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Conner AA, David D, Yim EKF. The Effects of Biomimetic Surface Topography on Vascular Cells: Implications for Vascular Conduits. Adv Healthc Mater 2024; 13:e2400335. [PMID: 38935920 DOI: 10.1002/adhm.202400335] [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: 01/28/2024] [Revised: 06/04/2024] [Indexed: 06/29/2024]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide and represent a pressing clinical need. Vascular occlusions are the predominant cause of CVD and necessitate surgical interventions such as bypass graft surgery to replace the damaged or obstructed blood vessel with a synthetic conduit. Synthetic small-diameter vascular grafts (sSDVGs) are desired to bypass blood vessels with an inner diameter <6 mm yet have limited use due to unacceptable patency rates. The incorporation of biophysical cues such as topography onto the sSDVG biointerface can be used to mimic the cellular microenvironment and improve outcomes. In this review, the utility of surface topography in sSDVG design is discussed. First, the primary challenges that sSDVGs face and the rationale for utilizing biomimetic topography are introduced. The current literature surrounding the effects of topographical cues on vascular cell behavior in vitro is reviewed, providing insight into which features are optimal for application in sSDVGs. The results of studies that have utilized topographically-enhanced sSDVGs in vivo are evaluated. Current challenges and barriers to clinical translation are discussed. Based on the wealth of evidence detailed here, substrate topography offers enormous potential to improve the outcome of sSDVGs and provide therapeutic solutions for CVDs.
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Affiliation(s)
- Abigail A Conner
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
| | - Dency David
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
- Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
- Center for Biotechnology and Bioengineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
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2
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Meng Y, Du X, Zhou S, Li J, Feng R, Zhang H, Xu Q, Zhao W, Liu Z, Zhong H. Investigation of Persistent Photoconductivity of Gallium Nitride Semiconductor and Differentiation of Primary Neural Stem Cells. Molecules 2024; 29:4439. [PMID: 39339434 PMCID: PMC11434078 DOI: 10.3390/molecules29184439] [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: 07/20/2024] [Revised: 09/01/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
A gallium nitride (GaN) semiconductor is one of the most promising materials integrated into biomedical devices to play the roles of connecting, monitoring, and manipulating the activity of biological components, due to its excellent photoelectric properties, chemical stability, and biocompatibility. In this work, it was found that the photogenerated free charge carriers of the GaN substrate, as an exogenous stimulus, served to promote neural stem cells (NSCs) to differentiate into neurons. This was observed through the systematic investigation of the effect of the persistent photoconductivity (PPC) of GaN on the differentiation of primary NSCs from the embryonic rat cerebral cortex. NSCs were directly cultured on the GaN surface with and without ultraviolet (UV) irradiation, with a control sample consisting of tissue culture polystyrene (TCPS) in the presence of fetal bovine serum (FBS) medium. Through optical microscopy, the morphology showed a greater number of neurons with the branching structures of axons and dendrites on GaN with UV irradiation. The immunocytochemical results demonstrated that GaN with UV irradiation could promote the NSCs to differentiate into neurons. Western blot analysis showed that GaN with UV irradiation significantly upregulated the expression of two neuron-related markers, βIII-tubulin (Tuj-1) and microtubule-associated protein 2 (MAP-2), suggesting that neurite formation and the proliferation of NSCs during differentiation were enhanced by GaN with UV irradiation. Finally, the results of the Kelvin probe force microscope (KPFM) experiments showed that the NSCs cultured on GaN with UV irradiation displayed about 50 mV higher potential than those cultured on GaN without irradiation. The increase in cell membrane potential may have been due to the larger number of photogenerated free charges on the GaN surface with UV irradiation. These results could benefit topical research and the application of GaN as a biomedical material integrated into neural interface systems or other bioelectronic devices.
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Affiliation(s)
- Yu Meng
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Xiaowei Du
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Shang Zhou
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Jiangting Li
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Rongrong Feng
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Huaiwei Zhang
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Qianhui Xu
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Weidong Zhao
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Zheng Liu
- School of Materials Science & Engineering, Nanyang Technological University, Singapore 639798, Singapore
| | - Haijian Zhong
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, China
- School of Medical Information Engineering, Gannan Medical University, Ganzhou 341000, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
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Conner AA, Yao Y, Chan SW, Jain D, Wong SM, Yim EKF, Rizwan M. High-throughput analysis of topographical cues for the expansion of murine pluripotent stem cells. NANOTECHNOLOGY 2024; 35:455101. [PMID: 39084233 DOI: 10.1088/1361-6528/ad6994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/31/2024] [Indexed: 08/02/2024]
Abstract
The expansion of pluripotent stem cells (PSCs)in vitroremains a critical barrier to their use in tissue engineering and regenerative medicine. Biochemical methods for PSC expansion are known to produce heterogeneous cell populations with varying states of pluripotency and are cost-intensive, hindering their clinical translation. Engineering biomaterials to physically control PSC fate offers an alternative approach. Surface or substrate topography is a promising design parameter for engineering biomaterials. Topographical cues have been shown to elicit profound effects on stem cell differentiation and proliferation. Previous reports have shown isotropic substrate topographies to be promising in expanding PSCs. However, the optimal feature to promote PSC proliferation and the pluripotent state has not yet been determined. In this work, the MultiARChitecture (MARC) plate is developed to conduct a high-throughput analysis of topographical cues in a 96-well plate format. The MARC plate is a reproducible and customizable platform for the analysis of multiple topographical patterns and features and is compatible with both microscopic assays and molecular biology techniques. The MARC plate is used to evaluate the expression of pluripotency markersOct4, Nanog, andSox2and the differentiation markerLmnAas well as the proliferation of murine embryonic stem (mES) cells. Our systematic analyses identified three topographical patterns that maintain pluripotency in mES cells after multiple passages: 1µm pillars (1µm spacing, square arrangement), 2µm wells (c-c (x, y) = 4, 4µm), and 5µm pillars (c-c (x, y) = 7.5, 7.5µm). This study represents a step towards developing a biomaterial platform for controlled murine PSC expansion.
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Affiliation(s)
- Abigail A Conner
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
| | - Yuan Yao
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
| | - Sarah W Chan
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
| | - Deepak Jain
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
| | - Suzanne M Wong
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
- Center for Biotechnology and Bioengineering, University of Waterloo, Waterloo, Canada
- Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Canada
| | - Muhammad Rizwan
- Department of Chemical Engineering, University of Waterloo, Waterloo, Canada
- Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, TX, United States of America
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Bakhshandeh B, Sorboni SG, Ranjbar N, Deyhimfar R, Abtahi MS, Izady M, Kazemi N, Noori A, Pennisi CP. Mechanotransduction in tissue engineering: Insights into the interaction of stem cells with biomechanical cues. Exp Cell Res 2023; 431:113766. [PMID: 37678504 DOI: 10.1016/j.yexcr.2023.113766] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/09/2023]
Abstract
Stem cells in their natural microenvironment are exposed to biochemical and biophysical cues emerging from the extracellular matrix (ECM) and neighboring cells. In particular, biomechanical forces modulate stem cell behavior, biological fate, and early developmental processes by sensing, interpreting, and responding through a series of biological processes known as mechanotransduction. Local structural changes in the ECM and mechanics are driven by reciprocal activation of the cell and the ECM itself, as the initial deposition of matrix proteins sequentially affects neighboring cells. Recent studies on stem cell mechanoregulation have provided insight into the importance of biomechanical signals on proper tissue regeneration and function and have shown that precise spatiotemporal control of these signals exists in stem cell niches. Against this background, the aim of this work is to review the current understanding of the molecular basis of mechanotransduction by analyzing how biomechanical forces are converted into biological responses via cellular signaling pathways. In addition, this work provides an overview of advanced strategies using stem cells and biomaterial scaffolds that enable precise spatial and temporal control of mechanical signals and offer great potential for the fields of tissue engineering and regenerative medicine will be presented.
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Affiliation(s)
- Behnaz Bakhshandeh
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.
| | | | - Nika Ranjbar
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Roham Deyhimfar
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Maryam Sadat Abtahi
- Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Mehrnaz Izady
- Department of Cellular and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Navid Kazemi
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Atefeh Noori
- Department of Biotechnology, Iranian Research Organization for Science and Technology (IROST), Tehran, Iran
| | - Cristian Pablo Pennisi
- Regenerative Medicine Group, Department of Health Science and Technology, Aalborg University, Denmark.
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Mattiassi S, Conner AA, Feng F, Goh ELK, Yim EKF. The Combined Effects of Topography and Stiffness on Neuronal Differentiation and Maturation Using a Hydrogel Platform. Cells 2023; 12:cells12060934. [PMID: 36980275 PMCID: PMC10047827 DOI: 10.3390/cells12060934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Biophysical parameters such as substrate topography and stiffness have been shown independently to elicit profound effects on neuronal differentiation and maturation from neural progenitor cells (NPCs) yet have not been investigated in combination. Here, the effects of various micrograting and stiffness combinations on neuronal differentiation and maturation were investigated using a polyacrylamide and N-acryloyl-6-aminocaproic acid copolymer (PAA-ACA) hydrogel with tunable stiffness. Whole laminin was conjugated onto the PAA-ACA surface indirectly or directly to facilitate long-term mouse and human NPC-derived neuron attachment. Three micrograting dimensions (2-10 µm) were patterned onto gels with varying stiffness (6.1-110.5 kPa) to evaluate the effects of topography, stiffness, and their interaction. The results demonstrate that the extracellular matrix (ECM)-modified PAA-ACA gels support mouse and human neuronal cell attachment throughout the differentiation and maturation stages (14 and 28 days, respectively). The interaction between topography and stiffness is shown to significantly increase the proportion of β-tubulin III (TUJ1) positive neurons and microtubule associated protein-2 (MAP2) positive neurite branching and length. Thus, the effects of topography and stiffness cannot be imparted. These results provide a novel platform for neural mechanobiology studies and emphasize the utility of optimizing numerous biophysical cues for improved neuronal yield in vitro.
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Affiliation(s)
- Sabrina Mattiassi
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
| | - Abigail A Conner
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
| | - Fan Feng
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
| | - Eyleen L K Goh
- Neuroscience and Mental Health Faculty, Lee Kong China School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
- Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
- Center for Biotechnology and Bioengineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
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6
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Bakhshandeh B, Ranjbar N, Abbasi A, Amiri E, Abedi A, Mehrabi M, Dehghani Z, Pennisi CP. Recent progress in the manipulation of biochemical and biophysical cues for engineering functional tissues. Bioeng Transl Med 2023; 8:e10383. [PMID: 36925674 PMCID: PMC10013802 DOI: 10.1002/btm2.10383] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/28/2022] [Accepted: 07/16/2022] [Indexed: 11/11/2022] Open
Abstract
Tissue engineering (TE) is currently considered a cutting-edge discipline that offers the potential for developing treatments for health conditions that negatively affect the quality of life. This interdisciplinary field typically involves the combination of cells, scaffolds, and appropriate induction factors for the regeneration and repair of damaged tissue. Cell fate decisions, such as survival, proliferation, or differentiation, critically depend on various biochemical and biophysical factors provided by the extracellular environment during developmental, physiological, and pathological processes. Therefore, understanding the mechanisms of action of these factors is critical to accurately mimic the complex architecture of the extracellular environment of living tissues and improve the efficiency of TE approaches. In this review, we recapitulate the effects that biochemical and biophysical induction factors have on various aspects of cell fate. While the role of biochemical factors, such as growth factors, small molecules, extracellular matrix (ECM) components, and cytokines, has been extensively studied in the context of TE applications, it is only recently that we have begun to understand the effects of biophysical signals such as surface topography, mechanical, and electrical signals. These biophysical cues could provide a more robust set of stimuli to manipulate cell signaling pathways during the formation of the engineered tissue. Furthermore, the simultaneous application of different types of signals appears to elicit synergistic responses that are likely to improve functional outcomes, which could help translate results into successful clinical therapies in the future.
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Affiliation(s)
- Behnaz Bakhshandeh
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Nika Ranjbar
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Elahe Amiri
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Ali Abedi
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Mohammad‐Reza Mehrabi
- Department of Microbial Biotechnology, School of Biology, College of ScienceUniversity of TehranTehranIran
| | - Zahra Dehghani
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Cristian Pablo Pennisi
- Regenerative Medicine Group, Department of Health Science and TechnologyAalborg UniversityAalborgDenmark
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Conklin B, Conley BM, Hou Y, Chen M, Lee KB. Advanced theragnostics for the central nervous system (CNS) and neurological disorders using functional inorganic nanomaterials. Adv Drug Deliv Rev 2023; 192:114636. [PMID: 36481291 PMCID: PMC11829738 DOI: 10.1016/j.addr.2022.114636] [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: 08/30/2022] [Revised: 10/13/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Various types of inorganic nanomaterials are capable of diagnostic biomarker detection and the therapeutic delivery of a disease or inflammatory modulating agent. Those multi-functional nanomaterials have been utilized to treat neurodegenerative diseases and central nervous system (CNS) injuries in an effective and personalized manner. Even though many nanomaterials can deliver a payload and detect a biomarker of interest, only a few studies have yet to fully utilize this combined strategy to its full potential. Combining a nanomaterial's ability to facilitate targeted delivery, promote cellular proliferation and differentiation, and carry a large amount of material with various sensing approaches makes it possible to diagnose a patient selectively and sensitively while offering preventative measures or early disease-modifying strategies. By tuning the properties of an inorganic nanomaterial, the dimensionality, hydrophilicity, size, charge, shape, surface chemistry, and many other chemical and physical parameters, different types of cells in the central nervous system can be monitored, modulated, or further studies to elucidate underlying disease mechanisms. Scientists and clinicians have better understood the underlying processes of pathologies for many neurologically related diseases and injuries by implementing multi-dimensional 0D, 1D, and 2D theragnostic nanomaterials. The incorporation of nanomaterials has allowed scientists to better understand how to detect and treat these conditions at an early stage. To this end, having the multi-modal ability to both sense and treat ailments of the central nervous system can lead to favorable outcomes for patients suffering from such injuries and diseases.
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Affiliation(s)
- Brandon Conklin
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123, Bevier Road, Piscataway, NJ 08854, USA
| | - Brian M Conley
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123, Bevier Road, Piscataway, NJ 08854, USA
| | - Yannan Hou
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123, Bevier Road, Piscataway, NJ 08854, USA
| | - Meizi Chen
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123, Bevier Road, Piscataway, NJ 08854, USA
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123, Bevier Road, Piscataway, NJ 08854, USA.
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Vermeulen S, Van Puyvelde B, Bengtsson del Barrio L, Almey R, van der Veer BK, Deforce D, Dhaenens M, de Boer J. Micro-Topographies Induce Epigenetic Reprogramming and Quiescence in Human Mesenchymal Stem Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 10:e2203880. [PMID: 36414384 PMCID: PMC9811462 DOI: 10.1002/advs.202203880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/19/2022] [Indexed: 06/16/2023]
Abstract
Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone-associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro-topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro-topographies after long-term culture conditions. Also, this influence of micro-topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re-cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype.
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Affiliation(s)
- Steven Vermeulen
- Department of Instructive Biomaterials EngineeringMERLN InstituteUniversity of MaastrichtMaastricht6229 ERThe Netherlands
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
| | - Bart Van Puyvelde
- Laboratory of Pharmaceutical BiotechnologyDepartment of PharmaceuticsGhent UniversityGhent9000Belgium
| | - Laura Bengtsson del Barrio
- Department of Instructive Biomaterials EngineeringMERLN InstituteUniversity of MaastrichtMaastricht6229 ERThe Netherlands
| | - Ruben Almey
- Laboratory of Pharmaceutical BiotechnologyDepartment of PharmaceuticsGhent UniversityGhent9000Belgium
| | - Bernard K. van der Veer
- Laboratory for Stem Cell and Developmental EpigeneticsDepartment of Development and RegenerationKU LeuvenLeuven3000Belgium
| | - Dieter Deforce
- Laboratory of Pharmaceutical BiotechnologyDepartment of PharmaceuticsGhent UniversityGhent9000Belgium
| | - Maarten Dhaenens
- Laboratory of Pharmaceutical BiotechnologyDepartment of PharmaceuticsGhent UniversityGhent9000Belgium
| | - Jan de Boer
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
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9
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Effect of Piezoelectric BaTiO 3 Filler on Mechanical and Magnetoelectric Properties of Zn 0.25Co 0.75Fe 2O 4/PVDF-TrFE Composites. Polymers (Basel) 2022; 14:polym14224807. [PMID: 36432934 PMCID: PMC9695481 DOI: 10.3390/polym14224807] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022] Open
Abstract
Polymer-based multiferroics, combining magnetic and piezoelectric properties, are studied experimentally-from synthesis to multi-parameter characterization-in view of their prospects for fabricating biocompatible scaffolds. The main advantage of these systems is facile generation of mechanical deformations and electric signals in response to external magnetic fields. Herein, we address the composites based on PVDF-TrFE polymer matrices filled with a combination of piezoelectric (BaTiO3, BTO) and/or ferrimagnetic (Zn0.25Co0.75Fe2O4, ZCFO) particles. It is shown that the presence of BTO micron-size particles favors stripe-type structuring of the ZCFO filler and enhances the magnetoelectric response of the sample up to 18.6 mV/(cm∙Oe). Besides that, the admixing of BTO particles is crucial because the mechanical properties of the composite filled with only ZCFO is much less efficient in transforming magnetic excitations into the mechanical and electric responses. Attention is focused on the local surfacial mechanical properties since those, to a great extent, determine the fate of stem cells cultivated on these surfaces. The nano-indentation tests are accomplished with the aid of scanning probe microscopy technique. With their proven suitable mechanical properties, a high level of magnetoelectric conversion and also biocompatibility, the composites of the considered type are enticing as the materials for multiferroic-based polymer scaffolds.
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10
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Mariano A, Bovio CL, Criscuolo V, Santoro F. Bioinspired micro- and nano-structured neural interfaces. NANOTECHNOLOGY 2022; 33:492501. [PMID: 35947922 DOI: 10.1088/1361-6528/ac8881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/10/2022] [Indexed: 06/15/2023]
Abstract
The development of a functional nervous system requires neurons to interact with and promptly respond to a wealth of biochemical, mechanical and topographical cues found in the neural extracellular matrix (ECM). Among these, ECM topographical cues have been found to strongly influence neuronal function and behavior. Here, we discuss how the blueprint of the architectural organization of the brain ECM has been tremendously useful as a source of inspiration to design biomimetic substrates to enhance neural interfaces and dictate neuronal behavior at the cell-material interface. In particular, we focus on different strategies to recapitulate cell-ECM and cell-cell interactions. In order to mimic cell-ECM interactions, we introduce roughness as a first approach to provide informative topographical biomimetic cues to neurons. We then examine 3D scaffolds and hydrogels, as softer 3D platforms for neural interfaces. Moreover, we will discuss how anisotropic features such as grooves and fibers, recapitulating both ECM fibrils and axonal tracts, may provide recognizable paths and tracks that neuron can follow as they develop and establish functional connections. Finally, we show how isotropic topographical cues, recapitulating shapes, and geometries of filopodia- and mushroom-like dendritic spines, have been instrumental to better reproduce neuron-neuron interactions for applications in bioelectronics and neural repair strategies. The high complexity of the brain architecture makes the quest for the fabrication of create more biologically relevant biomimetic architectures in continuous and fast development. Here, we discuss how recent advancements in two-photon polymerization and remotely reconfigurable dynamic interfaces are paving the way towards to a new class of smart biointerfaces forin vitroapplications spanning from neural tissue engineering as well as neural repair strategies.
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Affiliation(s)
- Anna Mariano
- Tissue Electronics, Istituto Italiano di Tecnologia, I-80125 Naples, Italy
| | - Claudia Latte Bovio
- Tissue Electronics, Istituto Italiano di Tecnologia, I-80125 Naples, Italy
- Dipartimento di Chimica, Materiali e Produzione Industriale, Università di Napoli Federico II, I-80125, Naples, Italy
| | - Valeria Criscuolo
- Faculty of Electrical Engineering and IT, RWTH Aachen, D-52074, Germany
| | - Francesca Santoro
- Tissue Electronics, Istituto Italiano di Tecnologia, I-80125 Naples, Italy
- Faculty of Electrical Engineering and IT, RWTH Aachen, D-52074, Germany
- Institute for Biological Information Processing-Bioelectronics, Forschungszentrum Juelich, D-52428, Germany
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Zhang Y, Habibovic P. Delivering Mechanical Stimulation to Cells: State of the Art in Materials and Devices Design. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2110267. [PMID: 35385176 DOI: 10.1002/adma.202110267] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/19/2022] [Indexed: 06/14/2023]
Abstract
Biochemical signals, such as growth factors, cytokines, and transcription factors are known to play a crucial role in regulating a variety of cellular activities as well as maintaining the normal function of different tissues and organs. If the biochemical signals are assumed to be one side of the coin, the other side comprises biophysical cues. There is growing evidence showing that biophysical signals, and in particular mechanical cues, also play an important role in different stages of human life ranging from morphogenesis during embryonic development to maturation and maintenance of tissue and organ function throughout life. In order to investigate how mechanical signals influence cell and tissue function, tremendous efforts have been devoted to fabricating various materials and devices for delivering mechanical stimuli to cells and tissues. Here, an overview of the current state of the art in the design and development of such materials and devices is provided, with a focus on their design principles, and challenges and perspectives for future research directions are highlighted.
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Affiliation(s)
- Yonggang Zhang
- Department of Instructive Biomaterials Engineering, Maastricht University, MERLN Institute for Technology-Inspired Regenerative Medicine, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands
| | - Pamela Habibovic
- Department of Instructive Biomaterials Engineering, Maastricht University, MERLN Institute for Technology-Inspired Regenerative Medicine, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands
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12
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Patel M, Ahn S, Koh WG. Topographical pattern for neuronal tissue engineering. J IND ENG CHEM 2022. [DOI: 10.1016/j.jiec.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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13
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Zhang SY, Zhao J, Ni JJ, Li H, Quan ZZ, Qing H. Application and prospects of high-throughput screening for in vitro neurogenesis. World J Stem Cells 2022; 14:393-419. [PMID: 35949394 PMCID: PMC9244953 DOI: 10.4252/wjsc.v14.i6.393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or developmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.
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Affiliation(s)
- Shu-Yuan Zhang
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Juan Zhao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing 100049, China
| | - Jun-Jun Ni
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Zhen-Zhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
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14
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Multiphoton microfabrication and micropatternining (MMM)-based screening of multiplex cell niche factors for phenotype maintenance - Bovine nucleus pulposus cell as an example. Biomaterials 2022; 281:121367. [DOI: 10.1016/j.biomaterials.2022.121367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 11/20/2022]
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15
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Sari B, Isik M, Eylem CC, Kilic C, Okesola BO, Karakaya E, Emregul E, Nemutlu E, Derkus B. Omics Technologies for High-Throughput-Screening of Cell-Biomaterial Interactions. Mol Omics 2022; 18:591-615. [DOI: 10.1039/d2mo00060a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Recent research effort in biomaterial development has largely focused on engineering bio-instructive materials to stimulate specific cell signaling. Assessing the biological performance of these materials using time-consuming and trial-and-error traditional...
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16
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Tian Y, Zheng H, Zheng G, Hu P, Li Y, Lin Y, Gao Q, Yao X, Gao R, Li C, Wu X, Sui L. Hierarchical microgroove/nanopore topography regulated cell adhesion to enhance osseointegration around intraosseous implants in vivo. Biomater Sci 2021; 10:560-580. [PMID: 34907409 DOI: 10.1039/d1bm01657a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Implant surface topography plays a crucial role in achieving successful implantation. Simple and controllable surface topographical modifications are considered a promising method to accelerate bone osseointegration for biomedical applications. Moreover, comprehension of the mechanism between surface topography and cell osteogenic differentiation is vital for the manipulation of these processes to promote bone tissue regeneration. In this study, we investigated the effects of implant surfaces with various sized hierarchical microgroove/nanopore topographies on cell adhesion, osteogenesis, and their underlying mechanism both in vitro and in vivo. Our findings reveal that a titanium surface with an appropriately sized microgroove/nanopore topography (SLM-1MAH) exhibits the more satisfactory adhesive and osteogenic efficiency than the clinically used sand-blasted, large-grit, and acid-etched (SLA) surface. The underlying molecular mechanism lies in the activation of the integrin α2-PI3K-Akt signaling pathway, where the SLM-1MAH surface increased the protein expressions of integrin α2 (Itga2), phosphatidylinositol 3-kinase (PI3K), and phosphorylated serine/threonine kinase Akt (p-Akt) to enhance osteogenesis and osseointegration. Furthermore, the SLM-1MAH surface also displays better osseointegration efficiency with stronger bonding strength than that on the SLA surface. This work provides a novel strategy for implant surface topography design to improve bone-implant osseointegration.
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Affiliation(s)
- Yujuan Tian
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China. .,Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
| | - Huimin Zheng
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China. .,Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
| | - Guoying Zheng
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Penghui Hu
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Ying Li
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Yi Lin
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Qian Gao
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China. .,Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
| | - Xiaoyu Yao
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Rui Gao
- International Education College, Tianjin University of Traditional Chinese Medicine, Tianjin, 300070, China
| | - Changyi Li
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
| | - Xudong Wu
- Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
| | - Lei Sui
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, 300070, China.
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17
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Investigating the Regulation of Neural Differentiation and Injury in PC12 Cells Using Microstructure Topographic Cues. BIOSENSORS-BASEL 2021; 11:bios11100399. [PMID: 34677355 PMCID: PMC8534126 DOI: 10.3390/bios11100399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 11/30/2022]
Abstract
In this study, we designed and manufactured a series of different microstructure topographical cues for inducing neuronal differentiation of cells in vitro, with different topography, sizes, and structural complexities. We cultured PC12 cells in these microstructure cues and then induced neural differentiation using nerve growth factor (NGF). The pheochromocytoma cell line PC12 is a validated neuronal cell model that is widely used to study neuronal differentiation. Relevant markers of neural differentiation and cytoskeletal F-actin were characterized. Cellular immunofluorescence detection and axon length analysis showed that the differentiation of PC12 cells was significantly different under different isotropic and anisotropic topographic cues. The expression differences of the growth cone marker growth-associated protein 43 (GAP-43) and sympathetic nerve marker tyrosine hydroxylase (TH) genes were also studied in different topographic cues. Our results revealed that the physical environment has an important influence on the differentiation of neuronal cells, and 3D constraints could be used to guide axon extension. In addition, the neurotoxin 6-hydroxydopamine (6-OHDA) was used to detect the differentiation and injury of PC12 cells under different topographic cues. Finally, we discussed the feasibility of combining the topographic cues and the microfluidic chip for neural differentiation research.
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18
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Harawaza K, Cousins B, Roach P, Fernandez A. Modification of the surface nanotopography of implant devices: A translational perspective. Mater Today Bio 2021; 12:100152. [PMID: 34746736 PMCID: PMC8554633 DOI: 10.1016/j.mtbio.2021.100152] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/16/2021] [Accepted: 10/19/2021] [Indexed: 01/24/2023] Open
Abstract
There is an increasing need for the development of superior, safe, and more sophisticated implants, especially as our society historically has been moving towards an increasingly aging population. Currently, most research is being focused on the next generation of advanced medical implants, that are not only biocompatible but have modified surfaces that direct specific immunomodulation at cellular level. While there is a plethora of information on cell-surface interaction and how surfaces can be nanofabricated at research level, less is known about how the academic knowledge has been translated into clinical trials and commercial technologies. In this review, we provide a clinical translational perspective on the use of controlled physical surface modification of medical implants, presenting an analysis of data acquired from clinical trials and commercial products. We also evaluate the state-of-the-art of nanofabrication techniques that are being applied for implant surface modification at a clinical level. Finally, we identify some current challenges in the field, including the need of more advanced nanopatterning techniques, the comparatively small number of clinical trials and comment on future avenues to be explored for a successful clinical translation.
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Affiliation(s)
- K. Harawaza
- Chemistry Department, School of Science, Loughborough University, Loughborough, LE11 3TU, UK
| | - B. Cousins
- Chemistry Department, School of Science, Loughborough University, Loughborough, LE11 3TU, UK
| | - P. Roach
- Chemistry Department, School of Science, Loughborough University, Loughborough, LE11 3TU, UK
| | - A. Fernandez
- Chemistry Department, School of Science, Loughborough University, Loughborough, LE11 3TU, UK
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19
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Vermeulen S, Honig F, Vasilevich A, Roumans N, Romero M, Dede Eren A, Tuvshindorj U, Alexander M, Carlier A, Williams P, Uquillas J, de Boer J. Expanding Biomaterial Surface Topographical Design Space through Natural Surface Reproduction. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2102084. [PMID: 34165820 PMCID: PMC11468538 DOI: 10.1002/adma.202102084] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/15/2021] [Indexed: 06/13/2023]
Abstract
Surface topography is a tool to endow biomaterials with bioactive properties. However, the large number of possible designs makes it challenging to find the optimal surface structure to induce a specific cell response. The TopoChip platform is currently the largest collection of topographies with 2176 in silico designed microtopographies. Still, it is exploring only a small part of the design space due to design algorithm limitations and the surface engineering strategy. Inspired by the diversity of natural surfaces, it is assessed as to what extent the topographical design space and consequently the resulting cellular responses can be expanded using natural surfaces. To this end, 26 plant and insect surfaces are replicated in polystyrene and their surface properties are quantified using white light interferometry. Through machine-learning algorithms, it is demonstrated that natural surfaces extend the design space of the TopoChip, which coincides with distinct morphological and focal adhesion profiles in mesenchymal stem cells (MSCs) and Pseudomonas aeruginosa colonization. Furthermore, differentiation experiments reveal the strong potential of the holy lotus to improve osteogenesis in MSCs. In the future, the design algorithms will be trained with the results obtained by natural surface imprint experiments to explore the bioactive properties of novel surface topographies.
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Affiliation(s)
- Steven Vermeulen
- MERLN InstituteMaastricht UniversityMaastricht6229 ERThe Netherlands
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
| | - Floris Honig
- MERLN InstituteMaastricht UniversityMaastricht6229 ERThe Netherlands
| | - Aliaksei Vasilevich
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
| | - Nadia Roumans
- MERLN InstituteMaastricht UniversityMaastricht6229 ERThe Netherlands
| | - Manuel Romero
- National Biofilms Innovation CentreBiodiscovery Institute and School of Life SciencesUniversity of NottinghamNottinghamNG7 2RDUK
| | - Aysegul Dede Eren
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
| | - Urnaa Tuvshindorj
- MERLN InstituteMaastricht UniversityMaastricht6229 ERThe Netherlands
| | - Morgan Alexander
- Advanced Materials and Healthcare TechnologiesThe School of PharmacyUniversity of NottinghamNottinghamNG7 2RDUK
| | - Aurélie Carlier
- MERLN InstituteMaastricht UniversityMaastricht6229 ERThe Netherlands
| | - Paul Williams
- National Biofilms Innovation CentreBiodiscovery Institute and School of Life SciencesUniversity of NottinghamNottinghamNG7 2RDUK
| | - Jorge Uquillas
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
| | - Jan de Boer
- Department of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhoven5600 MBThe Netherlands
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20
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Tang LJW, Zaseela A, Toh CCM, Adine C, Aydar AO, Iyer NG, Fong ELS. Engineering stromal heterogeneity in cancer. Adv Drug Deliv Rev 2021; 175:113817. [PMID: 34087326 DOI: 10.1016/j.addr.2021.05.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/19/2021] [Accepted: 05/29/2021] [Indexed: 02/09/2023]
Abstract
Based on our exponentially increasing knowledge of stromal heterogeneity from advances in single-cell technologies, the notion that stromal cell types exist as a spectrum of unique subpopulations that have specific functions and spatial distributions in the tumor microenvironment has significant impact on tumor modeling for drug development and personalized drug testing. In this Review, we discuss the importance of incorporating stromal heterogeneity and tumor architecture, and propose an overall approach to guide the reconstruction of stromal heterogeneity in vitro for tumor modeling. These next-generation tumor models may support the development of more precise drugs targeting specific stromal cell subpopulations, as well as enable improved recapitulation of patient tumors in vitro for personalized drug testing.
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Affiliation(s)
- Leon Jia Wei Tang
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Ayshath Zaseela
- Department of Biomedical Engineering, National University of Singapore, Singapore
| | | | - Christabella Adine
- Department of Biomedical Engineering, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore
| | - Abdullah Omer Aydar
- Department of Biomedical Engineering, National University of Singapore, Singapore
| | - N Gopalakrishna Iyer
- National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore.
| | - Eliza Li Shan Fong
- Department of Biomedical Engineering, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore.
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21
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The Influence of the Surface Topographical Cues of Biomaterials on Nerve Cells in Peripheral Nerve Regeneration: A Review. Stem Cells Int 2021; 2021:8124444. [PMID: 34349803 PMCID: PMC8328695 DOI: 10.1155/2021/8124444] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/05/2021] [Indexed: 01/01/2023] Open
Abstract
The surface topographies of artificial implants including surface roughness, surface groove size and orientation, and surface pore size and distribution have a great influence on the adhesion, migration, proliferation, and differentiation of nerve cells in the nerve regeneration process. Optimizing the surface topographies of biomaterials can be a key strategy for achieving excellent cell performance in various applications such as nerve tissue engineering. In this review, we offer a comprehensive summary of the surface topographies of nerve implants and their effects on nerve cell behavior. This review also emphasizes the latest work progress of the layered structure of the natural extracellular matrix that can be imitated by the material surface topology. Finally, the future development of surface topographies on nerve regeneration was prospectively remarked.
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22
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Soheilmoghaddam F, Rumble M, Cooper-White J. High-Throughput Routes to Biomaterials Discovery. Chem Rev 2021; 121:10792-10864. [PMID: 34213880 DOI: 10.1021/acs.chemrev.0c01026] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Many existing clinical treatments are limited in their ability to completely restore decreased or lost tissue and organ function, an unenviable situation only further exacerbated by a globally aging population. As a result, the demand for new medical interventions has increased substantially over the past 20 years, with the burgeoning fields of gene therapy, tissue engineering, and regenerative medicine showing promise to offer solutions for full repair or replacement of damaged or aging tissues. Success in these fields, however, inherently relies on biomaterials that are engendered with the ability to provide the necessary biological cues mimicking native extracellular matrixes that support cell fate. Accelerating the development of such "directive" biomaterials requires a shift in current design practices toward those that enable rapid synthesis and characterization of polymeric materials and the coupling of these processes with techniques that enable similarly rapid quantification and optimization of the interactions between these new material systems and target cells and tissues. This manuscript reviews recent advances in combinatorial and high-throughput (HT) technologies applied to polymeric biomaterial synthesis, fabrication, and chemical, physical, and biological screening with targeted end-point applications in the fields of gene therapy, tissue engineering, and regenerative medicine. Limitations of, and future opportunities for, the further application of these research tools and methodologies are also discussed.
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Affiliation(s)
- Farhad Soheilmoghaddam
- Tissue Engineering and Microfluidics Laboratory (TEaM), Australian Institute for Bioengineering and Nanotechnology (AIBN), University Of Queensland, St. Lucia, Queensland, Australia 4072.,School of Chemical Engineering, University Of Queensland, St. Lucia, Queensland, Australia 4072
| | - Madeleine Rumble
- Tissue Engineering and Microfluidics Laboratory (TEaM), Australian Institute for Bioengineering and Nanotechnology (AIBN), University Of Queensland, St. Lucia, Queensland, Australia 4072.,School of Chemical Engineering, University Of Queensland, St. Lucia, Queensland, Australia 4072
| | - Justin Cooper-White
- Tissue Engineering and Microfluidics Laboratory (TEaM), Australian Institute for Bioengineering and Nanotechnology (AIBN), University Of Queensland, St. Lucia, Queensland, Australia 4072.,School of Chemical Engineering, University Of Queensland, St. Lucia, Queensland, Australia 4072
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23
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Guttenplan APM, Tahmasebi Birgani Z, Giselbrecht S, Truckenmüller RK, Habibović P. Chips for Biomaterials and Biomaterials for Chips: Recent Advances at the Interface between Microfabrication and Biomaterials Research. Adv Healthc Mater 2021; 10:e2100371. [PMID: 34033239 PMCID: PMC11468311 DOI: 10.1002/adhm.202100371] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Indexed: 12/24/2022]
Abstract
In recent years, the use of microfabrication techniques has allowed biomaterials studies which were originally carried out at larger length scales to be miniaturized as so-called "on-chip" experiments. These miniaturized experiments have a range of advantages which have led to an increase in their popularity. A range of biomaterial shapes and compositions are synthesized or manufactured on chip. Moreover, chips are developed to investigate specific aspects of interactions between biomaterials and biological systems. Finally, biomaterials are used in microfabricated devices to replicate the physiological microenvironment in studies using so-called "organ-on-chip," "tissue-on-chip" or "disease-on-chip" models, which can reduce the use of animal models with their inherent high cost and ethical issues, and due to the possible use of human cells can increase the translation of research from lab to clinic. This review gives an overview of recent developments at the interface between microfabrication and biomaterials science, and indicates potential future directions that the field may take. In particular, a trend toward increased scale and automation is apparent, allowing both industrial production of micron-scale biomaterials and high-throughput screening of the interaction of diverse materials libraries with cells and bioengineered tissues and organs.
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Affiliation(s)
- Alexander P. M. Guttenplan
- Department of Instructive Biomaterials EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityUniversiteitssingel 40Maastricht6229ERThe Netherlands
| | - Zeinab Tahmasebi Birgani
- Department of Instructive Biomaterials EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityUniversiteitssingel 40Maastricht6229ERThe Netherlands
| | - Stefan Giselbrecht
- Department of Instructive Biomaterials EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityUniversiteitssingel 40Maastricht6229ERThe Netherlands
| | - Roman K. Truckenmüller
- Department of Instructive Biomaterials EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityUniversiteitssingel 40Maastricht6229ERThe Netherlands
| | - Pamela Habibović
- Department of Instructive Biomaterials EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityUniversiteitssingel 40Maastricht6229ERThe Netherlands
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24
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Mattiassi S, Rizwan M, Grigsby CL, Zaw AM, Leong KW, Yim EKF. Enhanced efficiency of nonviral direct neuronal reprogramming on topographical patterns. Biomater Sci 2021; 9:5175-5191. [PMID: 34128504 DOI: 10.1039/d1bm00400j] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Nonviral direct neuronal reprogramming holds significant potential in the fields of tissue engineering and regenerative medicine. However, the issue of low reprogramming efficiency poses a major barrier to its application. We propose that topographical cues, which have been applied successfully to enhance lineage-directed differentiation and multipotent stem cell transdifferentiation, could improve nonviral direct neuronal reprogramming efficiency. To investigate, we used a polymer-BAM (Brn2, Ascl1, Myt1l) factor transfection polypex to reprogram primary mouse embryonic fibroblasts. Using a multiarchitecture chip, we screened for patterns that may improve transfection and/or subsequent induced neuron reprogramming efficiency. Selected patterns were then investigated further by analyzing β-tubulin III (TUJ1) and microtubule-associated protein 2 (MAP2) protein expression, cell morphology and electrophysiological function of induced neurons. Certain hierarchical topographies, with nanopatterns imprinted on micropatterns, significantly improved the percentage of TUJ1+ and MAP2+ cells. It is postulated that the microscale base pattern enhances initial BAM expression while the nanoscale sub-pattern promotes subsequent maturation. This is because the base pattern alone increased expression of TUJ1 and MAP2, while the nanoscale pattern was the only pattern yielding induced neurons capable of firing multiple action potentials. Nanoscale patterns also produced the highest fraction of cells showing spontaneous synaptic activity. Overall, reprogramming efficiency with one dose of polyplex on hierarchical patterns was comparable to that of five doses without topography. Thus, topography can enhance nonviral direct reprogramming of fibroblasts into induced neurons.
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Affiliation(s)
- Sabrina Mattiassi
- Department of Chemical Engineering, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada.
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25
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Marinval N, Chew SY. Mechanotransduction assays for neural regeneration strategies: A focus on glial cells. APL Bioeng 2021; 5:021505. [PMID: 33948526 PMCID: PMC8088332 DOI: 10.1063/5.0037814] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/19/2021] [Indexed: 01/22/2023] Open
Abstract
Glial cells are mechanosensitive, and thus, engineered systems have taken a step forward to design mechanotransduction platforms in order to impart diverse mechanical stresses to cells. Mechanical strain encountered in the central nervous system can arise from diverse mechanisms, such as tissue reorganization, fluid flow, and axon growth, as well as pathological events including axon swelling or mechanical trauma. Biomechanical relevance of the in vitro mechanical testing requires to be placed in line with the physiological and mechanical changes in central nervous tissues that occur during the progression of neurodegenerative diseases. Mechanotransduction signaling utilized by glial cells and the recent approaches intended to model altered microenvironment adapted to pathological context are discussed in this review. New insights in systems merging substrate's stiffness and topography should be considered for further glial mechanotransduction studies, while testing platforms for drug discoveries promise great advancements in pharmacotherapy. Potential leads and strategies for clinical outcomes are expected to be developed following the exploration of these glial mechanosensitive signaling pathways.
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Affiliation(s)
- Nicolas Marinval
- School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459
| | - Sing Yian Chew
- Author to whom correspondence should be addressed: . Tel.: +65 6316 8812. Fax: +65 6794 7553
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Yang L, Pijuan-Galito S, Rho HS, Vasilevich AS, Eren AD, Ge L, Habibović P, Alexander MR, de Boer J, Carlier A, van Rijn P, Zhou Q. High-Throughput Methods in the Discovery and Study of Biomaterials and Materiobiology. Chem Rev 2021; 121:4561-4677. [PMID: 33705116 PMCID: PMC8154331 DOI: 10.1021/acs.chemrev.0c00752] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Indexed: 02/07/2023]
Abstract
The complex interaction of cells with biomaterials (i.e., materiobiology) plays an increasingly pivotal role in the development of novel implants, biomedical devices, and tissue engineering scaffolds to treat diseases, aid in the restoration of bodily functions, construct healthy tissues, or regenerate diseased ones. However, the conventional approaches are incapable of screening the huge amount of potential material parameter combinations to identify the optimal cell responses and involve a combination of serendipity and many series of trial-and-error experiments. For advanced tissue engineering and regenerative medicine, highly efficient and complex bioanalysis platforms are expected to explore the complex interaction of cells with biomaterials using combinatorial approaches that offer desired complex microenvironments during healing, development, and homeostasis. In this review, we first introduce materiobiology and its high-throughput screening (HTS). Then we present an in-depth of the recent progress of 2D/3D HTS platforms (i.e., gradient and microarray) in the principle, preparation, screening for materiobiology, and combination with other advanced technologies. The Compendium for Biomaterial Transcriptomics and high content imaging, computational simulations, and their translation toward commercial and clinical uses are highlighted. In the final section, current challenges and future perspectives are discussed. High-throughput experimentation within the field of materiobiology enables the elucidation of the relationships between biomaterial properties and biological behavior and thereby serves as a potential tool for accelerating the development of high-performance biomaterials.
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Affiliation(s)
- Liangliang Yang
- University
of Groningen, W. J. Kolff Institute for Biomedical Engineering and
Materials Science, Department of Biomedical Engineering, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Sara Pijuan-Galito
- School
of Pharmacy, Biodiscovery Institute, University
of Nottingham, University Park, Nottingham NG7 2RD, U.K.
| | - Hoon Suk Rho
- Department
of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired
Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Aliaksei S. Vasilevich
- Department
of Biomedical Engineering, Eindhoven University
of Technology, 5600 MB Eindhoven, The Netherlands
| | - Aysegul Dede Eren
- Department
of Biomedical Engineering, Eindhoven University
of Technology, 5600 MB Eindhoven, The Netherlands
| | - Lu Ge
- University
of Groningen, W. J. Kolff Institute for Biomedical Engineering and
Materials Science, Department of Biomedical Engineering, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Pamela Habibović
- Department
of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired
Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Morgan R. Alexander
- School
of Pharmacy, Boots Science Building, University
of Nottingham, University Park, Nottingham NG7 2RD, U.K.
| | - Jan de Boer
- Department
of Biomedical Engineering, Eindhoven University
of Technology, 5600 MB Eindhoven, The Netherlands
| | - Aurélie Carlier
- Department
of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired
Regenerative Medicine, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Patrick van Rijn
- University
of Groningen, W. J. Kolff Institute for Biomedical Engineering and
Materials Science, Department of Biomedical Engineering, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Qihui Zhou
- Institute
for Translational Medicine, Department of Stomatology, The Affiliated
Hospital of Qingdao University, Qingdao
University, Qingdao 266003, China
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Honig F, Vermeulen S, Zadpoor AA, de Boer J, Fratila-Apachitei LE. Natural Architectures for Tissue Engineering and Regenerative Medicine. J Funct Biomater 2020; 11:E47. [PMID: 32645945 PMCID: PMC7565607 DOI: 10.3390/jfb11030047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/27/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023] Open
Abstract
The ability to control the interactions between functional biomaterials and biological systems is of great importance for tissue engineering and regenerative medicine. However, the underlying mechanisms defining the interplay between biomaterial properties and the human body are complex. Therefore, a key challenge is to design biomaterials that mimic the in vivo microenvironment. Over millions of years, nature has produced a wide variety of biological materials optimised for distinct functions, ranging from the extracellular matrix (ECM) for structural and biochemical support of cells to the holy lotus with special wettability for self-cleaning effects. Many of these systems found in biology possess unique surface properties recognised to regulate cell behaviour. Integration of such natural surface properties in biomaterials can bring about novel cell responses in vitro and provide greater insights into the processes occurring at the cell-biomaterial interface. Using natural surfaces as templates for bioinspired design can stimulate progress in the field of regenerative medicine, tissue engineering and biomaterials science. This literature review aims to combine the state-of-the-art knowledge in natural and nature-inspired surfaces, with an emphasis on material properties known to affect cell behaviour.
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Affiliation(s)
- Floris Honig
- Laboratory for Cell Biology-Inspired Tissue Engineering, MERLN Institute, University of Maastricht, 6229 ET Maastricht, The Netherlands; (F.H.); (S.V.)
| | - Steven Vermeulen
- Laboratory for Cell Biology-Inspired Tissue Engineering, MERLN Institute, University of Maastricht, 6229 ET Maastricht, The Netherlands; (F.H.); (S.V.)
- BioInterface Science Group, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
| | - Amir A. Zadpoor
- Biomaterials and Tissue Biomechanics Section, Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology, 2628 CD Delft, The Netherlands;
| | - Jan de Boer
- BioInterface Science Group, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
| | - Lidy E. Fratila-Apachitei
- Biomaterials and Tissue Biomechanics Section, Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology, 2628 CD Delft, The Netherlands;
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Yang L, Jurczak KM, Ge L, Rijn P. High-Throughput Screening and Hierarchical Topography-Mediated Neural Differentiation of Mesenchymal Stem Cells. Adv Healthc Mater 2020; 9:e2000117. [PMID: 32363812 DOI: 10.1002/adhm.202000117] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/27/2020] [Indexed: 12/12/2022]
Abstract
Biophysical factors such as anisotropic topography composed of micro/nanosized structures are important for directing the fate of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and have been applied to neuronal differentiation. Via high-throughput screening (HTS) methods based on topography gradients, the optimum topography is determined and translated toward a hierarchical architecture designed to mimic the nerve nano/microstructure. The polydimethylsiloxane (PDMS)-based topography gradient with amplitudes (A) from 541 to 3073 nm and wavelengths (W) between 4 and 30 µm is developed and the fate commitment of MSC toward neuron lineage is investigated. The hierarchical structures, combining nano- and microtopography (W0.3/W26 parallel/perpendicular) are fabricated to explore the combined topography effects on neuron differentiation. From the immunofluorescent staining results (Tuj1 and MAP2), the substrate characterized by W: 26 µm; A: 2.9 µm shows highest potential for promoting neurogenesis. Furthermore, the hierarchical features (W0.3/W26 parallel) significantly enhance neural differentiation. The hBM-MSCs on the hierarchical substrates exhibit a significantly lower percentage of nuclear Yes-associated protein (YAP)/TAZ and weaker cell contractility indicating that the promoted neurogenesis is mediated by the cell tension and YAP/TAZ pathway. This research provides new insight into designing biomaterials for applications in neural tissue engineering and contributes to the understanding of topography-mediated neuronal differentiation.
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Affiliation(s)
- Liangliang Yang
- Department of Biomedical Engineering University Medical Center GroningenUniversity of Groningen Groningen, A. Deusinglaan 1 Groningen 9713 AV The Netherlands
| | - Klaudia Malgorzata Jurczak
- Department of Biomedical Engineering University Medical Center GroningenUniversity of Groningen Groningen, A. Deusinglaan 1 Groningen 9713 AV The Netherlands
| | - Lu Ge
- Department of Biomedical Engineering University Medical Center GroningenUniversity of Groningen Groningen, A. Deusinglaan 1 Groningen 9713 AV The Netherlands
| | - Patrick Rijn
- Department of Biomedical Engineering University Medical Center GroningenUniversity of Groningen Groningen, A. Deusinglaan 1 Groningen 9713 AV The Netherlands
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30
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Vermeulen S, de Boer J. Screening as a strategy to drive regenerative medicine research. Methods 2020; 190:80-95. [PMID: 32278807 DOI: 10.1016/j.ymeth.2020.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/30/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
In the field of regenerative medicine, optimization of the parameters leading to a desirable outcome remains a huge challenge. Examples include protocols for the guided differentiation of pluripotent cells towards specialized and functional cell types, phenotypic maintenance of primary cells in cell culture, or engineering of materials for improved tissue interaction with medical implants. This challenge originates from the enormous design space for biomaterials, chemical and biochemical compounds, and incomplete knowledge of the guiding biological principles. To tackle this challenge, high-throughput platforms allow screening of multiple perturbations in one experimental setup. In this review, we provide an overview of screening platforms that are used in regenerative medicine. We discuss their fabrication techniques, and in silico tools to analyze the extensive data sets typically generated by these platforms.
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Affiliation(s)
- Steven Vermeulen
- Laboratory for Cell Biology-Inspired Tissue Engineering, MERLN Institute, University of Maastricht, Maastricht, the Netherlands; BioInterface Science Group, Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands
| | - Jan de Boer
- BioInterface Science Group, Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands.
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31
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Huethorst E, Cutiongco MF, Campbell FA, Saeed A, Love R, Reynolds PM, Dalby MJ, Gadegaard N. Customizable, engineered substrates for rapid screening of cellular cues. Biofabrication 2020; 12:025009. [PMID: 31783378 PMCID: PMC7655147 DOI: 10.1088/1758-5090/ab5d3f] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biophysical cues robustly direct cell responses and are thus important tools for
in vitro and translational biomedical applications. High
throughput platforms exploring substrates with varying physical properties are
therefore valuable. However, currently existing platforms are limited in
throughput, the biomaterials used, the capability to segregate between different
cues and the assessment of dynamic responses. Here we present a multiwell array
(3 × 8) made of a substrate engineered to present topography or rigidity cues
welded to a bottomless plate with a 96-well format. Both the patterns on the
engineered substrate and the well plate format can be easily customized,
permitting systematic and efficient screening of biophysical cues. To
demonstrate the broad range of possible biophysical cues examinable, we designed
and tested three multiwell arrays to influence cardiomyocyte, chondrocyte and
osteoblast function. Using the multiwell array, we were able to measure
different cell functionalities using analytical modalities such as live
microscopy, qPCR and immunofluorescence. We observed that grooves (5
μm in size) induced less variation in contractile function
of cardiomyocytes. Compared to unpatterned plastic, nanopillars with 127 nm
height, 100 nm diameter and 300 nm pitch enhanced matrix deposition,
chondrogenic gene expression and chondrogenic maintenance. High aspect ratio
pillars with an elastic shear modulus of 16 kPa mimicking the matrix found in
early stages of bone development improved osteogenic gene expression compared to
stiff plastic. We envisage that our bespoke multiwell array will accelerate the
discovery of relevant biophysical cues through improved throughput and
variety.
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Affiliation(s)
- Eline Huethorst
- Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, G12 8LT, United Kingdom. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom
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32
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Topography elicits distinct phenotypes and functions in human primary and stem cell derived endothelial cells. Biomaterials 2020; 234:119747. [PMID: 31951971 DOI: 10.1016/j.biomaterials.2019.119747] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 11/25/2019] [Accepted: 12/25/2019] [Indexed: 12/20/2022]
Abstract
The effective deployment of arterial (AECs), venous (VECs) and stem cell-derived endothelial cells (PSC-ECs) in clinical applications requires understanding of their distinctive phenotypic and functional characteristics, including their responses to microenvironmental cues. Efforts to mimic the in-vivo vascular basement membrane milieu have led to the design and fabrication of nano- and micro-topographical substrates. Although the basement membrane architectures of arteries and veins are different, investigations into the effects of substrate topographies have so far focused on generic EC characteristics. Thus, topographical modulation of arterial- or venous-specific EC phenotype and function remains unknown. Here, we comprehensively evaluated the effects of 16 unique topographies on primary AECs, VECs and human PSC-ECs using a Multi Architectural (MARC) Chip. Gratings and micro-lenses augmented venous-specific phenotypes and depressed arterial functions in VECs; while AECs did not respond consistently to topography. PSC-ECs exhibited phenotypic and functional maturation towards an arterial subtype with increased angiogenic potential, NOTCH1 and Ac-LDL expression on gratings. Specific topographies could elicit different phenotypic and functional changes, despite similar morphological response in different ECs, demonstrating no direct correlation between the two responses.
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33
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Jain D, Mattiassi S, Goh EL, Yim EKF. Extracellular matrix and biomimetic engineering microenvironment for neuronal differentiation. Neural Regen Res 2020; 15:573-585. [PMID: 31638079 PMCID: PMC6975142 DOI: 10.4103/1673-5374.266907] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Extracellular matrix (ECM) influences cell differentiation through its structural and biochemical properties. In nervous system, neuronal behavior is influenced by these ECMs structures which are present in a meshwork, fibrous, or tubular forms encompassing specific molecular compositions. In addition to contact guidance, ECM composition and structures also exert its effect on neuronal differentiation. This short report reviewed the native ECM structure and composition in central nervous system and peripheral nervous system, and their impact on neural regeneration and neuronal differentiation. Using topographies, stem cells have been differentiated to neurons. Further, focussing on engineered biomimicking topographies, we highlighted the role of anisotropic topographies in stem cell differentiation to neurons and its recent temporal application for efficient neuronal differentiation.
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Affiliation(s)
- Deepak Jain
- Department of Chemical Engineering, University of Waterloo, Waterloo, Ontario, Canada
| | - Sabrina Mattiassi
- Department of Chemical Engineering, University of Waterloo, Waterloo, Ontario, Canada
| | - Eyleen L Goh
- Neuroscience Academic Clinical Programme, Duke-NUS Medical School, Singapore
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, Waterloo, Ontario, Canada
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34
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Zhang S, Sun P, Lin K, Chan FHL, Gao Q, Lau WF, Roy VAL, Zhang H, Lai KWC, Huang Z, Yung KKL. Extracellular Nanomatrix-Induced Self-Organization of Neural Stem Cells into Miniature Substantia Nigra-Like Structures with Therapeutic Effects on Parkinsonian Rats. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1901822. [PMID: 31871862 PMCID: PMC6918115 DOI: 10.1002/advs.201901822] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/29/2019] [Indexed: 05/14/2023]
Abstract
Substantia nigra (SN) is a complex and critical region of the brain wherein Parkinson's disease (PD) arises from the degeneration of dopaminergic neurons. Miniature SN-like structures (mini-SNLSs) constructed from novel combination of nanomaterials and cell technologies exhibit promise as potentially curative cell therapies for PD. In this work, a rapid self-organization of mini-SNLS, with an organizational structure and neuronal identities similar to those of the SN in vivo, is achieved by differentiating neural stem cells in vitro on biocompatible silica nanozigzags (NZs) sculptured by glancing angle deposition, without traditional chemical growth factors. The differentiated neurons exhibit electrophysiological activity in vitro. Diverse physical cues and signaling pathways that are determined by the nanomatrices and lead to the self-organization of the mini-SNLSs are clarified and elucidated. In vivo, transplantation of the neurons from a mini-SNLS results in an early and progressive amelioration of PD in rats. The sculptured medical device reported here enables the rapid and specific self-organization of region-specific and functional brain-like structures without an undesirable prognosis. This development provides promising and significant insights into the screening of potentially curative drugs and cell therapies for PD.
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Affiliation(s)
- Shiqing Zhang
- Department of BiologyHong Kong Baptist University (HKBU)Kowloon TongKowloonHong Kong SAR China
- Golden Meditech Center for NeuroRegeneration SciencesHKBUKowloon TongKowloonHong Kong SAR China
- HKBU Institute of Research and Continuing Education, 9FThe Industrialization Complex of Shenzhen Virtual University ParkNo. 2 Yuexing 3rd Road, South Zone, Hi‐tech Industrial Park, Nanshan DistrictShenzhen518057Guangdong ProvinceChina
| | - Peng Sun
- Department of PhysicsHKBUKowloon TongKowloonHong Kong SAR China
- Department of Materials Science and EngineeringSouthern University of Science and TechnologyShenzhen518000Guangdong ProvinceChina
| | - Kaili Lin
- Department of BiologyHong Kong Baptist University (HKBU)Kowloon TongKowloonHong Kong SAR China
- Golden Meditech Center for NeuroRegeneration SciencesHKBUKowloon TongKowloonHong Kong SAR China
| | - Florence Hiu Ling Chan
- Department of Biomedical EngineeringCity University of Hong Kong (CityU)Tat Chee Avenue, Kowloon TongKowloonHong Kong SAR China
| | - Qi Gao
- Department of Biomedical EngineeringCity University of Hong Kong (CityU)Tat Chee Avenue, Kowloon TongKowloonHong Kong SAR China
| | - Wai Fung Lau
- Department of PhysicsHKBUKowloon TongKowloonHong Kong SAR China
| | - Vellaisamy A. L. Roy
- Department of Materials Science and EngineeringCity University of Hong KongTat Chee Avenue, Kowloon TongKowloonHong Kong SAR China
| | - Hongqi Zhang
- School of Chinese MedicineHKBUKowloon TongKowloonHong Kong SAR China
| | - King Wai Chiu Lai
- Department of Biomedical EngineeringCity University of Hong Kong (CityU)Tat Chee Avenue, Kowloon TongKowloonHong Kong SAR China
| | - Zhifeng Huang
- Golden Meditech Center for NeuroRegeneration SciencesHKBUKowloon TongKowloonHong Kong SAR China
- HKBU Institute of Research and Continuing Education, 9FThe Industrialization Complex of Shenzhen Virtual University ParkNo. 2 Yuexing 3rd Road, South Zone, Hi‐tech Industrial Park, Nanshan DistrictShenzhen518057Guangdong ProvinceChina
- Department of PhysicsHKBUKowloon TongKowloonHong Kong SAR China
- Institute of Advanced MaterialsState Key Laboratory of Environmental and Biological AnalysisHKBUKowloon TongKowloonHong Kong SAR China
| | - Ken Kin Lam Yung
- Department of BiologyHong Kong Baptist University (HKBU)Kowloon TongKowloonHong Kong SAR China
- Golden Meditech Center for NeuroRegeneration SciencesHKBUKowloon TongKowloonHong Kong SAR China
- HKBU Institute of Research and Continuing Education, 9FThe Industrialization Complex of Shenzhen Virtual University ParkNo. 2 Yuexing 3rd Road, South Zone, Hi‐tech Industrial Park, Nanshan DistrictShenzhen518057Guangdong ProvinceChina
- Institute of Advanced MaterialsState Key Laboratory of Environmental and Biological AnalysisHKBUKowloon TongKowloonHong Kong SAR China
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35
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Zhou N, Li Y, Loveland CH, Wilson MJ, Cao B, Qiu P, Yang M, Mao C. Hierarchical Ordered Assembly of Genetically Modifiable Viruses into Nanoridge-in-Microridge Structures. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1905577. [PMID: 31736175 PMCID: PMC7055689 DOI: 10.1002/adma.201905577] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/13/2019] [Indexed: 05/22/2023]
Abstract
Hierarchically assembled nanomaterials can find a variety of applications in medicine, energy, and electronics. Here, an automatically controlled dip-pulling method is developed and optimized to generate an unprecedented ordered nano-to-micro hierarchical nanoridge-in-microridge (NiM) structure from a bacteria-specific human-safe virus, the filamentous phage with or without genetically displaying a foreign peptide. The NiM structure is pictured as a window blind with each lath (the microridge) made of parallel phage bundles (the nanoridges). It is independent of the substrate materials supporting it. Surprisingly, it can induce the bidirectional differentiation of stem cells into neurons and astrocytes within a short timeframe (only 8 d) not seen before, which is highly desired because both neurons and astrocytes are needed simultaneously in treating neurodegenerative diseases. Since phages can direct tissue regeneration, template materials formation, sense molecules, and build electrodes, the NiM structures displaying different peptides and on varying materials hold promise in many technologically important fields.
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Affiliation(s)
- Ningyun Zhou
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Yan Li
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Christian H Loveland
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Megan J Wilson
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Binrui Cao
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Penghe Qiu
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
| | - Mingying Yang
- Institute of Applied Bioresource Research, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, 310058, P. R. China
| | - Chuanbin Mao
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA
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Wang Z, Zhang L, Labib M, Chen H, Wei M, Poudineh M, Green BJ, Duong B, Das J, Ahmed S, Sargent EH, Kelley SO. Peptide-Functionalized Nanostructured Microarchitectures Enable Rapid Mechanotransductive Differentiation. ACS APPLIED MATERIALS & INTERFACES 2019; 11:41030-41037. [PMID: 31600052 DOI: 10.1021/acsami.9b13694] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Microenvironmental factors play critical roles in regulating stem cell fate, providing a rationale to engineer biomimetic microenvironments that facilitate rapid and effective stem cell differentiation. Three-dimensional (3D) hierarchical microarchitectures have been developed to enable rapid neural differentiation of multipotent human mesenchymal stromal cells (HMSCs) via mechanotransduction. However, low cell viability during long-term culture and poor cell recovery efficiency from the architectures were also observed. Such problems hinder further applications of the architectures in stem cell differentiation. Here, we present improved 3D nanostructured microarchitectures functionalized with cell-adhesion-promoting arginylglycylaspartic acid (RGD) peptides. These RGD-functionalized architectures significantly upregulated long-term cell viability and facilitated effective recovery of differentiated cells from the architectures while maintaining high differentiation efficiency. Efficient recovery of highly viable differentiated cells enabled the downstream analysis of morphology and protein expression to be performed. Remarkably, even after the removal of the mechanical stimulus provided by the 3D microarchitectures, the recovered HMSCs showed a neuron-like elongated morphology for 10 days and consistently expressed microtubule-associated protein 2, a mature neural marker. RGD-functionalized nanostructured microarchitectures hold great potential to guide effective differentiation of highly viable stem cells.
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Affiliation(s)
- Zongjie Wang
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
| | - Libing Zhang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Haijie Chen
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Mingyang Wei
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Mahla Poudineh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Brenda J Green
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
| | - Bill Duong
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto M5S 1A8 , Canada
| | - Jagotamoy Das
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Sharif Ahmed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Edward H Sargent
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Shana O Kelley
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto M5S 1A8 , Canada
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37
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der Boon TAB, Yang L, Li L, Córdova Galván DE, Zhou Q, Boer J, Rijn P. Well Plate Integrated Topography Gradient Screening Technology for Studying Cell‐Surface Topography Interactions. ACTA ACUST UNITED AC 2019; 4:e1900218. [DOI: 10.1002/adbi.201900218] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/02/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Torben A. B. der Boon
- W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical EngineeringUniversity Medical Center GroningenUniversity of Groningen A. Deusinglaan 1 9713 AV Groningen the Netherlands
| | - Liangliang Yang
- W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical EngineeringUniversity Medical Center GroningenUniversity of Groningen A. Deusinglaan 1 9713 AV Groningen the Netherlands
| | - Linfeng Li
- Merln Institue for Technology‐inspired Regenerative MedicineMaastricht University Universiteitssingel 40 6229 ER Maastricht the Netherlands
| | - Daniel E. Córdova Galván
- W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical EngineeringUniversity Medical Center GroningenUniversity of Groningen A. Deusinglaan 1 9713 AV Groningen the Netherlands
| | - Qihui Zhou
- W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical EngineeringUniversity Medical Center GroningenUniversity of Groningen A. Deusinglaan 1 9713 AV Groningen the Netherlands
- Institute for Translational Medicine State Key Laboratory of Bio‐fibers and Eco‐textilesQingdao University Qingdao 266021 China
| | - Jan Boer
- Department of Biomedical EngineeringEindhoven University of Technology De Zaale 5600 MB Eindhoven the Netherlands
| | - Patrick Rijn
- W.J. Kolff Institute for Biomedical Engineering and Materials Science Department of Biomedical EngineeringUniversity Medical Center GroningenUniversity of Groningen A. Deusinglaan 1 9713 AV Groningen the Netherlands
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38
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Chua ME, Farhat WA, Ming JM, McCammon KA. Review of clinical experience on biomaterials and tissue engineering of urinary bladder. World J Urol 2019; 38:2081-2093. [PMID: 31222507 DOI: 10.1007/s00345-019-02833-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
PURPOSE In recent pre-clinical studies, biomaterials and bladder tissue engineering have shown promising outcomes when addressing the need for bladder tissue replacement. To date, multiple clinical experiences have been reported. Herein, we aim to review and summarize the reported clinical experience of biomaterial usage and tissue engineering of the urinary bladder. METHODS A systematic literature search was performed on Feb 2019 to identify clinical reports on biomaterials for urinary bladder replacement or augmentation and clinical experiences with bladder tissue engineering. We identified and reviewed human studies using biomaterials and tissue-engineered bladder as bladder substitutes or augmentation implants. The studies were then summarized for each respective procedure indication, technique, follow-up period, outcome, and important findings of the studies. RESULTS An extensive literature search identified 25 studies of case reports and case series with a cumulative clinical experience of 222 patients. Various biomaterials and tissue-engineered bladder were used, including plastic/polyethylene mold, preserved dog bladder, gelatine sponge, Japanese paper with Nobecutane, lypholized human dura, bovine pericardium, amniotic membrane, small intestinal mucosa, and bladder tissue engineering with autologous cell-seeded biodegradable scaffolds. However, overall clinical experiences including the outcomes and safety reports were not satisfactory enough to replace enterocystoplasty. CONCLUSION To date, several clinical experiences of biomaterials and tissue-engineered bladder have been reported; however, various studies have reported non-satisfactory outcomes. Further technological advancements and a better understanding is needed to advance bladder tissue engineering as a future promising management option for patients requiring bladder drainage.
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Affiliation(s)
- Michael E Chua
- Eastern Virginia Medical School, Norfolk, VA, USA.,St. Luke's Medical Center, Quezon City, NCR, Philippines
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39
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Arora S, Yim EKF, Toh YC. Environmental Specification of Pluripotent Stem Cell Derived Endothelial Cells Toward Arterial and Venous Subtypes. Front Bioeng Biotechnol 2019; 7:143. [PMID: 31259171 PMCID: PMC6587665 DOI: 10.3389/fbioe.2019.00143] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/28/2019] [Indexed: 12/25/2022] Open
Abstract
Endothelial cells (ECs) are required for a multitude of cardiovascular clinical applications, such as revascularization of ischemic tissues or endothelialization of tissue engineered grafts. Patient derived primary ECs are limited in number, have donor variabilities and their in vitro phenotypes and functions can deteriorate over time. This necessitates the exploration of alternative EC sources. Although there has been a recent surge in the use of pluripotent stem cell derived endothelial cells (PSC-ECs) for various cardiovascular clinical applications, current differentiation protocols yield a heterogeneous EC population, where their specification into arterial or venous subtypes is undefined. Since arterial and venous ECs are phenotypically and functionally different, inappropriate matching of exogenous ECs to host sites can potentially affect clinical efficacy, as exemplified by venous graft mismatch when placed into an arterial environment. Therefore, there is a need to design and employ environmental cues that can effectively modulate PSC-ECs into a more homogeneous arterial or venous phenotype for better adaptation to the host environment, which will in turn contribute to better application efficacy. In this review, we will first give an overview of the developmental and functional differences between arterial and venous ECs. This provides the foundation for our subsequent discussion on the different bioengineering strategies that have been investigated to varying extent in providing biochemical and biophysical environmental cues to mature PSC-ECs into arterial or venous subtypes. The ability to efficiently leverage on a combination of biochemical and biophysical environmental cues to modulate intrinsic arterio-venous specification programs in ECs will greatly facilitate future translational applications of PSC-ECs. Since the development and maintenance of arterial and venous ECs in vivo occur in disparate physio-chemical microenvironments, it is conceivable that the application of these environmental factors in customized combinations or magnitudes can be used to selectively mature PSC-ECs into an arterial or venous subtype.
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Affiliation(s)
- Seep Arora
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.,Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, Singapore, Singapore
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, Waterloo, ON, Canada
| | - Yi-Chin Toh
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.,Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, Singapore, Singapore.,Biomedical Institute for Global Health Research and Technology (BIGHEART), National University of Singapore, Singapore, Singapore.,NUS Tissue Engineering Program, National University of Singapore, Singapore, Singapore
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40
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Grenci G, Bertocchi C, Ravasio A. Integrating Microfabrication into Biological Investigations: the Benefits of Interdisciplinarity. MICROMACHINES 2019; 10:E252. [PMID: 30995747 PMCID: PMC6523848 DOI: 10.3390/mi10040252] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/08/2019] [Accepted: 04/13/2019] [Indexed: 12/14/2022]
Abstract
The advent of micro and nanotechnologies, such as microfabrication, have impacted scientific research and contributed to meaningful real-world applications, to a degree seen during historic technological revolutions. Some key areas benefitting from the invention and advancement of microfabrication platforms are those of biological and biomedical sciences. Modern therapeutic approaches, involving point-of-care, precision or personalized medicine, are transitioning from the experimental phase to becoming the standard of care. At the same time, biological research benefits from the contribution of microfluidics at every level from single cell to tissue engineering and organoids studies. The aim of this commentary is to describe, through proven examples, the interdisciplinary process used to develop novel biological technologies and to emphasize the role of technical knowledge in empowering researchers who are specialized in a niche area to look beyond and innovate.
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Affiliation(s)
- Gianluca Grenci
- Mechanobiology Institute (MBI), National University of Singapore, Singapore 117411, Singapore.
- Biomedical Engineering Department, National University of Singapore, Singapore 117583, Singapore.
| | - Cristina Bertocchi
- Department of Physiology, School of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile.
| | - Andrea Ravasio
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
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41
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Wilems T, Vardhan S, Wu S, Sakiyama-Elbert S. The influence of microenvironment and extracellular matrix molecules in driving neural stem cell fate within biomaterials. Brain Res Bull 2019; 148:25-33. [PMID: 30898579 DOI: 10.1016/j.brainresbull.2019.03.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/07/2019] [Accepted: 03/12/2019] [Indexed: 12/17/2022]
Abstract
Transplantation of stem cells is a promising potential therapy for central nervous system disease and injury. The capacity for self-renewal, proliferation of progenitor cells, and multi-lineage potential underscores the need for controlling stem cell fate. Furthermore, transplantation within a hostile environment can lead to significant cell death and limited therapeutic potential. Tissue-engineered materials have been developed to both regulate stem cell fate, increase transplanted cell viability, and improve therapeutic outcomes. Traditionally, regulation of stem cell differentiation has been driven through soluble signals, such as growth factors. While these signals are important, insoluble factors from the local microenvironment or extracellular matrix (ECM) molecules also contribute to stem cell activity and fate. Understanding the microenvironment factors that influence stem cell fate, such as mechanical properties, topography, and presentation of specific ECM ligands, is necessary for designing improved biomaterials. Here we review some of the microenvironment factors that regulate stem cell fate and how they can be incorporated into biomaterials as part of potential CNS therapies.
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Affiliation(s)
- Thomas Wilems
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, 78712, USA
| | - Sangamithra Vardhan
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, 78712, USA
| | - Siliang Wu
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, 78712, USA
| | - Shelly Sakiyama-Elbert
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, 78712, USA.
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42
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Baranes K, Hibsh D, Cohen S, Yamin T, Efroni S, Sharoni A, Shefi O. Comparing Transcriptome Profiles of Neurons Interfacing Adjacent Cells and Nanopatterned Substrates Reveals Fundamental Neuronal Interactions. NANO LETTERS 2019; 19:1451-1459. [PMID: 30704243 DOI: 10.1021/acs.nanolett.8b03879] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Developing neuronal axons are directed by chemical and physical signals toward a myriad of target cells. According to current dogma, the resulting network architecture is critically shaped by electrical interconnections, the synapses; however, key mechanisms translating neuronal interactions into neuronal growth behavior during network formation are still unresolved. To elucidate these mechanisms, we examined neurons interfacing nanopatterned substrates and compared them to natural interneuron interactions. We grew similar neuronal populations under three connectivity conditions, (1) the neurons are isolated, (2) the neurons are interconnected, and (3) the neurons are connected only to artificial substrates, then quantitatively compared both the cell morphologies and the transcriptome-expression profiles. Our analysis shows that whereas axon-guidance signaling pathways in isolated neurons are predominant, in isolated neurons interfacing nanotopography, these pathways are downregulated, similar to the interconnected neurons. Moreover, in nanotopography, interfacing neuron genes related to synaptogenesis and synaptic regulation are highly expressed, that is, again resembling the behavior of interconnected neurons. These molecular findings demonstrate that interactions with nanotopographies, although not leading to electrical coupling, play a comparable functional role in two major routes, neuronal guidance and network formation, with high relevance to the design of regenerative interfaces.
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Affiliation(s)
- Koby Baranes
- Faculty of Engineering , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Dror Hibsh
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Faculty of Life Sciences , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Sharon Cohen
- Faculty of Engineering , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Gonda Multidisciplinary Brain Research Center , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Tony Yamin
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Department of Physics , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Sol Efroni
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Faculty of Life Sciences , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Amos Sharoni
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Department of Physics , Bar-Ilan University , Ramat-Gan 5290002 , Israel
| | - Orit Shefi
- Faculty of Engineering , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials , Bar-Ilan University , Ramat-Gan 5290002 , Israel
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Onesto V, Villani M, Narducci R, Malara N, Imbrogno A, Allione M, Costa N, Coppedè N, Zappettini A, Cannistraci CV, Cancedda L, Amato F, Di Fabrizio E, Gentile F. Cortical-like mini-columns of neuronal cells on zinc oxide nanowire surfaces. Sci Rep 2019; 9:4021. [PMID: 30858456 PMCID: PMC6411964 DOI: 10.1038/s41598-019-40548-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 02/18/2019] [Indexed: 11/25/2022] Open
Abstract
A long-standing goal of neuroscience is a theory that explains the formation of the minicolumns in the cerebral cortex. Minicolumns are the elementary computational units of the mature neocortex. Here, we use zinc oxide nanowires with controlled topography as substrates for neural-cell growth. We observe that neuronal cells form networks where the networks characteristics exhibit a high sensitivity to the topography of the nanowires. For certain values of nanowires density and fractal dimension, neuronal networks express small world attributes, with enhanced information flows. We observe that neurons in these networks congregate in superclusters of approximately 200 neurons. We demonstrate that this number is not coincidental: the maximum number of cells in a supercluster is limited by the competition between the binding energy between cells, adhesion to the substrate, and the kinetic energy of the system. Since cortical minicolumns have similar size, similar anatomical and topological characteristics of neuronal superclusters on nanowires surfaces, we conjecture that the formation of cortical minicolumns is likewise guided by the interplay between energy minimization, information optimization and topology. For the first time, we provide a clear account of the mechanisms of formation of the minicolumns in the brain.
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Affiliation(s)
- V Onesto
- Center for Advanced Biomaterials for HealthCare, Istituto Italiano di Tecnologia, 80125, Naples, Italy
- Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100, Catanzaro, Italy
| | - M Villani
- IMEM-CNR Parco Area delle Scienze 37/A, 43124, Parma, Italy
| | - R Narducci
- Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy
| | - N Malara
- Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100, Catanzaro, Italy
| | - A Imbrogno
- Tyndall National Institute, Cork, T12 R5CP, Ireland
| | - M Allione
- PSE division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia
| | - N Costa
- Health Department, University of Magna Graecia, 88100, Catanzaro, Italy
| | - N Coppedè
- IMEM-CNR Parco Area delle Scienze 37/A, 43124, Parma, Italy
| | - A Zappettini
- IMEM-CNR Parco Area delle Scienze 37/A, 43124, Parma, Italy
| | - C V Cannistraci
- Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Center for Systems Biology Dresden (CSBD), Department of Physics, Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany
- Brain Bio-Inspired Computing (BBC) Lab, IRCCS Centro Neurolesi "Bonino Pulejo", Messina, 98124, Italy
| | - L Cancedda
- Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy
- Dulbecco Telethon Institute, Rome, Italy
| | - F Amato
- Department of Electrical Engineering and Information Technology, University Federico II, Naples, Italy
| | - Enzo Di Fabrizio
- PSE division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia
| | - F Gentile
- Department of Electrical Engineering and Information Technology, University Federico II, Naples, Italy.
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44
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Yang SS, Cha J, Cho SW, Kim P. Time-Dependent Retention of Nanotopographical Cues in Differentiated Neural Stem Cells. ACS Biomater Sci Eng 2019; 5:3802-3807. [DOI: 10.1021/acsbiomaterials.8b01057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Seungwon S. Yang
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea
| | - Junghwa Cha
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea
- KAIST Institute for Health Science and Technology, Daejeon 34141, Korea
| | - Seung-Woo Cho
- Department of Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Pilnam Kim
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea
- KAIST Institute for Health Science and Technology, Daejeon 34141, Korea
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45
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Brusatin G, Panciera T, Gandin A, Citron A, Piccolo S. Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour. NATURE MATERIALS 2018; 17:1063-1075. [PMID: 30374202 PMCID: PMC6992423 DOI: 10.1038/s41563-018-0180-8] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/29/2018] [Indexed: 05/11/2023]
Abstract
Mechanical signals are increasingly recognized as overarching regulators of cell behaviour, controlling stemness, organoid biology, tissue development and regeneration. Moreover, aberrant mechanotransduction is a driver of disease, including cancer, fibrosis and cardiovascular defects. A central question remains how cells compute a host of biomechanical signals into meaningful biological behaviours. Biomaterials and microfabrication technologies are essential to address this issue. Here we review a large body of evidence that connects diverse biomaterial-based systems to the functions of YAP/TAZ, two highly related mechanosensitive transcriptional regulators. YAP/TAZ orchestrate the response to a suite of engineered microenviroments, emerging as a universal control system for cells in two and three dimensions, in static or dynamic fashions, over a range of elastic and viscoelastic stimuli, from solid to fluid states. This approach may guide the rational design of technological and material-based platforms with dramatically improved functionalities and inform the generation of new biomaterials for regenerative medicine applications.
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Affiliation(s)
- Giovanna Brusatin
- Department of Industrial Engineering (DII) and INSTM, University of Padua, Padua, Italy
| | - Tito Panciera
- Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy
| | - Alessandro Gandin
- Department of Industrial Engineering (DII) and INSTM, University of Padua, Padua, Italy
- Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy
| | - Anna Citron
- Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy
| | - Stefano Piccolo
- Department of Molecular Medicine (DMM), University of Padua School of Medicine, Padua, Italy.
- IFOM-the FIRC Institute of Molecular Oncology, .
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46
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Poudineh M, Wang Z, Labib M, Ahmadi M, Zhang L, Das J, Ahmed S, Angers S, Kelley SO. Three-Dimensional Nanostructured Architectures Enable Efficient Neural Differentiation of Mesenchymal Stem Cells via Mechanotransduction. NANO LETTERS 2018; 18:7188-7193. [PMID: 30335391 DOI: 10.1021/acs.nanolett.8b03313] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Cell morphology and geometry affect cellular processes such as stem cell differentiation, suggesting that these parameters serve as fundamental regulators of biological processes within the cell. Hierarchical architectures featuring micro- and nanotopographical features therefore offer programmable systems for stem cell differentiation. However, a limited number of studies have explored the effects of hierarchical architectures due to the complexity of fabricating systems with rationally tunable micro- and nanostructuring. Here, we report three-dimensional (3D) nanostructured microarchitectures that efficiently regulate the fate of human mesenchymal stem cells (hMSCs). These nanostructured architectures strongly promote cell alignment and efficient neurogenic differentiation where over 85% of hMSCs express microtubule-associated protein 2 (MAP2), a mature neural marker, after 7 days of culture on the nanostructured surface. Remarkably, we found that the surface morphology of nanostructured surface is a key factor that promotes neurogenesis and that highly spiky structures promote more efficient neuronal differentiation. Immunostaining and gene expression profiling revealed significant upregulation of neuronal markers compared to unpatterned surfaces. These findings suggest that the 3D nanostructured microarchitectures can play a critical role in defining stem cell behavior.
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Affiliation(s)
- Mahla Poudineh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Zongjie Wang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Moloud Ahmadi
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Libing Zhang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Jagotamoy Das
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Sharif Ahmed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Stephane Angers
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Shana O Kelley
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto , M5S 3M2 , Canada
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto , M5S 1A8 , Canada
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47
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Sthanam LK, Saxena N, Mistari VK, Roy T, Jadhav SR, Sen S. Initial Priming on Soft Substrates Enhances Subsequent Topography-Induced Neuronal Differentiation in ESCs but Not in MSCs. ACS Biomater Sci Eng 2018; 5:180-192. [PMID: 33405870 DOI: 10.1021/acsbiomaterials.8b00313] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Differentiation of stem cells into neurogenic lineage is of great interest for treatment of neurodegenerative diseases. While the role of chemical cues in regulating stem cell fate is well appreciated, the identification of physical cues has revolutionized the field of tissue engineering leading to development of scaffolds encoding one or more physical cues for inducing stem cell differentiation. In this study, using human mesenchymal stem cells (hMSCs) and mouse embryonic stem cells (mESCs), we have tested if stiffness and topography can be collectively tuned for inducing neuronal differentiation by culturing these cells on polyacrylamide hydrogels of varying stiffness (5, 10, and 20 kPa) containing rectangular grooves (10, 15, and 25 μm in width). While hMSCs maximally elongate and express neuronal markers on soft 5 kPa gels containing 10/15 μm grooves, single mESCs are unable to sense topographical features when cultured directly on grooved gels. However, this inability to sense topography is rescued by priming mESCs initially on soft 1 kPa flat gels and then replating these cells onto the grooved gels. Compared to direct culture on the grooved gels, this sequential adaptation increases both viability as well as neuronal differentiation. However, this two-step process does not enhance neuronal marker expression in hMSCs. In addition to highlighting important differences between hMSCs and mESCs in their responsiveness to physical cues, our study suggests that conditioning on soft substrates is essential for inducing topography-mediated neuronal differentiation in mESCs.
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Abstract
The blood-brain barrier (BBB) plays a vital role in the maintenance of brain homeostasis. It strictly restricts the passage of molecules from the brain vasculature into the brain via its high transendothelial electrical resistance and low paracellular and transcellular permeability. Specialized brain endothelial cells, astrocytes, pericytes, neurons, and microglia contribute synergistically to the functional properties of the BBB. Because of its complexity and relative inaccessibility, BBB research is fraught with difficulties. Most studies rely on animal or cell culture models, which are not able to fully recapitulate the properties of the human BBB. The recent development of three-dimensional (3D) microfluidic models of the BBB could address this issue. This chapter aims to provide an overview of the recent advances in modeling the BBB on microdevices, and illustrate important considerations for the design of such models. In addition, protocols for the fabrication of a 3D BBB microfluidic chip and BBB assessment experiments, including immunocytochemistry for analyzing cell morphology and protein marker expression, permeability assay, and calcium imaging for studying neuronal function as a measure of BBB integrity, are presented here. It is envisioned that continued advancements in microtechnology can lead to the creation of realistic in vivo-like BBB-on-chip models.
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Affiliation(s)
- Eunice Chin
- Neuroscience Academic Clinical Programme, Duke-NUS Medical School, Singapore
| | - Eyleen Goh
- Neuroscience Academic Clinical Programme, Duke-NUS Medical School, Singapore; Department of Research, National Neuroscience Institute, Singapore.
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49
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Sequential Application of Discrete Topographical Patterns Enhances Derivation of Functional Mesencephalic Dopaminergic Neurons from Human Induced Pluripotent Stem Cells. Sci Rep 2018; 8:9567. [PMID: 29934644 PMCID: PMC6014983 DOI: 10.1038/s41598-018-27653-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 06/04/2018] [Indexed: 01/07/2023] Open
Abstract
Parkinson’s Disease is a progressive neurodegenerative disorder attributed to death of mesencephalic dopaminergic (DA) neurons. Pluripotent stem cells have great potential in the study for this late-onset disease, but acquirement of cells that are robust in quantity and quality is still technically demanding. Biophysical cues have been shown to direct stem cell fate, but the effect of different topographies in the lineage commitment and subsequent maturation stages of cells have been less examined. Using human induced pluripotent stem cells (iPSCs), we applied topographical patterns sequentially during differentiation stages and examined their ability to influence derivation yield and functionality of regionalized subtype-specific DA neurons. Gratings showed higher yield of DA neurons and may be beneficial for initial lineage commitment. Cells derived on pillars in the terminal differentiation stage have increased neuronal complexity, and were more capable of firing repetitive action potentials, showing that pillars yielded better network formation and functionality. Our topography platform can be applied to patient-derived iPSCs as well, and that cells harbouring LRRK2 mutation were more functionally mature when optimal topographies were applied sequentially. This will hopefully accelerate development of robust cell models that will provide novel insights into discovering new therapeutic approaches for Parkinson’s Disease.
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50
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Affiliation(s)
- Parthiv Kant Chaudhuri
- Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Level 9, Singapore 117411, Singapore
- Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
| | - Boon Chuan Low
- Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Level 9, Singapore 117411, Singapore
- Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore
- University Scholars Programme, National University of Singapore, Singapore 138593, Singapore
| | - Chwee Teck Lim
- Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Level 9, Singapore 117411, Singapore
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore
- Biomedical Institute for Global Health Research and Technology (BIGHEART), National University of Singapore, Singapore 117599, Singapore
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