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1
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Shams F, Jamshidian M, Shaygani H, Maleki S, Soltani M, Shamloo A. A study on the cellular adhesion properties of a hybrid scaffold for vascular tissue engineering through molecular dynamics simulation. Sci Rep 2025; 15:16433. [PMID: 40355635 DOI: 10.1038/s41598-025-01545-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 05/07/2025] [Indexed: 05/14/2025] Open
Abstract
Utilizing biocompatible hybrid scaffolds that promote cell adhesion and proliferation is critically significant in the field of tissue engineering. In order to achieve this goal, the composition of polymers in the sample should be adjusted accordingly In this research, molecular dynamics simulations are utilized to investigate how the composition of blends influences the protein adsorption properties of hybrid scaffolds. Scaffolds considered here consist of Bombyx mori silk fibroin (B. mori SF) and thermoplastic polyurethane (TPU) intended for application in vascular grafts. Three different compositions are investigated in this study: One sample with 70% TPU by volume (SF:TPU-3/7), the second sample with 50% TPU (SF:TPU-1/1) and the last sample with 30% TPU (SF:TPU-7/3). The interaction between the polymeric scaffold surfaces and fibronectin and laminin, two major proteins found in vascular tissues, is studied using molecular dynamics simulations. The biocompatibility of each sample is examined based on calculated adhesion energy and final protein conformation. Furthermore, MTT cell viability, cell adhesion, and live/dead assays are performed to validate the simulation results. Third-passage human umbilical vein cell (HUVEC) is utilized in this study. The simulations revealed that B. mori SF (SF) content in the blend needs to be balanced with TPU to enhance the protein adsorption strength. The experimental results exhibited a correlation with the simulations and were verified with cell adhesion and staining assays. The SF:TPU-1/1 had the highest cell viability followed by SF:TPU-7/3 and SF:TPU-3/7 with [Formula: see text], [Formula: see text], and [Formula: see text], respectively, demonstrating the accuracy of the simulations and the possibility of predicting the biocompatibility of biomaterials through simulations.
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Affiliation(s)
- Faeze Shams
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
- Stem Cell and Regenerative Medicine Center, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Mostafa Jamshidian
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Hossein Shaygani
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
- Stem Cell and Regenerative Medicine Center, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Sasan Maleki
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Mohamadreza Soltani
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran
- Stem Cell and Regenerative Medicine Center, Sharif University of Technology, Tehran, 11365-11155, Iran
| | - Amir Shamloo
- Nano-Bioengineering laboratory, Department of Mechanical Engineering, Sharif University of Technology, Tehran, 11365-11155, Iran.
- Stem Cell and Regenerative Medicine Center, Sharif University of Technology, Tehran, 11365-11155, Iran.
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2
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Seifi S, Shaygani H, Bakhtiari MA, Rezaei Demneh SMH, Fathi M, Shamloo A. Motion of fullerene nanomachines on thermally activated curved gold substrates. Sci Rep 2025; 15:10892. [PMID: 40158008 PMCID: PMC11954908 DOI: 10.1038/s41598-025-95076-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/19/2025] [Indexed: 04/01/2025] Open
Abstract
This paper presents a comprehensive computational investigation aimed at optimizing nanomanipulation techniques by leveraging fullerene-based nanocarriers on curved gold surfaces. Through rigorous potential energy analyses and molecular dynamics simulations, we scrutinize the nuanced effects of temperature variations and nanocarrier wheel sizes on their behavior. Our results reveal an interplay between temperature and nanocarrier performance, wherein smaller-wheeled nanocarriers exhibit heightened efficacy at elevated temperatures, facilitating extended-range motion. Conversely, larger nanocarriers encounter impediments attributed to their augmented mass, constraining their mobility. Further scrutiny into effective velocities and angular velocities elucidate deviations from anticipated movement paths, notably observed in nanocarriers employing C60 fullerene wheels, advocating for the exploration of novel design alternatives. Additionally, our findings underscore the efficacy of specific nanocarrier configurations, notably those equipped with C80, C36, and C50 wheels, showcasing their potential as optimal candidates under distinct operating conditions. By shedding light on the intricate dynamics governing nanocarrier behavior on curved surfaces, this study contributes valuable insights to the advancement of nanoscale material transportation and manipulation methodologies, thereby enriching the discourse within the realms of nanotechnology and nanorobotics.
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Affiliation(s)
- Saeed Seifi
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave, Tehran, Iran
| | - Hossein Shaygani
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave, Tehran, Iran
| | - Mohammad Ali Bakhtiari
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave, Tehran, Iran
| | | | - Mohammad Fathi
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave, Tehran, Iran
| | - Amir Shamloo
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave, Tehran, Iran.
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3
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Ghobadi F, Saadatmand M, Simorgh S, Brouki Milan P. Microfluidic 3D cell culture: potential application of collagen hydrogels with an optimal dose of bioactive glasses. Sci Rep 2025; 15:569. [PMID: 39747624 PMCID: PMC11696724 DOI: 10.1038/s41598-024-84346-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
We engineered a microfluidic platform to study the effects of bioactive glass nanoparticles (BGNs) on cell viability under static culture. We incorporated different concentrations of BGNs (1%, 2%, and 3% w/v) in collagen hydrogel (with a concentration of 3.0 mg/mL). The microfluidic chip's dimensions were optimized through fluid flow and mass transfer simulations. Collagen type I extracted from rat tail tendons was used as the main material, and BGNs synthesized by the sol-gel method were used to enhance the mechanical properties of the hydrogel. The extracted collagen was characterized using FTIR and SDS-PAGE, and BGNs were analyzed using XRD, FTIR, DLS, and FE-SEM/EDX. The structure of the collagen-BGNs hydrogels was examined using SEM, and their mechanical properties were determined using rheological analysis. The cytotoxicity of BGNs was assessed using the MTT assay, and the viability of fibroblast (L929) cells encapsulated in the collagen-BGNs hydrogel inside the microfluidic device was assessed using a live/dead assay. Based on all these test results, the L929 cells showed high cell viability in vitro and promising microenvironment mimicry in a microfluidic device. Collagen3-BGNs3 (Collagen 3 mg/mL + BGNs 3% (w/v)) was chosen as the most suitable sample for further research on a microfluidic platform.
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Affiliation(s)
- Faezeh Ghobadi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Maryam Saadatmand
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran.
| | - Sara Simorgh
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies inMedicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies inMedicine, Iran University of Medical Sciences, Tehran, Iran
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4
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Shaygani H, Mofrad YM, Demneh SMR, Hafezi S, Almasi-Jaf A, Shamloo A. Cartilage and bone injectable hydrogels: A review of injectability methods and treatment strategies for repair in tissue engineering. Int J Biol Macromol 2024; 282:136689. [PMID: 39447779 DOI: 10.1016/j.ijbiomac.2024.136689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 10/08/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
Cartilage and bone are crucial tissues causing disability in the elderly population, often requiring prolonged treatment and surgical intervention due to limited regenerative capacity. Injectable hydrogels that closely mimic the extracellular matrix (ECM) of native hard tissue have attracted attention due to their minimally invasive application and ability to conform to irregular defect sites. These hydrogels facilitate key biological processes such as cell migration, chondrogenesis in cartilage repair, osteoinduction, angiogenesis, osteoconduction, and mineralization in bone repair. This review analyzes in-vitro and in-vivo biomedical databases over the past decade to identify advancements in hydrogel formulations, crosslinking mechanisms, and biomaterial selection for cartilage and bone tissue engineering. The review emphasizes the effectiveness of injectable hydrogels as carriers for cells, growth factors, and drugs, offering additional therapeutic benefits. The relevance of these findings is discussed in the context of their potential to serve as a robust alternative to current surgical and non-surgical treatments. This review also examines the advantages of injectable hydrogels, such as ease of administration, reduced patient recovery time, and enhanced bioactivity, thereby emphasizing their potential in clinical applications for cartilage and bone regeneration with emphasis on addressing the shortcomings of current treatments.
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Affiliation(s)
- Hossein Shaygani
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran; Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Tehran, Iran
| | - Yasaman Mozhdehbakhsh Mofrad
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran; Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Tehran, Iran; School of Mechanical Engineering, Iran University of Science and Technology, Tehran, Iran
| | - Seyed Mohammadhossein Rezaei Demneh
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran; Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Tehran, Iran
| | - Shayesteh Hafezi
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Aram Almasi-Jaf
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran; Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Tehran, Iran
| | - Amir Shamloo
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran; Stem Cell and Regenerative Medicine Institute, Sharif University of Technology, Tehran, Iran.
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5
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Reza Sayah M, Ebrahimi S, Mirafzal I, Shamloo A. Investigation of the size and shape of nano-microcarriers for targeted drug delivery to atherosclerotic plaque in ischemic stroke prevention. Int J Pharm 2024; 662:124469. [PMID: 39004292 DOI: 10.1016/j.ijpharm.2024.124469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 07/16/2024]
Abstract
Recognizing the significance of drug carriers in the treatment of atherosclerotic plaque is crucial in light of the worldwide repercussions of ischemic stroke. Conservative methodologies, specifically targeted drug delivery, present encouraging substitutes that mitigate the hazards linked to invasive procedures. With the intention of illuminating their considerable significance and prospective benefits, this study examines the impact of the geometry and dimensions of drug-loaded nano-microcarriers on atherosclerotic plaque. The research utilizes a finite element approach to simulate the motion and fluid dynamics of nano-microcarriers loaded with drugs within the carotid arteries. Carriers are available in a variety of shapes and sizes to accommodate patient-specific geometries, pulsatile fluid flow, and non-Newtonian blood properties. Optimization of drug delivery is achieved through the examination of carrier interaction with the inner wall. The results demonstrated that the interaction data between particles and the inner wall of atherosclerotic plaques exhibits micro- and nanoscale patterns that are distinct. Symmetric plaques demonstrate that nanoparticles with a 0.4 shape factor and diameters below 200 nm show the highest interaction rate. Conversely, larger particles (200 and 500 nm) with shape factors of 1 demonstrate comparatively elevated interaction rates. The optimal shape factor for drug-loaded microparticles has been determined to be one, and the number of interactions increases as the diameter of the nanoparticles increases, with a significant increase observed at a shape factor of one. Asymmetric plaques exhibit the maximum interaction rates among particles that have a shape factor of 0.4 and have diameters smaller than 500 µm. The findings establish a foundation for novel therapeutic strategies, establishing nano-microparticles as auspicious contenders for accurate and efficacious drug delivery systems that inhibit plaque proliferation.
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Affiliation(s)
- Mohammad Reza Sayah
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Sina Ebrahimi
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Iman Mirafzal
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Amir Shamloo
- School of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
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6
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Malandain N, Sanz-Fraile H, Farré R, Otero J, Roig A, Laromaine A. Cell-Laden 3D Hydrogels of Type I Collagen Incorporating Bacterial Nanocellulose Fibers. ACS APPLIED BIO MATERIALS 2023; 6:3638-3647. [PMID: 37669535 PMCID: PMC10521014 DOI: 10.1021/acsabm.3c00126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 08/08/2023] [Indexed: 09/07/2023]
Abstract
There is a growing interest in developing natural hydrogel-based scaffolds to culture cells in a three-dimensional (3D) millieu that better mimics the in vivo cells' microenvironment. A promising approach is to use hydrogels from animal tissues, such as decellularized extracellular matrices; however, they usually exhibit suboptimal mechanical properties compared to native tissue and their composition with hundreds of different protein complicates to elucidate which stimulus triggers cell's responses. As simpler scaffolds, type I collagen hydrogels are used to study cell behavior in mechanobiology even though they are also softer than native tissues. In this work, type I collagen is mixed with bacterial nanocellulose fibers (BCf) to develop reinforced scaffolds with mechanical properties suitable for 3D cell culture. BCf were produced from blended pellicles biosynthesized from Komagataeibacter xylinus. Then, BCf were mixed with concentrated collagen from rat-tail tendons to form composite hydrogels. Confocal laser scanning microscopy and scanning electron microscopy images confirmed the homogeneous macro- and microdistribution of both natural polymers. Porosity analysis confirmed that BCf do not disrupt the scaffold structure. Tensile strength and rheology measurements demonstrated the reinforcement action of BCf (43% increased stiffness) compared to the collagen hydrogel while maintaining the same viscoelastic response. Additionally, this reinforcement of collagen hydrogels with BCf offers the possibility to mix cells before gelation and then proceed to the culture of the 3D cell scaffolds. We obtained scaffolds with human bone marrow-derived mesenchymal stromal cells or human fibroblasts within the composite hydrogels, allowing a homogeneous 3D viable culture for at least 7 days. A smaller surface shrinkage in the reinforced hydrogels compared to type I collagen hydrogels confirmed the strengthening of the composite hydrogels. These collagen hydrogels reinforced with BCf might emerge as a promising platform for 3D in vitro organ modeling, tissue-engineering applications, and suitable to conduct fundamental mechanobiology studies.
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Affiliation(s)
- Nanthilde Malandain
- Institut
de Ciència de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain
- Unitat
de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències
de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Hector Sanz-Fraile
- Unitat
de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències
de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Ramon Farré
- Unitat
de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències
de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
- CIBER
de Enfermedades Respiratorias, 28029 Madrid, Spain
- Institut
d’Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain
| | - Jorge Otero
- Unitat
de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències
de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
- CIBER
de Enfermedades Respiratorias, 28029 Madrid, Spain
- The
Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Anna Roig
- Institut
de Ciència de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain
| | - Anna Laromaine
- Institut
de Ciència de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain
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7
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Merson J, Parvez N, Picu RC. Probing soft fibrous materials by indentation. Acta Biomater 2023; 163:25-34. [PMID: 35381401 PMCID: PMC9526757 DOI: 10.1016/j.actbio.2022.03.053] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 11/27/2022]
Abstract
Indentation is often used to measure the stiffness of soft materials whose main structural component is a network of filaments, such as the cellular cytoskeleton, connective tissue, gels, and the extracellular matrix. For elastic materials, the typical procedure requires fitting the experimental force-displacement curve with the Hertz model, which predicts that f=kδ1.5 and k is proportional to the reduced modulus of the indented material, E/(1-ν2). Here we show using explicit models of fiber networks that the Hertz model applies to indentation in network materials provided the indenter radius is larger than approximately 12lc, where lc is the mean segment length of the network. Using smaller indenters leads to a relation between force and indentation displacement of the form f=kδq, where q is observed to increase with decreasing indenter radius. Using the Hertz model to interpret results of indentations in network materials using small indenters leads to an inferred modulus smaller than the real modulus of the material. The origin of this departure from the classical Hertz model is investigated. A compacted, stiff network region develops under the indenter, effectively increasing the indenter size and modifying its shape. This modification is marginal when large indenters are used. However, when the indenter radius is small, the effect of the compacted layer is pronounced as it changes the indenter profile from spherical towards conical. This entails an increase of exponent q above the value of 1.5 corresponding to spherical indenters. STATEMENT OF SIGNIFICANCE: The article presents a study of indentation in network biomaterials and demonstrates a size effect which precludes the use of the Hertz model to infer the elastic constants of the material. The size effect occurs once the indenter radius is smaller than approximately 12 times the mean segment length of the network. This result provides guidelines for the selection of indentation conditions that guarantee the applicability of the Hertz model. At the same time, the finding may be used to infer the mean segment length of the network based on indentations with indenters of various sizes. Hence, the method can be used to evaluate this structural parameter which is not easily accessible in experiments.
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Affiliation(s)
- J Merson
- Department of Mechanical, Aerospace and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
| | - N Parvez
- Department of Mechanical, Aerospace and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
| | - R C Picu
- Department of Mechanical, Aerospace and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States.
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8
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Kretschmer M, Mamistvalov R, Sprinzak D, Vollmar AM, Zahler S. Matrix stiffness regulates Notch signaling activity in endothelial cells. J Cell Sci 2023; 136:286810. [PMID: 36718783 DOI: 10.1242/jcs.260442] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/22/2022] [Indexed: 02/01/2023] Open
Abstract
Notch signaling is critical for many developmental and disease-related processes. It is widely accepted that Notch has a mechanotransduction module that regulates receptor cleavage. However, the role of biomechanical properties of the cellular environment in Notch signaling in general is still poorly understood. During angiogenesis, differentiation of endothelial cells into tip and stalk cells is regulated by Notch signaling, and remodeling of the extracellular matrix occurs. We investigated the influence of substrate stiffness on the Notch signaling pathway in endothelial cells. Using stiffness-tuned polydimethylsiloxane (PDMS) substrates, we show that activity of the Notch signaling pathway inversely correlates with a physiologically relevant range of substrate stiffness (i.e. increased Notch signaling activity on softer substrates). Trans-endocytosis of the Notch extracellular domain, but not the overall endocytosis, is regulated by substrate stiffness, and integrin cell-matrix connections are both stiffness dependent and influenced by Notch signaling. We conclude that mechanotransduction of Notch activation is modulated by substrate stiffness, highlighting the role of substrate rigidity as an important cue for signaling. This might have implications in pathological situations associated with stiffening of the extracellular matrix, such as tumor growth.
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Affiliation(s)
- Maibritt Kretschmer
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 Munich, Germany
| | - Rose Mamistvalov
- The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - David Sprinzak
- The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - Angelika M Vollmar
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 Munich, Germany
| | - Stefan Zahler
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 Munich, Germany
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9
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Barrasa-Ramos S, Dessalles CA, Hautefeuille M, Barakat AI. Mechanical regulation of the early stages of angiogenesis. J R Soc Interface 2022; 19:20220360. [PMID: 36475392 PMCID: PMC9727679 DOI: 10.1098/rsif.2022.0360] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Favouring or thwarting the development of a vascular network is essential in fields as diverse as oncology, cardiovascular disease or tissue engineering. As a result, understanding and controlling angiogenesis has become a major scientific challenge. Mechanical factors play a fundamental role in angiogenesis and can potentially be exploited for optimizing the architecture of the resulting vascular network. Largely focusing on in vitro systems but also supported by some in vivo evidence, the aim of this Highlight Review is dual. First, we describe the current knowledge with particular focus on the effects of fluid and solid mechanical stimuli on the early stages of the angiogenic process, most notably the destabilization of existing vessels and the initiation and elongation of new vessels. Second, we explore inherent difficulties in the field and propose future perspectives on the use of in vitro and physics-based modelling to overcome these difficulties.
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Affiliation(s)
- Sara Barrasa-Ramos
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, Palaiseau, France
| | - Claire A. Dessalles
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, Palaiseau, France
| | - Mathieu Hautefeuille
- Laboratoire de Biologie du Développement (UMR7622), Institut de Biologie Paris Seine, Sorbonne Université, Paris, France,Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, Mexico
| | - Abdul I. Barakat
- LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, Palaiseau, France
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10
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Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers. Brain Sci 2022; 12:brainsci12070927. [PMID: 35884733 PMCID: PMC9313046 DOI: 10.3390/brainsci12070927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/04/2022] Open
Abstract
The evaluation of nanomechanical properties of tissues in health and disease is of increasing interest to scientists. It has been confirmed that these properties, determined in part by the composition of the extracellular matrix, significantly affect tissue physiology and the biological behavior of cells, mainly in terms of their adhesion, mobility, or ability to mutate. Importantly, pathophysiological changes that determine disease development within the tissue usually result in significant changes in tissue mechanics that might potentially affect the drug efficacy, which is important from the perspective of development of new therapeutics, since most of the currently used in vitro experimental models for drug testing do not account for these properties. Here, we provide a summary of the current understanding of how the mechanical properties of brain tissue change in pathological conditions, and how the activity of the therapeutic agents is linked to this mechanical state.
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11
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Fabiano E, Zhang J, Reinhart-King C. Tissue density in the progression of breast cancer: Bedside to bench and back again. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2022; 22. [DOI: 10.1016/j.cobme.2022.100383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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12
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Seymour AJ, Westerfield AD, Cornelius VC, Skylar-Scott MA, Heilshorn SC. Bioprinted microvasculature: progressing from structure to function. Biofabrication 2022; 14:10.1088/1758-5090/ac4fb5. [PMID: 35086069 PMCID: PMC8988885 DOI: 10.1088/1758-5090/ac4fb5] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/27/2022] [Indexed: 11/12/2022]
Abstract
Three-dimensional (3D) bioprinting seeks to unlock the rapid generation of complex tissue constructs, but long-standing challenges with efficientin vitromicrovascularization must be solved before this can become a reality. Microvasculature is particularly challenging to biofabricate due to the presence of a hollow lumen, a hierarchically branched network topology, and a complex signaling milieu. All of these characteristics are required for proper microvascular-and, thus, tissue-function. While several techniques have been developed to address distinct portions of this microvascularization challenge, no single approach is capable of simultaneously recreating all three microvascular characteristics. In this review, we present a three-part framework that proposes integration of existing techniques to generate mature microvascular constructs. First, extrusion-based 3D bioprinting creates a mesoscale foundation of hollow, endothelialized channels. Second, biochemical and biophysical cues induce endothelial sprouting to create a capillary-mimetic network. Third, the construct is conditioned to enhance network maturity. Across all three of these stages, we highlight the potential for extrusion-based bioprinting to become a central technique for engineering hierarchical microvasculature. We envision that the successful biofabrication of functionally engineered microvasculature will address a critical need in tissue engineering, and propel further advances in regenerative medicine andex vivohuman tissue modeling.
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Affiliation(s)
- Alexis J. Seymour
- Department of Bioengineering, Stanford University, 443 Via Ortega, Shriram Center Room 119, Stanford, CA 94305, USA
| | - Ashley D. Westerfield
- Department of Bioengineering, Stanford University, 443 Via Ortega, Shriram Center Room 119, Stanford, CA 94305, USA
| | - Vincent C. Cornelius
- Department of Bioengineering, Stanford University, 443 Via Ortega, Shriram Center Room 119, Stanford, CA 94305, USA
| | - Mark A. Skylar-Scott
- Department of Bioengineering, Stanford University, 443 Via Ortega, Shriram Center Room 119, Stanford, CA 94305, USA
| | - Sarah C. Heilshorn
- Department of Materials Science & Engineering, Stanford University, 476 Lomita Mall, McCullough Room 246, Stanford, CA 94305, USA
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13
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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14
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Soltani M. Capillary network formation and structure in a modified discrete mathematical model of angiogenesis. Biomed Phys Eng Express 2021; 8. [PMID: 34883475 DOI: 10.1088/2057-1976/ac4175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 12/09/2021] [Indexed: 01/01/2023]
Abstract
Angiogenesis, as part of cancer development, involves hierarchical complicated events and processes. Multiple studies have revealed the significance of the formation and structure of tumor-induced capillary networks. In this study, a discrete mathematical model of angiogenesis is studied and modified to capture the realistic physics of capillary network formation. Modifications are performed on the mathematical foundations of an existing discrete model of angiogenesis. The main modifications are the imposition of the matrix density effect, implementation of realistic boundary and initial conditions, and improvement of the method of governing equations based on physical observation. Results show that endothelial cells accelerate angiogenesis and capillary formation as they migrate toward the tumor and clearly exhibit the physical concept of haptotactic movement. On the other hand, consideration of blood flow-induced stress leads to a dynamic adaptive vascular network of capillaries which intelligibly reflects the brush border effect . The present modified model of capillary network formation is based on the physical rationale that defines a clear mathematical and physical interpretation of angiogenesis, which is likely to be used in cancer development modeling and anti-angiogenic therapies.
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Affiliation(s)
- M Soltani
- Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran.,Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Ontario, Canada.,Centre for Biotechnology and Bioengineering (CBB), University of Waterloo, Waterloo, Ontario, Canada.,Advanced Bioengineering Initiative Center, Computational Medicine Center, K. N. Toosi University of Technology, Tehran, Tehran Province, Iran
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15
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Mechanical Aspects of Angiogenesis. Cancers (Basel) 2021; 13:cancers13194987. [PMID: 34638470 PMCID: PMC8508205 DOI: 10.3390/cancers13194987] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/01/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The formation of new blood vessels from already existing ones is a process of high clinical relevance, since it is of great importance for both physiological and pathological processes. In regard to tumors, the process is crucial, since it ensures the supply with nutrients and the growth of the tumor. The influence of mechanical factors on this biological process is an emerging field. Until now, the shear force of the blood flow has been considered the main mechanical parameter during angiogenesis. This review article provides an overview of further mechanical cues, with particular focus on the surrounding extracellular matrix impacting the cell behavior and, thus, regulating angiogenesis. This underlines the enormous importance of the mechanical properties of the extracellular matrix on cell biological processes and shows how changing the mechanics of the extracellular matrix could be used as a possible therapeutic approach in cancer therapy. Abstract Angiogenesis is of high clinical relevance as it plays a crucial role in physiological (e.g., tissue regeneration) and pathological processes (e.g., tumor growth). Besides chemical signals, such as VEGF, the relationship between cells and the extracellular matrix (ECM) can influence endothelial cell behavior during angiogenesis. Previously, in terms of the connection between angiogenesis and mechanical factors, researchers have focused on shear forces due to blood flow. However, it is becoming increasingly important to include the direct influence of the ECM on biological processes, such as angiogenesis. In this context, we focus on the stiffness of the surrounding ECM and the adhesion of cells to the ECM. Furthermore, we highlight the mechanical cues during the main stages of angiogenesis: cell migration, tip and stalk cells, and vessel stabilization. It becomes clear that the different stages of angiogenesis require various chemical and mechanical cues to be modulated by/modulate the stiffness of the ECM. Thus, changes of the ECM during tumor growth represent additional potential dysregulations of angiogenesis in addition to erroneous biochemical signals. This awareness could be the basis of therapeutic approaches to counteract specific processes in tumor angiogenesis.
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16
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Seymour AJ, Shin S, Heilshorn SC. 3D Printing of Microgel Scaffolds with Tunable Void Fraction to Promote Cell Infiltration. Adv Healthc Mater 2021; 10:e2100644. [PMID: 34342179 PMCID: PMC8612872 DOI: 10.1002/adhm.202100644] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/23/2021] [Indexed: 12/18/2022]
Abstract
Granular, microgel-based materials have garnered interest as promising tissue engineering scaffolds due to their inherent porosity, which can promote cell infiltration. Adapting these materials for 3D bioprinting, while maintaining sufficient void space to enable cell migration, can be challenging, since the rheological properties that determine printability are strongly influenced by microgel packing and void fraction. In this work, a strategy is proposed to decouple printability and void fraction by blending UV-crosslinkable gelatin methacryloyl (GelMA) microgels with sacrificial gelatin microgels to form composite inks. It is observed that inks with an apparent viscosity greater than ≈100 Pa s (corresponding to microgel concentrations ≥5 wt%) have rheological properties that enable extrusion-based printing of multilayered structures in air. By altering the ratio of GelMA to sacrificial gelatin microgels, while holding total concentration constant at 6 wt%, a family of GelMA:gelatin microgel inks is created that allows for tuning of void fraction from 0.20 to 0.57. Furthermore, human umbilical vein endothelial cells (HUVEC) seeded onto printed constructs are observed to migrate into granular inks in a void fraction-dependent manner. Thus, the family of microgel inks holds promise for use in 3D printing and tissue engineering applications that rely upon cell infiltration.
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Affiliation(s)
- Alexis J Seymour
- Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
| | - Sungchul Shin
- Department of Materials Science & Engineering, Stanford University, Stanford, CA, 94305, USA
| | - Sarah C Heilshorn
- Department of Materials Science & Engineering, Stanford University, Stanford, CA, 94305, USA
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17
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Blake C, Massey O, Boyd-Moss M, Firipis K, Rifai A, Franks S, Quigley A, Kapsa R, Nisbet DR, Williams RJ. Replace and repair: Biomimetic bioprinting for effective muscle engineering. APL Bioeng 2021; 5:031502. [PMID: 34258499 PMCID: PMC8270648 DOI: 10.1063/5.0040764] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
The debilitating effects of muscle damage, either through ischemic injury or volumetric muscle loss (VML), can have significant impacts on patients, and yet there are few effective treatments. This challenge arises when function is degraded due to significant amounts of skeletal muscle loss, beyond the regenerative ability of endogenous repair mechanisms. Currently available surgical interventions for VML are quite invasive and cannot typically restore function adequately. In response to this, many new bioengineering studies implicate 3D bioprinting as a viable option. Bioprinting for VML repair includes three distinct phases: printing and seeding, growth and maturation, and implantation and application. Although this 3D bioprinting technology has existed for several decades, the advent of more advanced and novel printing techniques has brought us closer to clinical applications. Recent studies have overcome previous limitations in diffusion distance with novel microchannel construct architectures and improved myotubule alignment with highly biomimetic nanostructures. These structures may also enhance angiogenic and nervous ingrowth post-implantation, though further research to improve these parameters has been limited. Inclusion of neural cells has also shown to improve myoblast maturation and development of neuromuscular junctions, bringing us one step closer to functional, implantable skeletal muscle constructs. Given the current state of skeletal muscle 3D bioprinting, the most pressing future avenues of research include furthering our understanding of the physical and biochemical mechanisms of myotube development and expanding our control over macroscopic and microscopic construct structures. Further to this, current investigation needs to be expanded from immunocompromised rodent and murine myoblast models to more clinically applicable human cell lines as we move closer to viable therapeutic implementation.
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Affiliation(s)
- Cooper Blake
- Institute of Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | - Oliver Massey
- Institute of Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | | | | | | | - Stephanie Franks
- Laboratory of Advanced Biomaterials, The Australian National University, Canberra, ACT 2601, Australia
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18
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Hwangbo H, Kim W, Kim GH. Lotus-Root-Like Microchanneled Collagen Scaffold. ACS APPLIED MATERIALS & INTERFACES 2021; 13:12656-12667. [PMID: 33263976 DOI: 10.1021/acsami.0c14670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
In the human body, there are numerous microtubular tissue structures, such as muscles, vessels, nerves, and tendons. Tissue engineering scaffolds have been regarded as a high-potential candidate for providing such aligned instructive niches to facilitate cell-recruitment and differentiation, and eventually, successful tissue regeneration. Moreover, scaffolds derived from the extracellular matrix (ECM) can provide excellent biocompatibility. However, the fabrication of such microtubular hierarchical scaffolds using ECM has proven to be difficult, and thus, innovative fabrication approaches are required. Herein, we have developed a biofabrication system involving a sequential removal of supporting materials (polycaprolactone (PCL) and poly(vinyl alcohol) (PVA)) to fabricate a uniaxially aligned microtubular collagen scaffold, a lotus-like structure. To generate the unique morphological structures of the scaffold, we manipulated various material-related and processing factors, such as the molecular weight of PVA and the weight fraction of collagen coating. Physical and biological activities of the aligned hierarchical microtubular collagen scaffolds were compared with those of the controls (conventional collagen struts and microtubular collagen scaffolds void of a uniaxial topographical cue). In conclusion, the instructive niche on the aligned hierarchical microtubular collagen structure induced high degrees of myoblast alignment and efficient myogenic differentiation.
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Affiliation(s)
- Hanjun Hwangbo
- Department of Biomechatronics Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
| | - WonJin Kim
- Department of Biomechatronics Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
| | - Geun Hyung Kim
- Department of Biomechatronics Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
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19
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Kazerouni AS, Gadde M, Gardner A, Hormuth DA, Jarrett AM, Johnson KE, Lima EAF, Lorenzo G, Phillips C, Brock A, Yankeelov TE. Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology. iScience 2020; 23:101807. [PMID: 33299976 PMCID: PMC7704401 DOI: 10.1016/j.isci.2020.101807] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
We provide an overview on the use of biological assays to calibrate and initialize mechanism-based models of cancer phenomena. Although artificial intelligence methods currently dominate the landscape in computational oncology, mathematical models that seek to explicitly incorporate biological mechanisms into their formalism are of increasing interest. These models can guide experimental design and provide insights into the underlying mechanisms of cancer progression. Historically, these models have included a myriad of parameters that have been difficult to quantify in biologically relevant systems, limiting their practical insights. Recently, however, there has been much interest calibrating biologically based models with the quantitative measurements available from (for example) RNA sequencing, time-resolved microscopy, and in vivo imaging. In this contribution, we summarize how a variety of experimental methods quantify tumor characteristics from the molecular to tissue scales and describe how such data can be directly integrated with mechanism-based models to improve predictions of tumor growth and treatment response.
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Affiliation(s)
- Anum S. Kazerouni
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Manasa Gadde
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA
| | - Andrea Gardner
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - David A. Hormuth
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA
| | - Angela M. Jarrett
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA
| | - Kaitlyn E. Johnson
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Ernesto A.B. F. Lima
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
- Texas Advanced Computing Center, The University of Texas at Austin, Austin, TX 78712, USA
| | - Guillermo Lorenzo
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Caleb Phillips
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Amy Brock
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA
| | - Thomas E. Yankeelov
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Oncology, The University of Texas at Austin, Austin, TX 78712, USA
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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20
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Lugo-Cintrón KM, Ayuso JM, White BR, Harari PM, Ponik S, Beebe DJ, Gong MM, Virumbrales-Muñoz M. Matrix density drives 3D organotypic lymphatic vessel activation in a microfluidic model of the breast tumor microenvironment. LAB ON A CHIP 2020; 20:1586-1600. [PMID: 32297896 PMCID: PMC7330815 DOI: 10.1039/d0lc00099j] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Lymphatic vessels (LVs) have been suggested as a preferential conduit for metastatic progression in breast cancer, where a correlation between the occurrence of lymph node metastasis and an increased extracellular matrix (ECM) density has been reported. However, the effect of ECM density on LV function is largely unknown. To better understand these effects, we used a microfluidic device to recreate tubular LVs in a collagen type I matrix. The density of the matrix was tailored to mimic normal breast tissue using a low-density collagen (LD-3 mg mL-1) and cancerous breast tissue using a high-density collagen (HD-6 mg mL-1). We investigated the effect of ECM density on LV morphology, growth, cytokine secretion, and barrier function. LVs cultured in HD matrices showed morphological changes as compared to LVs cultured in a LD matrix. Specifically, LVs cultured in HD matrices had a 3-fold higher secretion of the pro-inflammatory cytokine, IL-6, and a leakier phenotype, suggesting LVs acquired characteristics of activated vessels. Interestingly, LV leakiness was mitigated by blocking the IL-6 receptor on the lymphatic ECs, maintaining endothelium permeability at similar levels of LV cultured in a LD matrix. To recreate a more in vivo microenvironment, we incorporated metastatic breast cancer cells (MDA-MB-231) into the LD and HD matrices. For HD matrices, co-culture with MDA-MB-231 cells exacerbated vessel leakiness and secretion of IL-6. In summary, our data suggest that (1) ECM density is an important microenvironmental cue that affects LV function in the breast tumor microenvironment (TME), (2) dense matrices condition LVs towards an activated phenotype and (3) blockade of IL-6 signaling may be a potential therapeutic target to mitigate LV dysfunction. Overall, modeling LVs and their interactions with the TME can help identify novel therapeutic targets and, in turn, advance therapeutic discovery.
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Affiliation(s)
- Karina M. Lugo-Cintrón
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - José M. Ayuso
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Bridget R. White
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Suzanne Ponik
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - David J. Beebe
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Max M. Gong
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Biomedical Engineering, Trine University, Angola, IN, USA
| | - María Virumbrales-Muñoz
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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21
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Ferro MP, Heilshorn SC, Owens RM. Materials for blood brain barrier modeling in vitro. MATERIALS SCIENCE & ENGINEERING. R, REPORTS : A REVIEW JOURNAL 2020; 140:100522. [PMID: 33551572 PMCID: PMC7864217 DOI: 10.1016/j.mser.2019.100522] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Brain homeostasis relies on the selective permeability property of the blood brain barrier (BBB). The BBB is formed by a continuous endothelium that regulates exchange between the blood stream and the brain. This physiological barrier also creates a challenge for the treatment of neurological diseases as it prevents most blood circulating drugs from entering into the brain. In vitro cell models aim to reproduce BBB functionality and predict the passage of active compounds through the barrier. In such systems, brain microvascular endothelial cells (BMECs) are cultured in contact with various biomaterial substrates. However, BMEC interactions with these biomaterials and their impact on BBB functions are poorly described in the literature. Here we review the most common materials used to culture BMECs and discuss their potential impact on BBB integrity in vitro. We investigate the biophysical properties of these biomaterials including stiffness, porosity and material degradability. We highlight a range of synthetic and natural materials and present three categories of cell culture dimensions: cell monolayers covering non-degradable materials (2D), cell monolayers covering degradable materials (2.5D) and vascularized systems developing into degradable materials (3D).
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Affiliation(s)
- Magali P. Ferro
- Department of Bioelectronics, Mines Saint-Étienne, 880 route de Mimet, F-13541, Gardanne, France
| | - Sarah C. Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - Roisin M. Owens
- Department of Chemical Engineering and Biotechnology, Philippa Fawcett Drive, CB30AS, Cambridge, UK
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22
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Sapudom J, Mohamed WKE, Garcia-Sabaté A, Alatoom A, Karaman S, Mahtani N, Teo JCM. Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair. Bioengineering (Basel) 2020; 7:E33. [PMID: 32244521 PMCID: PMC7356036 DOI: 10.3390/bioengineering7020033] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/26/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022] Open
Abstract
Monocytes circulate in the bloodstream, extravasate into the tissue and differentiate into specific macrophage phenotypes to fulfill the immunological needs of tissues. During the tissue repair process, tissue density transits from loose to dense tissue. However, little is known on how changes in tissue density affects macrophage activation and their cellular functions. In this work, monocytic cell line THP-1 cells were embedded in three-dimensional (3D) collagen matrices with different fibril density and were then differentiated into uncommitted macrophages (MPMA) using phorbol-12-myristate-13-acetate (PMA). MPMA macrophages were subsequently activated into pro-inflammatory macrophages (MLPS/IFNγ) and anti-inflammatory macrophages (MIL-4/IL-13) using lipopolysaccharide and interferon-gamma (IFNγ), and interleukin 4 (IL-4) and IL-13, respectively. Although analysis of cell surface markers, on both gene and protein levels, was inconclusive, cytokine secretion profiles, however, demonstrated differences in macrophage phenotype. In the presence of differentiation activators, MLPS/IFNγ secreted high amounts of IL-1β and tumor necrosis factor alpha (TNFα), while M0PMA secreted similar cytokines to MIL-4/IL-13, but low IL-8. After removing the activators and further culture for 3 days in fresh cell culture media, the secretion of IL-6 was found in high concentrations by MIL-4/IL-13, followed by MLPS/IFNγ and MPMA. Interestingly, the secretion of cytokines is enhanced with an increase of fibril density. Through the investigation of macrophage-associated functions during tissue repair, we demonstrated that M1LPS/IFNγ has the potential to enhance monocyte infiltration into tissue, while MIL-4/IL-13 supported fibroblast differentiation into myofibroblasts via transforming growth factor beta 1 (TGF-β1) in dependence of fibril density, suggesting a M2a-like phenotype. Overall, our results suggest that collagen fibril density can modulate macrophage response to favor tissue functions. Understanding of immune response in such complex 3D microenvironments will contribute to the novel therapeutic strategies for improving tissue repair, as well as guidance of the design of immune-modulated materials.
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Affiliation(s)
- Jiranuwat Sapudom
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
| | - Walaa Kamal E. Mohamed
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
- Department of Genetics and Microbiology, Autonomous University of Barcelona, 08193 Barcelona, Spain
| | - Anna Garcia-Sabaté
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
| | - Aseel Alatoom
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
| | - Shaza Karaman
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
| | - Nikhil Mahtani
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
| | - Jeremy C. M. Teo
- Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, UAE; (J.S.); (W.K.E.M.); (A.G.-S.); (A.A.); (S.K.); (N.M.)
- Department of Mechanical and Biomedical Engineering, New York University, New York, NY 10003, USA
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23
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Notch signaling and taxis mechanisms regulate early stage angiogenesis: A mathematical and computational model. PLoS Comput Biol 2020; 16:e1006919. [PMID: 31986145 PMCID: PMC7021322 DOI: 10.1371/journal.pcbi.1006919] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 02/14/2020] [Accepted: 10/16/2019] [Indexed: 12/20/2022] Open
Abstract
During angiogenesis, new blood vessels sprout and grow from existing ones. This process plays a crucial role in organ development and repair, in wound healing and in numerous pathological processes such as cancer progression or diabetes. Here, we present a mathematical model of early stage angiogenesis that permits exploration of the relative importance of mechanical, chemical and cellular cues. Endothelial cells proliferate and move over an extracellular matrix by following external gradients of Vessel Endothelial Growth Factor, adhesion and stiffness, which are incorporated to a Cellular Potts model with a finite element description of elasticity. The dynamics of Notch signaling involving Delta-4 and Jagged-1 ligands determines tip cell selection and vessel branching. Through their production rates, competing Jagged-Notch and Delta-Notch dynamics determine the influence of lateral inhibition and lateral induction on the selection of cellular phenotypes, branching of blood vessels, anastomosis (fusion of blood vessels) and angiogenesis velocity. Anastomosis may be favored or impeded depending on the mechanical configuration of strain vectors in the ECM near tip cells. Numerical simulations demonstrate that increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can be compensated by augmenting the production of Delta ligands. Angiogenesis is the process by which new blood vessels grow from existing ones. This process plays a crucial role in organ development, in wound healing and in numerous pathological processes such as cancer growth or in diabetes. Angiogenesis is a complex, multi-step and well regulated process where biochemistry and physics are intertwined. The process entails signaling in vessel cells being driven by both chemical and mechanical mechanisms that result in vascular cell movement, deformation and proliferation. Mathematical models have the ability to bring together these mechanisms in order to explore their relative relevance in vessel growth. Here, we present a mathematical model of early stage angiogenesis that is able to explore the role of biochemical signaling and tissue mechanics. We use this model to unravel the regulating role of Jagged, Notch and Delta dynamics in vascular cells. These membrane proteins have an important part in determining the leading cell in each neo-vascular sprout. Numerical simulations demonstrate that increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can be compensated by augmenting the production of Delta ligands.
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24
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Saeedi M, Shamloo A, Mohammadi A. Fluid-Structure Interaction Simulation of Blood Flow and Cerebral Aneurysm: Effect of Partly Blocked Vessel. J Vasc Res 2019; 56:296-307. [PMID: 31671424 DOI: 10.1159/000503786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 09/30/2019] [Indexed: 11/19/2022] Open
Abstract
In this study, using fluid-structure interaction (FSI), 3-dimensional blood flow in an aneurysm in the circle of Willis - which is located in the middle cerebral artery (MCA) - has been simulated. The purpose of this study is to evaluate the effect of a partly blocked vessel on an aneurysm. To achieve this purpose, two cases have been investigated using the FSI method: in the first case, an ideal geometry of aneurysm in the MCA has been simulated; in the second case, modeling is performed for an ideal geometry of the aneurysm in the MCA with a partly blocked vessel. All boundary conditions, properties and modeling methods were considered the same for both cases. The only difference between the two cases was that part of the MCA parent artery was blocked in the second case. In order to consider the hyperelastic property of the wall and the non-Newtonian properties of the blood, the Mooney-Rivlin model and the Carreau model have been used, respectively. In the second case, the Von Mises stress in the peak systole is 26% higher than in the first case. With regard to the high amount of Von Mises stress, the risk of rupture of the aneurysm is higher in this case. In the second case, the maximum wall shear stress (WSS) is 12% higher than in the first case. And maximum displacement in the second case is also higher than in the first. So, the risk of growth of the aneurysm is higher in cases with a partly blocked vessel.
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Affiliation(s)
- Milad Saeedi
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
| | - Amir Shamloo
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran,
| | - Ariz Mohammadi
- Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
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Rauff A, LaBelle SA, Strobel HA, Hoying JB, Weiss JA. Imaging the Dynamic Interaction Between Sprouting Microvessels and the Extracellular Matrix. Front Physiol 2019; 10:1011. [PMID: 31507428 PMCID: PMC6713949 DOI: 10.3389/fphys.2019.01011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022] Open
Abstract
Thorough understanding of growth and evolution of tissue vasculature is fundamental to many fields of medicine including cancer therapy, wound healing, and tissue engineering. Angiogenesis, the growth of new vessels from existing ones, is dynamically influenced by a variety of environmental factors, including mechanical and biophysical factors, chemotactic factors, proteolysis, and interaction with stromal cells. Yet, dynamic interactions between neovessels and their environment are difficult to study with traditional fixed time imaging techniques. Advancements in imaging technologies permit time-series and volumetric imaging, affording the ability to visualize microvessel growth over 3D space and time. Time-lapse imaging has led to more informative investigations of angiogenesis. The environmental factors implicated in angiogenesis span a wide range of signals. Neovessels advance through stromal matrices by forming attachments and pulling and pushing on their microenvironment, reorganizing matrix fibers, and inducing large deformations of the surrounding stroma. Concurrently, neovessels secrete proteolytic enzymes to degrade their basement membrane, create space for new vessels to grow, and release matrix-bound cytokines. Growing neovessels also respond to a host of soluble and matrix-bound growth factors, and display preferential growth along a cytokine gradient. Lastly, stromal cells such as macrophages and mesenchymal stem cells (MSCs) interact directly with neovessels and their surrounding matrix to facilitate sprouting, vessel fusion, and tissue remodeling. This review highlights how time-lapse imaging techniques advanced our understanding of the interaction of blood vessels with their environment during sprouting angiogenesis. The technology provides means to characterize the evolution of microvessel behavior, providing new insights and holding great promise for further research on the process of angiogenesis.
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Affiliation(s)
- Adam Rauff
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
| | - Steven A. LaBelle
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
| | - Hannah A. Strobel
- Innovations Laboratory, Advanced Solutions Life Sciences, Manchester, NH, United States
| | - James B. Hoying
- Innovations Laboratory, Advanced Solutions Life Sciences, Manchester, NH, United States
| | - Jeffrey A. Weiss
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
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Baday M, Ercal O, Sahan AZ, Sahan A, Ercal B, Inan H, Demirci U. Density Based Characterization of Mechanical Cues on Cancer Cells Using Magnetic Levitation. Adv Healthc Mater 2019; 8:e1801517. [PMID: 30946539 DOI: 10.1002/adhm.201801517] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/28/2019] [Indexed: 12/14/2022]
Abstract
Extracellular matrix (ECM) stiffness is correlated to malignancy and invasiveness of cancer cells. Although the mechanism of change is unclear, mechanical signals from the ECM may affect physical properties of cells such as their density profile. The current methods, such as Percoll density-gradient centrifugation, are unable to detect minute density differences. A magnetic levitation device is developed (i.e., MagDense platform) where cells are levitated in a magnetic gradient allowing them to equilibrate to a levitation height that corresponds to their unique cellular density. In application of this system, MDA-MB-231 breast and A549 lung cancer cells are cultured and overall differences in cell density are observed in response to increasing collagen fiber density. Overall, density values are significantly more spread out for MDA-MB-231 cells extracted from the 1.44 mg mL-1 collagen gels compared to those from 0.72 mg mL-1 collagen, whereas no significant difference with A549 cell lines is observed. The MagDense platform can determine differences in cellular densities under various microenvironmental conditions. The imaging of cancer cells in a magnetic levitation device serves as a unique tool to observe changes in phenotypic properties of cancer cells as they relate to micromechanical cues encoded by the ECM.
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Affiliation(s)
- Murat Baday
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Ozlem Ercal
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Ayse Zisan Sahan
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Asude Sahan
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Baris Ercal
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Hakan Inan
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
| | - Utkan Demirci
- Radiology Department Canary Center for Early Cancer Detection Stanford University School of Medicine Stanford University 3155 Porter Driver Palo Alto 94304 CA USA
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Senchukova MA, Makarova EV, Kalinin EA, Tkachev VV. Modern ideas about the origin, features of morphology, prognostic and predictive significance of tumor vessels. RUSSIAN JOURNAL OF BIOTHERAPY 2019; 18:6-15. [DOI: 10.17650/1726-9784-2019-18-1-6-15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The review presents modern ideas about the origin of tumor vessels and the features of their morphology. The various approaches to the classification of tumor vessel types and to the assessment of their clinical and prognostic significance are described. Also, the main problems associated with the use of angiogenesis blockers in the treatment of malignancies and their possible solutions are reflected in the review.
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Affiliation(s)
- M. A. Senchukova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
| | - E. V. Makarova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
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28
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Ammann KR, DeCook KJ, Li M, Slepian MJ. Migration versus proliferation as contributor to in vitro wound healing of vascular endothelial and smooth muscle cells. Exp Cell Res 2019; 376:58-66. [PMID: 30660619 PMCID: PMC6988716 DOI: 10.1016/j.yexcr.2019.01.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/31/2018] [Accepted: 01/10/2019] [Indexed: 12/27/2022]
Abstract
Wound closure, as a result of collective cell growth, is an essential biological response to injury. In the field of vascular biology, the response of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to injury and substrate surface is important in therapeutic clinical treatment interventions such as angioplasty and atherectomy. Specifically, the mechanism by which cells close wounds (i.e. proliferation versus migration) in response to injury stimuli is of interest to better modulate recurrent vascular stenosis, prevent thrombus formation, occlusion, and life-threatening cardiovascular events. Here, we examine growth extent and temporal sequence of events following wound or gap introduction to a confluent monolayer of vascular SMCs or ECs. Significant differences in the preferred mechanisms of these cells to close wounds or gaps were observed; after 48 h, 73% of SMC wound closure was observed to be due to proliferation, while 75% of EC wound closure resulted from migration. These mechanisms were further modulated via addition or removal of extracellular matrix substrate and injury, with ECs more responsive to substrate composition and less to injury, in comparison to SMCs. Our results indicate that ECs and SMCs heal wounds differently, and that the time and mode of injury and associated substrate surface all impact this response.
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Affiliation(s)
- Kaitlyn R Ammann
- Department of Biomedical Engineering, College of Engineering, University of Arizona,1127 E James E Rogers Way, PO Box 210020, Tucson, AZ 85721, USA
| | - Katrina J DeCook
- Department of Biomedical Engineering, College of Engineering, University of Arizona,1127 E James E Rogers Way, PO Box 210020, Tucson, AZ 85721, USA
| | - Maxwell Li
- Department of Biomedical Engineering, College of Engineering, University of Arizona,1127 E James E Rogers Way, PO Box 210020, Tucson, AZ 85721, USA
| | - Marvin J Slepian
- Department of Biomedical Engineering, College of Engineering, University of Arizona,1127 E James E Rogers Way, PO Box 210020, Tucson, AZ 85721, USA; Department of Medicine, Sarver Heart Center, University of Arizona, 1501 N Campbell Ave, PO Box 245035, Tucson, AZ 85724, USA.
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Crosby CO, Zoldan J. Mimicking the physical cues of the ECM in angiogenic biomaterials. Regen Biomater 2019; 6:61-73. [PMID: 30967961 PMCID: PMC6447000 DOI: 10.1093/rb/rbz003] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 12/02/2018] [Accepted: 12/29/2018] [Indexed: 12/12/2022] Open
Abstract
A functional microvascular system is imperative to build and maintain healthy tissue. Impaired microvasculature results in ischemia, thereby limiting the tissue's intrinsic regeneration capacity. Therefore, the ability to regenerate microvascular networks is key to the development of effective cardiovascular therapies. To stimulate the formation of new microvasculature, researchers have focused on fabricating materials that mimic the angiogenic properties of the native extracellular matrix (ECM). Here, we will review biomaterials that seek to imitate the physical cues that are natively provided by the ECM to encourage the formation of microvasculature in engineered constructs and ischemic tissue in the body.
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Affiliation(s)
- Cody O Crosby
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Janet Zoldan
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
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30
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In silico study of patient-specific magnetic drug targeting for a coronary LAD atherosclerotic plaque. Int J Pharm 2019; 559:113-129. [DOI: 10.1016/j.ijpharm.2018.12.088] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/08/2018] [Accepted: 12/28/2018] [Indexed: 02/06/2023]
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31
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Personalised deposition maps for micro- and nanoparticles targeting an atherosclerotic plaque: attributions to the receptor-mediated adsorption on the inflamed endothelial cells. Biomech Model Mechanobiol 2019; 18:813-828. [DOI: 10.1007/s10237-018-01116-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 12/29/2018] [Indexed: 01/25/2023]
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32
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Bilayered heparinized vascular graft fabricated by combining electrospinning and freeze drying methods. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 94:1067-1076. [DOI: 10.1016/j.msec.2018.10.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 09/16/2018] [Accepted: 10/03/2018] [Indexed: 01/15/2023]
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33
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Nematollahisarvestani A, Shamloo A. Dynamics of a magnetically rotated micro swimmer inspired by paramecium metachronal wave. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2018; 142:32-42. [PMID: 30096335 DOI: 10.1016/j.pbiomolbio.2018.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 08/05/2018] [Accepted: 08/06/2018] [Indexed: 11/29/2022]
Abstract
In the past few years, a significant body of research has been devoted to designing magnetic micron scale robotic systems for minimally invasive medicine. The motion of different microorganisms is the nature's solution for efficient propulsion of these swimmers. So far, there has been a considerable effort in designing micro swimmers based on the propulsion of bacteria while the motion of numerous other microorganisms has not been a source of inspiration for designing micro swimmers yet. Inspired by propulsion of Paramecium which is a ciliate microorganism, a novel micro swimmer is proposed in this article which is capable of cargo transport. This novel swimmer is composed of multiple equally spaced rigid loxodromic rods spanning the surface of a sphere which can carry a cargo placed inside it. The propulsion of this swimmer is influenced by the geometry of the swimmer (diameter, number of rods, cargo size), therefore, CFD simulations have been performed to investigate it. Finally, the dynamics of this swimmer is investigated analytically which sheds light into the complex dynamics of a swimmer with this geometry.
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Affiliation(s)
- Ali Nematollahisarvestani
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave., 11155-9567, Tehran, Iran
| | - Amir Shamloo
- School of Mechanical Engineering, Sharif University of Technology, Azadi Ave., 11155-9567, Tehran, Iran.
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34
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Yeon JH, Chung SH, Baek C, Hwang H, Min J. A Simple Pipetting-based Method for Encapsulating Live Cells into Multi-layered Hydrogel Droplets. BIOCHIP JOURNAL 2018. [DOI: 10.1007/s13206-018-2307-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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35
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Kukumberg M, Yao Y, Goh SH, Neo DJ, Yao JY, Yim EK. Evaluation of the topographical influence on the cellular behavior of human umbilical vein endothelial cells. ADVANCED BIOSYSTEMS 2018; 2:1700217. [PMID: 30766915 PMCID: PMC6370334 DOI: 10.1002/adbi.201700217] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Indexed: 12/17/2022]
Abstract
Adhesion and proliferation of vascular endothelial cells are important parameters in the endothelialization of biomedical devices for vascular applications. Endothelialization is a complex process affected by endothelial cells and their interaction with the extracellular microenvironment. Although numerous approaches are taken to study the influence of the external environment, a systematic investigation of the impact of an engineered microenvironment on endothelial cell processes is needed. This study aims to investigate the influence of topography, initial cell seeding density, and collagen coating on human umbilical vein endothelial cells (HUVECs). Utilizing the MultiARChitecture (MARC) chamber, the effects of various topographies on HUVECs are identified, and those with more prominent effects were further evaluated individually using the MARC plate. Endothelial cell marker expression and monocyte adhesion assay are examined on the HUVEC monolayer. HUVECs on 1.8 μm convex and concave microlens topographies demonstrate the lowest cell adhesion and proliferation, regardless of initial cell seeding density and collagen I coating, and the HUVEC monolayer on the microlens shows the lowest monocyte adhesion. This property of lens topographies would potentially be a useful parameter in designing vascular biomedical devices. The MARC chamber and MARC plate show a great potential for faster and easy pattern identification for various cellular processes.
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Affiliation(s)
- Marek Kukumberg
- Mechanobiology Institute, National University of Singapore, #05-01 T-lab, 5A Engineering Drive 1, Singapore 117411
| | - Yuan Yao
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada
| | - Seok Hong Goh
- Institute of Materials Research and Engineering, Agency for Science, Technology and Research (ASTAR), 2 Fusionopolis Way, Innovis, 138634, Singapore, Department of Biomedical Engineering, National University of Singapore, E4, #04-10,4 Engineering Drive 3, Singapore 117583
| | - Dawn Jh Neo
- Mechanobiology Institute, National University of Singapore, #05-01 T-lab, 5A Engineering Drive 1, Singapore 117411
| | - Jia Yi Yao
- Department of Biomedical Engineering, National University of Singapore, E4, #04-10,4 Engineering Drive 3, Singapore 117583
| | - Evelyn Kf Yim
- Mechanobiology Institute, National University of Singapore, #05-01 T-lab, 5A Engineering Drive 1, Singapore 117411, Department of Biomedical Engineering, National University of Singapore, E4, #04-10,4 Engineering Drive 3, Singapore 117583, Department of Surgery, National University of Singapore, NUHS Tower Block, Level 8,1E Kent Ridge Road, Singapore 119228, Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada
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36
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Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development. Dev Cell 2018; 45:153-169.e6. [PMID: 29689192 DOI: 10.1016/j.devcel.2018.03.019] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 02/02/2018] [Accepted: 03/26/2018] [Indexed: 12/14/2022]
Abstract
During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts. Here, we investigated Hippo kinases Lats1 and Lats2 in epicardial diversification. Epicardial-specific deletion of Lats1/2 was embryonic lethal, and mutant embryos had defective coronary vasculature remodeling. Single-cell RNA sequencing revealed that Lats1/2 mutant cells failed to activate fibroblast differentiation but remained in an intermediate cell state with both epicardial and fibroblast characteristics. Lats1/2 mutant cells displayed an arrested developmental trajectory with persistence of epicardial markers and expanded expression of Yap targets Dhrs3, an inhibitor of retinoic acid synthesis, and Dpp4, a protease that modulates extracellular matrix (ECM) composition. Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics.
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37
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Soleimani S, Shamsi M, Ghazani MA, Modarres HP, Valente KP, Saghafian M, Ashani MM, Akbari M, Sanati-Nezhad A. Translational models of tumor angiogenesis: A nexus of in silico and in vitro models. Biotechnol Adv 2018; 36:880-893. [PMID: 29378235 DOI: 10.1016/j.biotechadv.2018.01.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 01/10/2018] [Accepted: 01/20/2018] [Indexed: 12/13/2022]
Abstract
Emerging evidence shows that endothelial cells are not only the building blocks of vascular networks that enable oxygen and nutrient delivery throughout a tissue but also serve as a rich resource of angiocrine factors. Endothelial cells play key roles in determining cancer progression and response to anti-cancer drugs. Furthermore, the endothelium-specific deposition of extracellular matrix is a key modulator of the availability of angiocrine factors to both stromal and cancer cells. Considering tumor vascular network as a decisive factor in cancer pathogenesis and treatment response, these networks need to be an inseparable component of cancer models. Both computational and in vitro experimental models have been extensively developed to model tumor-endothelium interactions. While informative, they have been developed in different communities and do not yet represent a comprehensive platform. In this review, we overview the necessity of incorporating vascular networks for both in vitro and in silico cancer models and discuss recent progresses and challenges of in vitro experimental microfluidic cancer vasculature-on-chip systems and their in silico counterparts. We further highlight how these two approaches can merge together with the aim of presenting a predictive combinatorial platform for studying cancer pathogenesis and testing the efficacy of single or multi-drug therapeutics for cancer treatment.
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Affiliation(s)
- Shirin Soleimani
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada; Center for BioEngineering Research and Education, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Milad Shamsi
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada; Center for BioEngineering Research and Education, University of Calgary, Calgary, AB T2N 1N4, Canada; Department of Mechanical Engineering, Isfahan University of Technology, Isfahan 8415683111, Iran
| | - Mehran Akbarpour Ghazani
- Department of Mechanical Engineering, Isfahan University of Technology, Isfahan 8415683111, Iran
| | - Hassan Pezeshgi Modarres
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Karolina Papera Valente
- Laboratory for Innovations in MicroEngineering (LiME), Department of Mechanical Engineering, University of Victoria, Victoria, BC V8P 5C2, Canada
| | - Mohsen Saghafian
- Department of Mechanical Engineering, Isfahan University of Technology, Isfahan 8415683111, Iran
| | - Mehdi Mohammadi Ashani
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Mohsen Akbari
- Laboratory for Innovations in MicroEngineering (LiME), Department of Mechanical Engineering, University of Victoria, Victoria, BC V8P 5C2, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada
| | - Amir Sanati-Nezhad
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada; Center for BioEngineering Research and Education, University of Calgary, Calgary, AB T2N 1N4, Canada.
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38
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Zhao F, Vaughan TJ, Mc Garrigle MJ, McNamara LM. A coupled diffusion-fluid pressure model to predict cell density distribution for cells encapsulated in a porous hydrogel scaffold under mechanical loading. Comput Biol Med 2017; 89:181-189. [DOI: 10.1016/j.compbiomed.2017.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/28/2017] [Accepted: 08/02/2017] [Indexed: 12/19/2022]
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39
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See HH, Herath SCB, Arayanarakool R, Du Y, Tan E, Ge R, Asada H, Chen PCY. An Electromagnetic System for Inducing a Localized Force Gradient in an ECM and Its Influence on HMVEC Sprouting. SLAS Technol 2017; 23:70-82. [PMID: 28922618 DOI: 10.1177/2472630317730002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mechanical properties of the extracellular matrix (ECM) have been observed to influence the behavior of cells. Investigations on such an influence commonly rely on using soluble cues to alter the global intrinsic ECM properties in order to study the subsequent response of cells. This article presents an electromagnetic system for inducing a localized force gradient in an ECM, and reports the experimentally observed effect of such a force gradient on in vitro angiogenic sprouting of human microvascular endothelial cells (HMVECs). This force gradient is realized through the induction of magnetic forces on the superparamagnetic microparticle-embedded ECM ( sECM). Both analytical and statistically meaningful experimental results demonstrate the effectiveness of this approach in influencing the behavior of a targeted HMVEC sprout without affecting that of other sprouts nearby. These results suggest the possibility of selectively controlling the in vitro behavior of cells by the induction of a localized force gradient in the ECM.
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Affiliation(s)
- Hian Hian See
- 1 Department of Mechanical Engineering, National University of Singapore, Singapore
| | - Sahan C B Herath
- 1 Department of Mechanical Engineering, National University of Singapore, Singapore.,2 Biosystem and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore
| | | | - Yue Du
- 1 Department of Mechanical Engineering, National University of Singapore, Singapore
| | - Evan Tan
- 2 Biosystem and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore.,3 Department of Biological Sciences, National University of Singapore, Singapore
| | - Ruowen Ge
- 2 Biosystem and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore.,3 Department of Biological Sciences, National University of Singapore, Singapore
| | - Harry Asada
- 2 Biosystem and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore.,4 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Peter C Y Chen
- 1 Department of Mechanical Engineering, National University of Singapore, Singapore.,2 Biosystem and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore
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40
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Abstract
In vivo, cells of the vascular system are subjected to various mechanical stimuli and have demonstrated the ability to adapt their behavior via mechanotransduction. Recent advances in microfluidic and "on-chip" techniques have provided the technology to study these alterations in cell behavior. Contrary to traditional in vitro assays such as transwell plates and parallel plate flow chambers, these microfluidic devices (MFDs) provide the opportunity to integrate multiple mechanical cues (e.g. shear stress, confinement, substrate stiffness, vessel geometry and topography) with in situ quantification capabilities. As such, MFDs can be used to recapitulate the in vivo mechanical setting and systematically vary microenvironmental conditions for improved mechanobiological studies of the endothelium. Additionally, adequate modelling provides for enhanced understanding of disease progression, design of cell separation and drug delivery systems, and the development of biomaterials for tissue engineering applications. Here, we will discuss the advances in knowledge about endothelial cell mechanosensing resulting from the design and application of biomimetic on-chip and microfluidic platforms.
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41
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Sun M, Zaman MH. Modeling, signaling and cytoskeleton dynamics: integrated modeling-experimental frameworks in cell migration. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2017; 9:10.1002/wsbm.1365. [PMID: 27863122 PMCID: PMC5338640 DOI: 10.1002/wsbm.1365] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 08/29/2016] [Accepted: 09/14/2016] [Indexed: 12/20/2022]
Abstract
Cell migration is a complex and multistep process involved in homeostasis maintenance, morphogenesis, and disease development, such as cancer metastasis. Modeling cell migration and the relevant cytoskeleton dynamics have profound implications for studying fundamental development and disease diagnosis. This review focuses on some recent models of both cell migration and migration-related cytoskeleton dynamics, addressing issues such as the difference between amoeboid and mesenchymal migration modes, and between single-cell migration and collective cell migration. The review also highlights the computational integration among variable external cues, especially the biochemical and mechanical signaling that affects cell migration. Finally, we aim to identify the gaps in our current knowledge and potential strategies to develop integrated modeling-experimental frameworks for multiscale behavior integrating gene expression, cell signaling, mechanics, and multicellular dynamics. WIREs Syst Biol Med 2017, 9:e1365. doi: 10.1002/wsbm.1365 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Meng Sun
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America
| | - Muhammad H. Zaman
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America
- Howard Hughes Medical Institute
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Du Y, Herath SCB, Wang QG, Wang DA, Asada HH, Chen PCY. Three-Dimensional Characterization of Mechanical Interactions between Endothelial Cells and Extracellular Matrix during Angiogenic Sprouting. Sci Rep 2016; 6:21362. [PMID: 26903154 PMCID: PMC4763258 DOI: 10.1038/srep21362] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 01/19/2016] [Indexed: 01/15/2023] Open
Abstract
We studied the three-dimensional cell-extracellular matrix interactions of endothelial cells that form multicellular structures called sprouts. We analyzed the data collected in-situ from angiogenic sprouting experiments and identified the differentiated interaction behavior exhibited by the tip and stalk cells. Moreover, our analysis of the tip cell lamellipodia revealed the diversity in their interaction behavior under certain conditions (e.g., when the heading of a sprout is switched approximately between the long-axis direction of two different lamellipodia). This study marks the first time that new characteristics of such interactions have been identified with shape changes in the sprouts and the associated rearrangements of collagen fibers. Clear illustrations of such changes are depicted in three-dimensional views.
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Affiliation(s)
- Yue Du
- Department of Mechanical Engineering, National University of Singapore, Singapore.,BioSystems and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore
| | - Sahan C B Herath
- Department of Mechanical Engineering, National University of Singapore, Singapore.,BioSystems and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore
| | - Qing-guo Wang
- Department of Electrical and Electronic Engineering Science, University of Johannesburg, South Africa
| | - Dong-an Wang
- Division of Bioengineering, Nanyang Technological University, Singapore
| | - H Harry Asada
- BioSystems and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore.,Department of Mechanical Engineering, Massachusetts Institute of Technology, USA
| | - Peter C Y Chen
- Department of Mechanical Engineering, National University of Singapore, Singapore.,BioSystems and Micromechanics Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Program, Singapore
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