Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Sci Adv ; 7(11)2021 03.
Article in English | MEDLINE | ID: mdl-33712463

ABSTRACT

Here, we present an approach to model and adapt the mechanical regulation of morphogenesis that uses contractile cells as sculptors of engineered tissue anisotropy in vitro. Our method uses heterobifunctional cross-linkers to create mechanical boundary constraints that guide surface-directed sculpting of cell-laden extracellular matrix hydrogel constructs. Using this approach, we engineered linearly aligned tissues with structural and mechanical anisotropy. A multiscale in silico model of the sculpting process was developed to reveal that cell contractility increases as a function of principal stress polarization in anisotropic tissues. We also show that the anisotropic biophysical microenvironment of linearly aligned tissues potentiates soluble factor-mediated tenogenic and myogenic differentiation of mesenchymal stem cells. The application of our method is demonstrated by (i) skeletal muscle arrays to screen therapeutic modulators of acute oxidative injury and (ii) a 3D microphysiological model of lung cancer cachexia to study inflammatory and oxidative muscle injury induced by tumor-derived signals.


Subject(s)
Mesenchymal Stem Cells , Tissue Engineering , Anisotropy , Cell Differentiation , Extracellular Matrix/chemistry , Hydrogels/chemistry , Tissue Engineering/methods , Tissue Scaffolds/chemistry
2.
Small ; 17(15): e2004889, 2021 04.
Article in English | MEDLINE | ID: mdl-33150735

ABSTRACT

Hemostasis is an innate protective mechanism that plays a central role in maintaining the homeostasis of the vascular system during vascular injury. Studying this essential physiological process is often challenged by the difficulty of modeling and probing the complex dynamics of hemostatic responses in the native context of human blood vessels. To address this major challenge, this paper describes a microengineering approach for in vitro modeling of hemostasis. This microphysiological model replicates the living endothelium, multilayered microarchitecture, and procoagulant activity of human blood vessels, and is also equipped with a microneedle that is actuated with spatial precision to simulate penetrating vascular injuries. The system recapitulates key features of the hemostatic response to acute vascular injury as observed in vivo, including i) thrombin-driven accumulation of platelets and fibrin, ii) formation of a platelet- and fibrin-rich hemostatic plug that halts blood loss, and iii) matrix deformation driven by platelet contraction for wound closure. Moreover, the potential use of this model for drug testing applications is demonstrated by evaluating the effects of anticoagulants and antiplatelet agents that are in current clinical use. The vascular injury-on-a-chip may serve as an enabling platform for preclinical investigation of hematological disorders and emerging therapeutic approaches against them.


Subject(s)
Thrombosis , Vascular System Injuries , Fibrin , Hemostasis , Humans , Lab-On-A-Chip Devices
3.
Nat Med ; 25(8): 1310-1318, 2019 08.
Article in English | MEDLINE | ID: mdl-31384041

ABSTRACT

Here we present a miniaturized analog of a blinking human eye to reverse engineer the complexity of the interface between the ocular system and the external environment. Our model comprises human cells and provides unique capabilities to replicate multiscale structural organization, biological phenotypes and dynamically regulated environmental homeostasis of the human ocular surface. Using this biomimetic system, we discovered new biological effects of blink-induced mechanical forces. Furthermore, we developed a specialized in vitro model of evaporative dry-eye disease for high-content drug screening. This work advances our ability to emulate how human physiological systems interface with the external world, and may contribute to the future development of novel screening platforms for biopharmaceutical and environmental applications.


Subject(s)
Blinking/physiology , Dry Eye Syndromes/etiology , Tissue Engineering/methods , Biomechanical Phenomena , Cells, Cultured , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/physiopathology , Glycoproteins/therapeutic use , Humans , Phenotype
4.
Biomicrofluidics ; 12(4): 042211, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29887935

ABSTRACT

Occlusion of distal airways due to mucus plugs is a key pathological feature common to a wide variety of obstructive pulmonary diseases. Breathing-induced movement of airway mucus plugs along the respiratory tract has been shown to generate abnormally large mechanical stresses, acting as an insult that can incite acute injury to the airway epithelium. Here, we describe a unique microengineering strategy to model this pathophysiological process using a bioinspired microfluidic device. Our system combines an air-liquid interface culture of primary human small airway epithelial cells with a microengineered biomimetic platform to replicate the process of mucus exudation induced by airway constriction that leads to the formation of mucus plugs across the airway lumen. Specifically, we constructed a compartmentalized three-dimensional (3D) microfluidic device in which extracellular matrix hydrogel scaffolds reminiscent of airway stroma were compressed to discharge fluid into the airway compartment and form liquid plugs. We demonstrated that this plug formation process and subsequent movement of liquid plugs through the airway channel can be regulated in a precisely controlled manner. Furthermore, we examined the detrimental effect of plug propagation on the airway epithelium to simulate acute epithelial injury during airway closure. Our system allows for a novel biomimetic approach to modeling a complex and dynamic biophysical microenvironment of diseased human airways and may serve as an enabling platform for mechanistic investigation of key disease processes that drive the progression and exacerbation of obstructive pulmonary diseases.

5.
Sci Rep ; 7(1): 3413, 2017 06 13.
Article in English | MEDLINE | ID: mdl-28611413

ABSTRACT

Red blood cell (RBC) transfusion poses significant risks to critically ill patients by increasing their susceptibility to acute respiratory distress syndrome. While the underlying mechanisms of this life-threatening syndrome remain elusive, studies suggest that RBC-induced microvascular injury in the distal lung plays a central role in the development of lung injury following blood transfusion. Here we present a novel microengineering strategy to model and investigate this key disease process. Specifically, we created a microdevice for culturing primary human lung endothelial cells under physiological flow conditions to recapitulate the morphology and hemodynamic environment of the pulmonary microvascular endothelium in vivo. Perfusion of the microengineered vessel with human RBCs resulted in abnormal cytoskeletal rearrangement and release of intracellular molecules associated with regulated necrotic cell death, replicating the characteristics of acute endothelial injury in transfused lungs in vivo. Our data also revealed the significant effect of hemodynamic shear stress on RBC-induced microvascular injury. Furthermore, we integrated the microfluidic endothelium with a computer-controlled mechanical stretching system to show that breathing-induced physiological deformation of the pulmonary microvasculature may exacerbate vascular injury during RBC transfusion. Our biomimetic microsystem provides an enabling platform to mechanistically study transfusion-associated pulmonary vascular complications in susceptible patient populations.


Subject(s)
Endothelium, Vascular/cytology , Erythrocyte Transfusion/adverse effects , Lung Injury/etiology , Microfluidics/methods , Stress, Mechanical , Cells, Cultured , Endothelium, Vascular/injuries , Hemodynamics , Humans , Lung Injury/pathology , Pulmonary Circulation
6.
Environ Geochem Health ; 37(6): 1063-72, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26224682

ABSTRACT

An MgO-based binder was developed that could stabilize fine dredged sediments for reuse and store CO2. Initially, a binder consisting of fly ash (FA) and blast furnace slag (BFS) was developed by using alkaline activators such as KOH, NaOH, and lime. The FA0.4-BFS0.6 binder (mixed at a FA-to-BFS weight ratio of 4:6) showed the highest compressive strength of 10.7 MPa among FA/BFS binders when 5 M KOH was used. When lime (L) was tested as an alkaline activator, the strength was comparable with those obtained when KOH or NaOH was used. The L0.1-(FA0.4BFS0.6)0.9 binder (10 % lime mixed with the FA/BFS binder) showed the highest strength of 11.0 MPa. Finally, by amending this L0.1-(FA0.4BFS0.6)0.9 binder with MgO, a novel MgO-based binder (MgO0.5-(L0.1-(FA0.4BFS0.6)0.9) 0.5) was developed, which demonstrated the 28th day strength of 11.9 MPa. The MgO-based binder was successfully applied to stabilize a fine sediment to yield a compressive strength of 4.78 MPa in 365 days, which was higher than that obtained by the Portland cement (PC) system (3.22 MPa). Carbon dioxide sequestration was evidenced by three observations: (1) the decrease in pH of the treated sediment from 12.2 to 11.0; (2) the progress of the carbonation front inward the treated sediment; and (3) the presence of magnesium carbonates. The thermogravimetric analysis (TGA) results showed that 67.2 kg of CO2 per ton of the treated sediment could be stored under the atmospheric condition during 1 year.


Subject(s)
Carbon Dioxide/chemistry , Construction Materials , Geologic Sediments/chemistry , Magnesium Oxide/chemistry , Waste Management/methods , Calcium Compounds/chemistry , Coal Ash/chemistry , Compressive Strength , Oxides/chemistry
7.
Lab Chip ; 15(16): 3350-7, 2015 Aug 21.
Article in English | MEDLINE | ID: mdl-26158500

ABSTRACT

A mounting body of evidence in cancer research suggests that the local microenvironment of tumor cells has a profound influence on cancer progression and metastasis. In vitro studies on the tumor microenvironment and its pharmacological modulation, however, are often hampered by the technical challenges associated with creating physiological cell culture environments that integrate cancer cells with the key components of their native niche such as neighboring cells and extracellular matrix (ECM) to mimic complex microarchitecture of cancerous tissue. Using early-stage breast cancer as a model disease, here we describe a biomimetic microengineering strategy to reconstitute three-dimensional (3D) structural organization and microenvironment of breast tumors in human cell-based in vitro models. Specifically, we developed a microsystem that enabled co-culture of breast tumor spheroids with human mammary ductal epithelial cells and mammary fibroblasts in a compartmentalized 3D microfluidic device to replicate microarchitecture of breast ductal carcinoma in situ (DCIS). We also explored the potential of this breast cancer-on-a-chip system as a drug screening platform by evaluating the efficacy and toxicity of an anticancer drug (paclitaxel). Our microengineered disease model represents the first critical step towards recapitulating pathophysiological complexity of breast cancer, and may serve as an enabling tool to systematically examine the contribution of the breast cancer microenvironment to the progression of DCIS to an invasive form of the disease.


Subject(s)
Breast Neoplasms/physiopathology , Carcinoma/physiopathology , Microfluidic Analytical Techniques/methods , Models, Biological , Antineoplastic Agents, Phytogenic/toxicity , Cell Culture Techniques , Cell Survival/drug effects , Cells, Cultured , Extracellular Matrix/metabolism , Female , Genes, Reporter , Humans , Mammary Glands, Human/cytology , Microfluidic Analytical Techniques/instrumentation , Paclitaxel/toxicity , Tumor Microenvironment
8.
Am J Respir Crit Care Med ; 190(11): 1243-54, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25329368

ABSTRACT

RATIONALE: Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown. OBJECTIVES: To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1. METHODS: In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation. MEASUREMENTS AND MAIN RESULTS: After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1. CONCLUSIONS: RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients.


Subject(s)
Endothelial Cells/pathology , Erythrocyte Transfusion/adverse effects , HMGB1 Protein/physiology , Lung/pathology , Pneumonia/etiology , Respiratory Distress Syndrome/etiology , Animals , Critical Illness , Disease Models, Animal , HMGB1 Protein/immunology , Humans , In Vitro Techniques , Mice , Middle Aged , Necrosis
SELECTION OF CITATIONS
SEARCH DETAIL
...