (HM3; Abbott) LVAD implantation in those with various concurrent valve procedures (HM3+VP) with those with an isolated LVAD implant (HM3 alone). METHODS: The study included 2200 patients with HM3 implanted within the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial portfolio who underwent 820 concurrent procedures among which 466 (21.8%) were HM3+VP. VPs included 101 aortic, 61 mitral, 163 tricuspid; 85 patients had multiple VPs. Perioperative complications, major adverse events, and survival were analyzed. RESULTS: Patients who underwent HM3+VP had higher-acuity Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles (1-2: 41% vs 31%) compared with no VPs (P < .05). The cardiopulmonary bypass time (124 vs 76 minutes; P < .0001) and hospital length of stay (20 vs 18 days; P < .0001) were longer in HM3+VP. A higher incidence of stroke (4.9% vs 2.4%), bleeding (33.9% vs 23.8%), and right heart failure (41.5% vs 29.6%) was noted in HM3+VP at 0 to 30 days (P < .01), with no difference in 30-day mortality (3.9% vs 3.3%) or 2-year survival (81.7% vs 80.8%). Analysis of individual VP showed no differences in survival compared to HM3 alone. No differences were noted among patients with either significant mitral (moderate or worse) or tricuspid (moderate or worse) regurgitation with or without corrective surgery. CONCLUSIONS: Concurrent VPs, commonly performed during LVAD implantation, are associated with increased morbidity during the index hospitalization, with no effect on short- and long-term survival. There is sufficient equipoise to consider a randomized trial on the benefit of commonly performed VPs (such as mitral or tricuspid regurgitation correction), during LVAD implantation.
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Insuficiência Cardíaca , Coração Auxiliar , Acidente Vascular Cerebral , Procedimentos Cirúrgicos Torácicos , Humanos , Catéteres , Coração Auxiliar/efeitos adversos , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Estudos Multicêntricos como AssuntoRESUMO
The current standard treatment for Type 1 diabetes is the administration of exogenous insulin to manage blood glucose levels. Cellular therapies are in development to address this dependency and allow patients to produce their own insulin. Studies have shown that viable, functional allogenic islets can be encapsulated inside alginate-based materials as a potential treatment for Type 1 diabetes. The capability of these grafts is limited by several factors, among which is the stability and longevity of the encapsulating material in vivo. Previous studies have shown that multilayer Alginate-Poly-L-Ornithine-Alginate (A-PLO-A) microbeads are effective in maintaining cellular function in vivo. This study expands upon the existing encapsulation material by investigating whether covalent crosslinking of the outer alginate layer increases stability. The alginate comprising the outer layer was methacrylated, allowing it to be covalently crosslinked. Microbeads with a crosslinked outer layer exhibited a consistent outer layer thickness and increased stability when exposed to chelating agents in vitro. The outer layer was maintained in vivo even in the presence of a robust inflammatory response. The results demonstrate a technique for generating A-PLO-A with a covalently crosslinked outer layer.
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BACKGROUND: In a randomized controlled trial (MOMENTUM 3), the HeartMate 3 (HM3) fully magnetically levitated centrifugal-flow left ventricular assist device (LVAD) demonstrated superiority over the HeartMate II (HMII) axial-flow LVAD. These findings were driven by hemocompatibility-related outcomes, but infection-related outcomes were not altered by device choice. In this trial-level analysis, we analyzed the clinical patterns of infection-related outcomes over 2 years of support. METHODS: In MOMENTUM 3, 1,020 patients were implanted with either the HM3 (nâ¯=â¯515) or HMII (nâ¯=â¯505) pump. Clinical characteristics and morbidity- and mortality-related outcomes were evaluated to identify predictors associated with major infectious complications, using univariable and multivariable models. RESULTS: The cumulative number of infections at 2 years was 1,213 (634 HM3 and 579 HMII), and major infection occurred in 58% of patients with the HM3 and 56% of patients with the HMII (pâ¯=â¯0.57). Infections of a local nature unrelated to pump components were most common (nâ¯=â¯681/1,213; 56%), followed by driveline-associated infection (nâ¯=â¯329/1,213; 27%), sepsis (nâ¯=â¯194/1,213; 16%), and other events (nâ¯=â¯9/1,213; 0.7%). Bacterial pathogens were implicated in 806 of 1,213 events (66%); significant predictors of infection included sex (women vs men; hazard ratio [HR]: 1.38, pâ¯=â¯0.003), pre-implant use of intra-aortic balloon pump (HR: 1.33, pâ¯=â¯0.02), pre-implant history of cardiac surgery (HR: 1.28, pâ¯=â¯0.01), and body mass index ≥ 30 (HR: 1.40, p < 0.0001). Most deaths in those with infection occurred owing to non-infectious causes. CONCLUSION: Infection is the most common adverse effect in patients implanted with contemporary continuous-flow LVADs, with most such events unrelated to the pump or its peripheral components. Whether chronic mechanical circulatory devices confer an immunomodulatory effect pre-disposing to infection warrants closer scrutiny to understand and ameliorate this morbidity.
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Insuficiência Cardíaca/cirurgia , Ventrículos do Coração/fisiopatologia , Coração Auxiliar/efeitos adversos , Infecções Relacionadas à Prótese/epidemiologia , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Relacionadas à Prótese/etiologia , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia , Função Ventricular EsquerdaRESUMO
BACKGROUND: Increased shear stress conferred upon the circulation by continuous-flow pumps is associated with hemocompatibility-related adverse events, principally bleeding within the gastrointestinal system, and linked to the degradation of high-molecular-weight multimers (HMWMs) of von Willebrand factor (vWF). We evaluated the structure and functional characteristics of vWF HMWMs in patients with the fully magnetically levitated centrifugal-flow HeartMate 3 (HM3) and the continuous axial-flow HeartMate II (HMII) pump. Findings were correlated with bleeding events. METHODS: In a prospective, multicenter, comparative cohort study, 60 patients from the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 Continued Access Protocol (NCT02892955) with an HM3 pump were compared with 30 randomly selected HMII patients from the PREVENtion of HeartMate II Pump Thrombosis study (NCT02158403) biobank. The primary end point was the difference in the normalized vWF HMWM ratio (ratio of the HMWMs to the intermediate- and low-molecular-weight multimers, normalized to pooled plasma from healthy volunteers) between the HM3 and the HMII pump at 90 days after implantation. Assay tests for vWF activity, vWF antigen, vWF activity to antigen ratio, coagulation factor VIII activity, and ADAMTS13 activity were measured by using standard protocols. Differences in these markers were compared in the context of clinical characteristics and correlated with adjudicated bleeding events within the HM3 group. RESULTS: Of 51 and 29 evaluable patients in the HM3 and HMII arms, respectively, those implanted with the HM3 pump exhibited greater preservation of the vWF HMWM ratio than those with the HMII pump at 90 days after implantation (54.1% vs 42.4%, p < 0.0001). Laboratory values for all vWF assays (antigen, activity, and coagulation factor VIII activity) remained within the normal functional range with no significant differences observed between the pumps at 90 days after implantation. At baseline, there was a decrease in the structural integrity of vWF HMWMs that correlated with increasing heart failure severity as measured by the Interagency Registry for Mechanically Assisted Circulatory Support profile. Multivariable modeling identified the HM3 pump as the only independent variable that determined post-implantation preservation of the structural integrity of vWF HMWMs. CONCLUSIONS: This prospective, multicenter comparative analysis study demonstrates that the fully magnetically levitated centrifugal-flow HM3 left ventricular assist device is associated with greater preservation of the structure of vWF HMWMs than the HMII mechanical bearing axial-flow pump.
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Coração Auxiliar , Fator de von Willebrand/análise , Adulto , Idoso , Centrifugação , Feminino , Humanos , Fenômenos Magnéticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Desenho de Prótese , Multimerização ProteicaRESUMO
Alginate hydrogels have been investigated for a broad variety of medical applications. The ability to assemble hydrogels at neutral pH and mild temperatures makes alginate a popular choice for the encapsulation and delivery of cells and proteins. Alginate has been studied extensively for the delivery of islets as a treatment for type 1 diabetes. However, poor stability of the encapsulation systems after implantation remains a challenge. In this paper, alginate was modified with 2-aminoethyl methacrylate hydrochloride (AEMA) to introduce groups that can be photoactivated to generate covalent bonds. This enabled formation of dual crosslinked structure upon exposure to ultraviolet light following initial ionic crosslinking into bead structures. The degree of methacrylation was varied and in vitro stability, long term swelling, and cell viability examined. At low levels of the methacrylation, the beads could be formed by first ionic crosslinks followed by exposure to ultraviolet light to generate covalent bonds. The methacrylated alginate resulted in more stable beads and cells were viable following encapsulation. Alginate microbeads, ionic (unmodified) and dual crosslinked, were implanted into a rat omentum pouch model. Implantation was performed with a local injection of 100⯵l of 50⯵g/ml of Lipopolysaccharide (LPS) to stimulate a robust inflammatory challenge in vivo. Implants were retrieved at 1 and 3â¯weeks for analysis. The unmodified alginate microbeads had all failed by week 1, whereas the dual-crosslinked alginate microbeads remained stable up through 3â¯weeks. The modified alginate microbeads may provide a more stable alternative to current alginate-based systems for cell encapsulation. STATEMENT OF SIGNIFICANCE: Alginate, a naturally occurring polysaccharide, has been used for cell encapsulation to prevent graft rejection of cell transplants for people with type I diabetes. Although some success has been observed in clinical trials, the lack of reproducibility and failure to reach insulin dependence for longer periods of time indicates the need for improvements in the procedure. A major requirement for the long-term function of alginate encapsulated cells is the mechanical stability of microcapsules. Insufficient mechanical integrity of the capsules can lead to immunological reactions in the recipients. In this work, alginate was modified to allow photoactivatable groups in order to allow formation of covalent crosslinks in addition to ionic crosslinking. The dual crosslinking design prevents capsule breakdown following implantation in vivo.
Assuntos
Alginatos/síntese química , Reagentes de Ligações Cruzadas/química , Microesferas , Alginatos/química , Animais , Hidrogéis , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Masculino , Metacrilatos/química , Modelos Animais , Omento , Ratos , Ratos Sprague-Dawley , Raios UltravioletaRESUMO
Alginate hydrogels have been used for a broad variety of medical applications. The ability to assemble alginate gels at neutral pH and mild temperatures makes alginate a promising choice for the encapsulation and delivery of cells and proteins. This chapter covers the basics of cell encapsulation and protein delivery using two different variations of alginate microbeads, single layered and multilayer systems. The first section describes a method for encapsulating cells within alginate microbeads coated with a permselective polymer layer. The second section describes a multilayer alginate microbead system that allows simultaneous encapsulation of cells and delivery of growth factors. The primary goal of the systems described is for encapsulation of islets as a treatment for type I diabetes. However, these microbeads can be used for a broad variety of applications in tissue engineering, cell encapsulation, and regenerative medicine.
Assuntos
Alginatos/química , Células Imobilizadas/citologia , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Células Secretoras de Insulina/citologia , Proteínas/administração & dosagem , Animais , Linhagem Celular , Reagentes de Ligações Cruzadas/química , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Camundongos , MicroesferasRESUMO
Human trials have demonstrated the feasibility of alginate-encapsulated islet cells for the treatment of type 1 diabetes. Encapsulated islets can be protected from the host's immune system and remain viable and functional following transplantation. However, the long-term success of these therapies requires that alginate microcapsules maintain their immunoprotective capacity and stability in vivo for sustained periods. In part, as a consequence of different encapsulation strategies, islet encapsulation studies have produced inconsistent results in regard to graft functioning time, stability, and overall metabolic benefits. Alginate composition (proportion of M- and G-blocks), alginate purity, the cross-linking ions (calcium or barium), and the presence or absence of additional polymer coating layers influence the success of cell encapsulation. This review summarizes the outcomes of long-term studies of alginate-encapsulated islet transplants in animals and humans and provides a critical discussion of the graft failure mechanisms, including issues with graft biocompatibility, transplantation site, and integrity of the encapsulated islet grafts. Strategies to improve the mechanical stability of alginate capsules and methods for monitoring graft survival and function in vivo are presented.
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Stable and extensive blood vessel networks are required for cell function and survival in engineered tissues. A number of different strategies are currently being investigated to enhance biomaterial vascularization with screening primarily through extensive in vitro and in vivo experiments. In this article, we describe an agent-based model (ABM) developed to evaluate various strategies in silico, including design of optimal biomaterial structure, delivery of angiogenic factors, and application of prevascularized biomaterials. The model predictions are evaluated using experimental data. The ABM developed provides insight into different strategies currently applied for scaffold vascularization and will enable researchers to rapidly screen new hypotheses and explore alternative strategies for enhancing vascularization.
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Transplantation of functional islets encapsulated in stable biomaterials has the potential to cure Type I diabetes. However, the success of these materials requires the ability to quantitatively evaluate their stability. Imaging techniques that enable monitoring of biomaterial performance are critical to further development in the field. X-ray phase-contrast (XPC) imaging is an emerging class of X-ray techniques that have shown significant promise for imaging biomaterial and soft tissue structures. In this study, XPC imaging techniques are shown to enable three dimensional (3D) imaging and evaluation of islet volume, alginate hydrogel structure, and local soft tissue features ex vivo. Rat islets were encapsulated in sterile ultrapurified alginate systems produced using a high-throughput microfluidic system. The encapsulated islets were implanted in omentum pouches created in a rodent model of type 1 diabetes. Microbeads were imaged with XPC imaging before implantation and as whole tissue samples after explantation from the animals. XPC microcomputed tomography (µCT) was performed with systems using tube-based and synchrotron X-ray sources. Islets could be identified within alginate beads and the islet volume was quantified in the synchrotron-based µCT volumes. Omental adipose tissue could be distinguished from inflammatory regions resulting from implanted beads in harvested samples with both XPC imaging techniques. Individual beads and the local encapsulation response were observed and quantified using quantitative measurements, which showed good agreement with histology. The 3D structure of the microbeads could be characterized with XPC imaging and failed beads could also be identified. These results point to the substantial potential of XPC imaging as a tool for imaging biomaterials in small animal models and deliver a critical step toward in vivo imaging.
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Corpos Estranhos/fisiopatologia , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Processamento de Imagem Assistida por Computador/métodos , Ilhotas Pancreáticas/patologia , Microscopia de Contraste de Fase/métodos , Microesferas , Alginatos/química , Animais , Materiais Biocompatíveis/química , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Ilhotas Pancreáticas/diagnóstico por imagem , Masculino , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Microtomografia por Raio-XRESUMO
Gradients of soluble factors play an important role in many biological processes, including blood vessel assembly. Gradients can be studied in detail in vitro, but methods that enable the study of spatially distributed soluble factors and multi-cellular processes in vivo are limited. Here, we report on a method for the generation of persistent in vivo gradients of growth factors in a three-dimensional (3D) biomaterial system. Fibrin loaded porous poly (ethylene glycol) (PEG) scaffolds were generated using a particulate leaching method. Platelet derived growth factor BB (PDGF-BB) was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres which were placed distal to the tissue-material interface. PLGA provides sustained release of PDGF-BB and its diffusion through the porous structure results in gradient formation. Gradients within the scaffold were confirmed in vivo using near-infrared fluorescence imaging and gradients were present for more than 3 weeks. The diffusion of PDGF-BB was modeled and verified with in vivo imaging findings. The depth of tissue invasion and density of blood vessels formed in response to the biomaterial increased with magnitude of the gradient. This biomaterial system allows for generation of sustained growth factor gradients for the study of tissue response to gradients in vivo.
Assuntos
Materiais Biocompatíveis/farmacologia , Vasos Sanguíneos/crescimento & desenvolvimento , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis/farmacologia , Animais , Becaplermina , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Colágeno/metabolismo , Difusão , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Masculino , Porosidade , Ratos Endogâmicos Lew , Regeneração/efeitos dos fármacos , Solubilidade , Alicerces Teciduais/químicaRESUMO
Rapid and controlled vascularization within biomaterials is essential for many applications in regenerative medicine. The extent of vascularization is influenced by a number of factors, including scaffold architecture. While properties such as pore size and total porosity have been studied extensively, the importance of controlling the interconnectivity of pores has received less attention. A sintering method was used to generate hydrogel scaffolds with controlled pore interconnectivity. Poly(methyl methacrylate) microspheres were used as a sacrificial agent to generate porous poly(ethylene glycol) diacrylate hydrogels with interconnectivity varying based on microsphere sintering conditions. Interconnectivity levels increased with sintering time and temperature with resultant hydrogel structure showing agreement with template structure. Porous hydrogels with a narrow pore size distribution (130-150 µm) and varying interconnectivity were investigated for their ability to influence vascularization in response to gradients of platelet-derived growth factor-BB (PDGF-BB). A rodent subcutaneous model was used to evaluate vascularized tissue formation in the hydrogels in vivo. Vascularized tissue invasion varied with interconnectivity. At week 3, higher interconnectivity hydrogels had completely vascularized with twice as much invasion. Interconnectivity also influenced PDGF-BB transport within the scaffolds. An agent-based model was used to explore the relative roles of steric and transport effects on the observed results. In conclusion, a technique for the preparation of hydrogels with controlled pore interconnectivity has been developed and evaluated. This method has been used to show that pore interconnectivity can independently influence vascularization of biomaterials.
Assuntos
Hidrogéis/química , Microesferas , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis , Alicerces Teciduais/química , Animais , Becaplermina , Masculino , Polietilenoglicóis/química , Polimetil Metacrilato/química , Porosidade , Proteínas Proto-Oncogênicas c-sis/química , Proteínas Proto-Oncogênicas c-sis/farmacologia , Ratos , Ratos Endogâmicos LewRESUMO
A multi-layer agent-based model (ABM) of biomaterial scaffold vascularization is extended to consider the effects of scaffold degradation kinetics on blood vessel formation. A degradation model describing the bulk disintegration of porous hydrogels is incorporated into the ABM. The combined degradation-angiogenesis model is used to investigate growing blood vessel networks in the presence of a degradable scaffold structure. Simulation results indicate that higher porosity, larger mean pore size, and rapid degradation allow faster vascularization when not considering the structural support of the scaffold. However, premature loss of structural support results in failure for the material. A strategy using multi-layer scaffold with different degradation rates in each layer was investigated as a way to address this issue. Vascularization was improved with the multi-layered scaffold model compared to the single-layer model. The ABM developed provides insight into the characteristics that influence the selection of optimal geometric parameters and degradation behavior of scaffolds, and enables easy refinement of the model as new knowledge about the underlying biological phenomena becomes available. STATEMENT OF SIGNIFICANCE: This paper proposes a multi-layer agent-based model (ABM) of biomaterial scaffold vascularization integrated with a structural-kinetic model describing bulk degradation of porous hydrogels to consider the effects of scaffold degradation kinetics on blood vessel formation. This enables the assessment of scaffold characteristics and in particular the disintegration characteristics of the scaffold on angiogenesis. Simulation results indicate that higher porosity, larger mean pore size, and rapid degradation allow faster vascularization when not considering the structural support of the scaffold. However, premature loss of structural support by scaffold disintegration results in failure of the material and disruption of angiogenesis. A strategy using multi-layer scaffold with different degradation rates in each layer was investigated as away to address this issue. Vascularization was improved with the multi-layered scaffold model compared to the single-layer model. The ABM developed provides insight into the characteristics that influence the selection of optimal geometric and degradation characteristics of tissue engineering scaffolds.
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Implantes Absorvíveis , Prótese Vascular , Vasos Sanguíneos/crescimento & desenvolvimento , Modelos Cardiovasculares , Neovascularização Fisiológica/fisiologia , Alicerces Teciduais , Animais , Órgãos Bioartificiais , Materiais Biocompatíveis/química , Vasos Sanguíneos/citologia , Simulação por Computador , Desenho Assistido por Computador , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Análise de Falha de Equipamento , Humanos , Hidrogéis/química , Cinética , Porosidade , Desenho de PróteseRESUMO
Mesenchymal stem cells (MSC) have shown promise in tissue engineering applications due to their potential for differentiating into mesenchymal tissues such as osteocytes, chondrocytes, and adipocytes and releasing proteins to promote tissue regeneration. One application involves seeding MSCs in biomaterial scaffolds to promote osteogenesis in the repair of bone defects following implantation. However, predicting in vivo survival and differentiation of MSCs in biomaterials is challenging. Rapid and stable vascularization of scaffolds is required to supply nutrients and oxygen that MSCs need to survive as well as to go through osteogenic differentiation. The objective of this study is to develop an agent-based model and simulator that can be used to investigate the effects of using gradient growth factors on survival and differentiation of MSCs seeded in scaffolds. An agent-based model is developed to simulate the MSC behavior. The effect of vascular endothelial growth factor (VEGF) and bone morphogenic protein-2 (BMP-2) on both survival and osteogenic differentiation is studied. Results showed that the survival ratio of MSCs can be enhanced by increasing VEGF concentration. BMP-2 caused a slight increase on survival ratio. Osteogenesis strongly depends on the VEGF concentration as well because of its effect on vascularization. BMP-2 increased the osteogenic differentiation of MSCs.