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Huang R, Gao F, Yu L, Chen H, Zhu R. Generation of Neural Organoids and Their Application in Disease Modeling and Regenerative Medicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e01198. [PMID: 40411400 DOI: 10.1002/advs.202501198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/17/2025] [Indexed: 05/26/2025]
Abstract
The complexity and precision of the human nervous system have posed significant challenges for researchers seeking suitable models to elucidate refractory neural disorders. Traditional approaches, including monolayer cell cultures and animal models, often fail to replicate the intricacies of human neural tissue. The advent of organoid technology derived from stem cells has addressed many of these limitations, providing highly representative platforms for studying the structure and function of the human embryonic brain and spinal cord. Researchers have induced neural organoids with regional characteristics by mimicking morphogen gradients in neural development. Recent advancements have demonstrated the utility of neural organoids in disease modeling, offering insights into the pathophysiology of various neural disorders, as well as in the field of neural regeneration. Developmental defects in neural organoids due to the lack of microglia or vascular systems are addressed. In addition to induction methods, microfluidics is used to simulate the dynamic physiological environment; bio-manufacturing technologies are employed to regulate physical signaling and shape the structure of complex organs. These technologies further expand the construction strategies and application scope of neural organoids. With the emergence of new material paradigms and advances in AI, new possibilities in the realm of neural organoids are witnessed.
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Affiliation(s)
- Ruiqi Huang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, 200065, China
- Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, 200065, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China
| | - Feng Gao
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, 200065, China
- Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, 200065, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China
| | - Liqun Yu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, 200065, China
- Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, 200065, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China
| | - Haokun Chen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, 200065, China
- Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, 200065, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China
| | - Rongrong Zhu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, School of Life Science and Technology, Tongji University, Shanghai, 200065, China
- Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, 200065, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China
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Vetter J, Palagi I, Waisman A, Blaeser A. Recent advances in blood-brain barrier-on-a-chip models. Acta Biomater 2025; 197:1-28. [PMID: 40127880 DOI: 10.1016/j.actbio.2025.03.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/19/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
The blood-brain barrier is a physiological barrier between the vascular system and the nervous system. Under healthy conditions, it restricts the passage of most biomolecules into the brain, making drug development exceedingly challenging. Conventional cell-based in vitro models provide valuable insights into certain features of the BBB. Nevertheless, these models often lack the three-dimensional structure and dynamic interactions of the surrounding microenvironment, which greatly influence cell functionality. Consequently, considerable efforts have been made to enhance in vitro models for drug development and disease research. Recently, microfluidic organ-on-a-chip systems have emerged as promising candidates to better mimic the dynamic nature of the BBB. This review provides a comprehensive overview of recent BBB-on-chip devices. The typical building blocks, chip designs, the perfusion infrastructure, and readouts used to characterize and evaluate BBB formation are presented, analyzed, and discussed in detail. STATEMENT OF SIGNIFICANCE: The blood-brain barrier (BBB) is a highly selective barrier that controls what can enter the brain. While it protects the brain from harmful substances, it also hinders the delivery of treatments for neurological diseases such as Alzheimer's and Parkinson's. Due to its complexity, studying the BBB in living organisms remains difficult. However, recent advances in "organ-on-a-chip" technology have allowed scientists to create small, engineered models that replicate the BBB. These models provide a powerful platform to study diseases and test potential drugs with greater accuracy than traditional methods. Organ-on-a-chip devices are designed to mimic the behavior of organs or tissues in the human body, offering a more realistic and controlled environment for research. This review highlights recent breakthroughs in BBB-on-a-chip technology, showing how these models enhance current research and have the potential to transform the way we study brain diseases and develop new drugs. By integrating biology and engineering, BBB-on-a-chip technology has the potential to transform neuroscience research, improve drug development, and enhance our understanding of brain disorders.
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Affiliation(s)
- Johanna Vetter
- Institute for BioMedical Printing Technology, Technical University of Darmstadt, Darmstadt, Germany
| | - Ilaria Palagi
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Andreas Blaeser
- Institute for BioMedical Printing Technology, Technical University of Darmstadt, Darmstadt, Germany; Centre for Synthetic Biology, Technical University of Darmstadt, Darmstadt, Germany.
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Bektas CK, Luo J, Conley B, Le KPN, Lee KB. 3D bioprinting approaches for enhancing stem cell-based neural tissue regeneration. Acta Biomater 2025; 193:20-48. [PMID: 39793745 DOI: 10.1016/j.actbio.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/12/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025]
Abstract
Three-dimensional (3D) bioprinting holds immense promise for advancing stem cell research and developing novel therapeutic strategies in the field of neural tissue engineering and disease modeling. This paper critically analyzes recent breakthroughs in 3D bioprinting, specifically focusing on its application in these areas. We comprehensively explore the advantages and limitations of various 3D printing methods, the selection and formulation of bioink materials tailored for neural stem cells, and the incorporation of nanomaterials with dual functionality, enhancing the bioprinting process and promoting neurogenesis pathways. Furthermore, the paper reviews the diverse range of stem cells employed in neural bioprinting research, discussing their potential applications and associated challenges. We also introduce the emerging field of 4D bioprinting, highlighting current efforts to develop time-responsive constructs that improve the integration and functionality of bioprinted neural tissues. In short, this manuscript aims to provide a comprehensive understanding of this rapidly evolving field. It underscores the transformative potential of 3D and 4D bioprinting technologies in revolutionizing stem cell research and paving the way for novel therapeutic solutions for neurological disorders and injuries, ultimately contributing significantly to the advancement of regenerative medicine. STATEMENT OF SIGNIFICANCE: This comprehensive review critically examines the current bioprinting research landscape, highlighting efforts to overcome key limitations in printing technologies-improving cell viability post-printing, enhancing resolution, and optimizing cross-linking efficiencies. The continuous refinement of material compositions aims to control the spatiotemporal delivery of therapeutic agents, ensuring better integration of transplanted cells with host tissues. Specifically, the review focuses on groundbreaking advancements in neural tissue engineering. The development of next-generation bioinks, hydrogels, and scaffolds specifically designed for neural regeneration complexities holds the potential to revolutionize treatments for debilitating neural conditions, especially when nanotechnologies are being incorporated. This review offers the readers both a comprehensive analysis of current breakthroughs and an insightful perspective on the future trajectory of neural tissue engineering.
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Affiliation(s)
- Cemile Kilic Bektas
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Jeffrey Luo
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Brian Conley
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Kim-Phuong N Le
- 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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Cadena MA, Sing A, Taylor K, Jin L, Ning L, Amoli MS, Singh Y, The Brain Organoid Hub, Lanjewar SN, Tomov ML, Serpooshan V, Sloan SA. A 3D Bioprinted Cortical Organoid Platform for Modeling Human Brain Development. Adv Healthc Mater 2024; 13:e2401603. [PMID: 38815975 PMCID: PMC11518656 DOI: 10.1002/adhm.202401603] [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: 05/03/2024] [Revised: 05/24/2024] [Indexed: 06/01/2024]
Abstract
The ability to promote three-dimensional (3D) self-organization of induced pluripotent stem cells into complex tissue structures called organoids presents new opportunities for the field of developmental biology. Brain organoids have been used to investigate principles of neurodevelopment and neuropsychiatric disorders and serve as a drug screening and discovery platform. However, brain organoid cultures are currently limited by a lacking ability to precisely control their extracellular environment. Here, this work employs 3D bioprinting to generate a high-throughput, tunable, and reproducible scaffold for controlling organoid development and patterning. Additionally, this approach supports the coculture of organoids and vascular cells in a custom architecture containing interconnected endothelialized channels. Printing fidelity and mechanical assessments confirm that fabricated scaffolds closely match intended design features and exhibit stiffness values reflective of the developing human brain. Using organoid growth, viability, cytoarchitecture, proliferation, and transcriptomic benchmarks, this work finds that organoids cultured within the bioprinted scaffold long-term are healthy and have expected neuroectodermal differentiation. Lastly, this work confirms that the endothelial cells (ECs) in printed channel structures can migrate toward and infiltrate into the embedded organoids. This work demonstrates a tunable 3D culturing platform that can be used to create more complex and accurate models of human brain development and underlying diseases.
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Affiliation(s)
- Melissa A. Cadena
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Anson Sing
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Kylie Taylor
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Linqi Jin
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Liqun Ning
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Mechanical Engineering, Cleveland State University, Cleveland, OH, United States
| | - Mehdi Salar Amoli
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Yamini Singh
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - The Brain Organoid Hub
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Samantha N. Lanjewar
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Martin L. Tomov
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Vahid Serpooshan
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Children’s Healthcare of Atlanta, Atlanta, GA 30322, US
| | - Steven A. Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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Ku J, Asuri P. Stem cell-based approaches for developmental neurotoxicity testing. FRONTIERS IN TOXICOLOGY 2024; 6:1402630. [PMID: 39238878 PMCID: PMC11374538 DOI: 10.3389/ftox.2024.1402630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/05/2024] [Indexed: 09/07/2024] Open
Abstract
Neurotoxicants are substances that can lead to adverse structural or functional effects on the nervous system. These can be chemical, biological, or physical agents that can cross the blood brain barrier to damage neurons or interfere with complex interactions between the nervous system and other organs. With concerns regarding social policy, public health, and medicine, there is a need to ensure rigorous testing for neurotoxicity. While the most common neurotoxicity tests involve using animal models, a shift towards stem cell-based platforms can potentially provide a more biologically accurate alternative in both clinical and pharmaceutical research. With this in mind, the objective of this article is to review both current technologies and recent advancements in evaluating neurotoxicants using stem cell-based approaches, with an emphasis on developmental neurotoxicants (DNTs) as these have the most potential to lead to irreversible critical damage on brain function. In the next section, attempts to develop novel predictive model approaches for the study of both neural cell fate and developmental neurotoxicity are discussed. Finally, this article concludes with a discussion of the future use of in silico methods within developmental neurotoxicity testing, and the role of regulatory bodies in promoting advancements within the space.
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Affiliation(s)
- Joy Ku
- Department of Bioengineering, Santa Clara University, Santa Clara, CA, United States
| | - Prashanth Asuri
- Department of Bioengineering, Santa Clara University, Santa Clara, CA, United States
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Sands I, Demarco R, Thurber L, Esteban-Linares A, Song D, Meng E, Chen Y. Interface-Mediated Neurogenic Signaling: The Impact of Surface Geometry and Chemistry on Neural Cell Behavior for Regenerative and Brain-Machine Interfacing Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2401750. [PMID: 38961531 PMCID: PMC11326983 DOI: 10.1002/adma.202401750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 06/17/2024] [Indexed: 07/05/2024]
Abstract
Nanomaterial advancements have driven progress in central and peripheral nervous system applications such as tissue regeneration and brain-machine interfacing. Ideally, neural interfaces with native tissue shall seamlessly integrate, a process that is often mediated by the interfacial material properties. Surface topography and material chemistry are significant extracellular stimuli that can influence neural cell behavior to facilitate tissue integration and augment therapeutic outcomes. This review characterizes topographical modifications, including micropillars, microchannels, surface roughness, and porosity, implemented on regenerative scaffolding and brain-machine interfaces. Their impact on neural cell response is summarized through neurogenic outcome and mechanistic analysis. The effects of surface chemistry on neural cell signaling with common interfacing compounds like carbon-based nanomaterials, conductive polymers, and biologically inspired matrices are also reviewed. Finally, the impact of these extracellular mediated neural cues on intracellular signaling cascades is discussed to provide perspective on the manipulation of neuron and neuroglia cell microenvironments to drive therapeutic outcomes.
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Affiliation(s)
- Ian Sands
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
| | - Ryan Demarco
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
| | - Laura Thurber
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
| | - Alberto Esteban-Linares
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA
| | - Dong Song
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA
| | - Ellis Meng
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA
| | - Yupeng Chen
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
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Jo HJ, Kang MS, Heo HJ, Jang HJ, Park R, Hong SW, Kim YH, Han DW. Skeletal muscle regeneration with 3D bioprinted hyaluronate/gelatin hydrogels incorporating MXene nanoparticles. Int J Biol Macromol 2024; 265:130696. [PMID: 38458288 DOI: 10.1016/j.ijbiomac.2024.130696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/31/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
There has been significant progress in the field of three-dimensional (3D) bioprinting technology, leading to active research on creating bioinks capable of producing structurally and functionally tissue-mimetic constructs. Ti3C2Tx MXene nanoparticles (NPs), promising two-dimensional nanomaterials, are being investigated for their potential in muscle regeneration due to their unique physicochemical properties. In this study, we integrated MXene NPs into composite hydrogels made of gelatin methacryloyl (GelMA) and hyaluronic acid methacryloyl (HAMA) to develop bioinks (namely, GHM bioink) that promote myogenesis. The prepared GHM bioinks were found to offer excellent printability with structural integrity, cytocompatibility, and microporosity. Additionally, MXene NPs within the 3D bioprinted constructs encouraged the differentiation of C2C12 cells into skeletal muscle cells without additional support of myogenic agents. Genetic analysis indicated that representative myogenic markers both for early and late myogenesis were significantly up-regulated. Moreover, animal studies demonstrated that GHM bioinks contributed to enhanced regeneration of skeletal muscle while reducing immune responses in mice models with volumetric muscle loss (VML). Our results suggest that the GHM hydrogel can be exploited to craft a range of strategies for the development of a novel bioink to facilitate skeletal muscle regeneration because these MXene-incorporated composite materials have the potential to promote myogenesis.
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Affiliation(s)
- Hyo Jung Jo
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea
| | - Moon Sung Kang
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea
| | - Hye Jin Heo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hee Jeong Jang
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea
| | - Rowoon Park
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea
| | - Suck Won Hong
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea; Engineering Research Center for Color-Modulated Extra-Sensory Perception Technology, Pusan National University, Busan 46241, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Periodontal Disease Signaling Network Research Center & Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Dong-Wook Han
- Department of Cogno-Mechatronics Engineering, College of Nanoscience and Nanotechnology, Pusan National University, Busan 46241, Republic of Korea; BIO-IT Fusion Technology Research Institute, Pusan National University, Busan 46241, Republic of Korea.
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Dai X, Yuan M, Yang Y, Dang M, Yang J, Shi J, Liu D, Li M, Yao H, Fei W. Dual cross-linked COL1/HAp bionic gradient scaffolds containing human amniotic mesenchymal stem cells promote rotator cuff tendon-bone interface healing. BIOMATERIALS ADVANCES 2024; 158:213799. [PMID: 38364326 DOI: 10.1016/j.bioadv.2024.213799] [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: 09/06/2023] [Revised: 01/17/2024] [Accepted: 02/08/2024] [Indexed: 02/18/2024]
Abstract
The tendon-bone interface heals through scar tissue, while the lack of a natural interface gradient structure and collagen fibre alignment leads to the occurrence of retearing. Therefore, the promotion of tendon healing has become the focus of regenerative medicine. The purpose of this study was to develop a gradient COL1/ hydroxyapatite (HAp) biomaterial loaded with human amniotic mesenchymal stem cells (hAMSCs). The performance of common cross-linking agents, Genipin, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS), and dual cross-linked materials were compared to select the best cross-linking mechanism to optimize the biological and mechanical properties of the scaffold. The optimal COL1/HAp-loaded with hAMSCs were implanted into the tendon-bone rotator cuff interfaces in rats and the effect on the tendon-bone healing was assessed by micro-CT, histological analysis, and biomechanical properties. The results showed that Genipin and EDC/NHS dual cross-linked COL1/HAp had good biological activity and mechanical properties and promoted the proliferation and differentiation of hAMSCs. Animal experiments showed that the group using a scaffold loaded with hAMSCs had excellent continuity and orientation of collagen fibers, increased fibrocartilage and bone formation, and significantly higher biomechanical functions than the control group at the interface at 12 weeks post operation. This study demonstrated that dual cross-linked gradient COL1/HAp-loaded hAMSCs could promote interface healing, thereby providing a feasible strategy for tendon-bone interface regeneration.
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Affiliation(s)
- Xiaomei Dai
- School of Nursing and School of Public Health, Yangzhou University, Yangzhou 225001, PR China; Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China
| | - Meijuan Yuan
- School of Nursing and School of Public Health, Yangzhou University, Yangzhou 225001, PR China; Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China
| | - Yuxia Yang
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China; Medical College, Yangzhou University, Yangzhou 225001, PR China
| | - Mengbo Dang
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China; Dalian Medical University, Dalian 116044, PR China
| | - Jian Yang
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China; Medical College, Yangzhou University, Yangzhou 225001, PR China
| | - Junli Shi
- School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225009, PR China
| | - Dianwei Liu
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China; Dalian Medical University, Dalian 116044, PR China
| | - Mingjun Li
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China; Dalian Medical University, Dalian 116044, PR China
| | - Hang Yao
- School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225009, PR China.
| | - Wenyong Fei
- Department of Orthopedics and Sports Medicine, Northern Jiangsu People's Hospital, Affiliated to Yangzhou University, Yangzhou 225001, PR China.
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Yang Y, Fan R, Li H, Chen H, Gong H, Guo G. Polysaccharides as a promising platform for the treatment of spinal cord injury: A review. Carbohydr Polym 2024; 327:121672. [PMID: 38171685 DOI: 10.1016/j.carbpol.2023.121672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/20/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024]
Abstract
Spinal cord injury is incurable and often results in irreversible damage to motor function and autonomic sensory abilities. To enhance the effectiveness of therapeutic substances such as cells, growth factors, drugs, and nucleic acids for treating spinal cord injuries, as well as to reduce the toxic side effects of chemical reagents, polysaccharides have been gained attention due to their immunomodulatory properties and the biocompatibility and biodegradability of polysaccharide scaffolds. Polysaccharides hold potential as drug delivery systems in treating spinal cord injuries. This article aims to present an extensive evaluation of the potential applications of polysaccharide materials in scaffold construction, drug delivery, and immunomodulation over the past five years so that offering new directions and opportunities for the treatment of spinal cord injuries.
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Affiliation(s)
- Yuanli Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rangrang Fan
- Department of Neurosurgery and Institute of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hui Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Haifeng Chen
- Department of Neurosurgery and Institute of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hanlin Gong
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Gang Guo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Marques-Almeida T, Lanceros-Mendez S, Ribeiro C. State of the Art and Current Challenges on Electroactive Biomaterials and Strategies for Neural Tissue Regeneration. Adv Healthc Mater 2024; 13:e2301494. [PMID: 37843074 DOI: 10.1002/adhm.202301494] [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: 05/09/2023] [Revised: 09/22/2023] [Indexed: 10/17/2023]
Abstract
The loss or failure of an organ/tissue stands as one of the healthcare system's most prevalent, devastating, and costly challenges. Strategies for neural tissue repair and regeneration have received significant attention due to their particularly strong impact on patients' well-being. Many research efforts are dedicated not only to control the disease symptoms but also to find solutions to repair the damaged tissues. Neural tissue engineering (TE) plays a key role in addressing this problem and significant efforts are being carried out to develop strategies for neural repair treatment. In the last years, active materials allowing to tune cell-materials interaction are being increasingly used, representing a recent paradigm in TE applications. Among the most important stimuli influencing cell behavior are the electrical and mechanical ones. In this way, materials with the ability to provide this kind of stimuli to the neural cells seem to be appropriate to support neural TE. In this scope, this review summarizes the different biomaterials types used for neural TE, highlighting the relevance of using active biomaterials and electrical stimulation. Furthermore, this review provides not only a compilation of the most relevant studies and results but also strategies for novel and more biomimetic approaches for neural TE.
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Affiliation(s)
- Teresa Marques-Almeida
- Physics Centre of Minho and Porto Universities (CF-UM-UP), University of Minho, Braga, 4710-057, Portugal
- LaPMET - Laboratory of Physics for Materials and Emergent Technologies, University of Minho, Braga, 4710-057, Portugal
| | - Senentxu Lanceros-Mendez
- Physics Centre of Minho and Porto Universities (CF-UM-UP), University of Minho, Braga, 4710-057, Portugal
- LaPMET - Laboratory of Physics for Materials and Emergent Technologies, University of Minho, Braga, 4710-057, Portugal
- BCMaterials, Basque Center for Materials, Applications and Nanostructures, UPV/EHU Science Park, Leioa, 48940, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, 48009, Spain
| | - Clarisse Ribeiro
- Physics Centre of Minho and Porto Universities (CF-UM-UP), University of Minho, Braga, 4710-057, Portugal
- LaPMET - Laboratory of Physics for Materials and Emergent Technologies, University of Minho, Braga, 4710-057, Portugal
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11
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Eftekhari BS, Song D, Janmey PA. Electrical Stimulation of Human Mesenchymal Stem Cells on Conductive Substrates Promotes Neural Priming. Macromol Biosci 2023; 23:e2300149. [PMID: 37571815 PMCID: PMC10880582 DOI: 10.1002/mabi.202300149] [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: 04/06/2023] [Revised: 06/29/2023] [Indexed: 08/13/2023]
Abstract
Electrical stimulation (ES) within a conductive scaffold is potentially beneficial in encouraging the differentiation of stem cells toward a neuronal phenotype. To improve stem cell-based regenerative therapies, it is essential to use electroconductive scaffolds with appropriate stiffnesses to regulate the amount and location of ES delivery. Herein, biodegradable electroconductive substrates with different stiffnesses are fabricated from chitosan-grafted-polyaniline (CS-g-PANI) copolymers. Human mesenchymal stem cells (hMSCs) cultured on soft conductive scaffolds show a morphological change with significant filopodial elongation after electrically stimulated culture along with upregulation of neuronal markers and downregulation of glial markers. Compared to stiff conductive scaffolds and non-conductive CS scaffolds, soft conductive CS-g-PANI scaffolds promote increased expression of microtubule-associated protein 2 (MAP2) and neurofilament heavy chain (NF-H) after application of ES. At the same time, there is a decrease in the expression of the glial markers glial fibrillary acidic protein (GFAP) and vimentin after ES. Furthermore, the elevation of intracellular calcium [Ca2+ ] during spontaneous, cell-generated Ca2+ transients further suggests that electric field stimulation of hMSCs cultured on conductive substrates can promote a neural-like phenotype. The findings suggest that the combination of the soft conductive CS-g-PANI substrate and ES is a promising new tool for enhancing neuronal tissue engineering outcomes.
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Affiliation(s)
| | - Dawei Song
- Department of Physiology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul A. Janmey
- Department of Bioengineering, University of Pennsylvania, Philadelphia, USA
- Department of Physiology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA
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12
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Gomila Pelegri N, Stanczak AM, Bottomley AL, Cummins ML, Milthorpe BK, Gorrie CA, Padula MP, Santos J. Neural Marker Expression in Adipose-Derived Stem Cells Grown in PEG-Based 3D Matrix Is Enhanced in the Presence of B27 and CultureOne Supplements. Int J Mol Sci 2023; 24:16269. [PMID: 38003460 PMCID: PMC10671562 DOI: 10.3390/ijms242216269] [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: 10/11/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) have incredible potential as an avenue to better understand and treat neurological disorders. While they have been successfully differentiated into neural stem cells and neurons, most such protocols involve 2D environments, which are not representative of in vivo physiology. In this study, human ADSCs were cultured in 1.1 kPa polyethylene-glycol 3D hydrogels for 10 days with B27, CultureOne (C1), and N2 neural supplements to examine the neural differentiation potential of ADSCs using both chemical and mechanical cues. Following treatment, cell viability, proliferation, morphology, and proteome changes were assessed. Results showed that cell viability was maintained during treatments, and while cells continued to proliferate over time, proliferation slowed down. Morphological changes between 3D untreated cells and treated cells were not observed. However, they were observed among 2D treatments, which exhibited cellular elongation and co-alignment. Proteome analysis showed changes consistent with early neural differentiation for B27 and C1 but not N2. No significant changes were detected using immunocytochemistry, potentially indicating a greater differentiation period was required. In conclusion, treatment of 3D-cultured ADSCs in PEG-based hydrogels with B27 and C1 further enhances neural marker expression, however, this was not observed using supplementation with N2.
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Affiliation(s)
- Neus Gomila Pelegri
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
- Neural Injury Research Unit, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Aleksandra M. Stanczak
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (A.M.S.); (M.P.P.)
| | - Amy L. Bottomley
- Microbial Imaging Facility, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Max L. Cummins
- Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW 2007, Australia;
- The Australian Centre for Genomic Epidemiological Microbiology, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Bruce K. Milthorpe
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
| | - Catherine A. Gorrie
- Neural Injury Research Unit, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Matthew P. Padula
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (A.M.S.); (M.P.P.)
| | - Jerran Santos
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
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13
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Pereira I, Lopez-Martinez MJ, Samitier J. Advances in current in vitro models on neurodegenerative diseases. Front Bioeng Biotechnol 2023; 11:1260397. [PMID: 38026882 PMCID: PMC10658011 DOI: 10.3389/fbioe.2023.1260397] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Many neurodegenerative diseases are identified but their causes and cure are far from being well-known. The problem resides in the complexity of the neural tissue and its location which hinders its easy evaluation. Although necessary in the drug discovery process, in vivo animal models need to be reduced and show relevant differences with the human tissues that guide scientists to inquire about other possible options which lead to in vitro models being explored. From organoids to organ-on-a-chips, 3D models are considered the cutting-edge technology in cell culture. Cell choice is a big parameter to take into consideration when planning an in vitro model and cells capable of mimicking both healthy and diseased tissue, such as induced pluripotent stem cells (iPSC), are recognized as good candidates. Hence, we present a critical review of the latest models used to study neurodegenerative disease, how these models have evolved introducing microfluidics platforms, 3D cell cultures, and the use of induced pluripotent cells to better mimic the neural tissue environment in pathological conditions.
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Affiliation(s)
- Inês Pereira
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Maria J. Lopez-Martinez
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro Investigación Biomédica en Red: Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain
| | - Josep Samitier
- Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro Investigación Biomédica en Red: Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain
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14
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Gomila Pelegri N, Stanczak AM, Bottomley AL, Milthorpe BK, Gorrie CA, Padula MP, Santos J. Adipose-Derived Stem Cells Spontaneously Express Neural Markers When Grown in a PEG-Based 3D Matrix. Int J Mol Sci 2023; 24:12139. [PMID: 37569515 PMCID: PMC10418654 DOI: 10.3390/ijms241512139] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Neurological diseases are among the leading causes of disability and death worldwide and remain difficult to treat. Tissue engineering offers avenues to test potential treatments; however, the development of biologically accurate models of brain tissues remains challenging. Given their neurogenic potential and availability, adipose-derived stem cells (ADSCs) are of interest for creating neural models. While progress has been made in differentiating ADSCs into neural cells, their differentiation in 3D environments, which are more representative of the in vivo physiological conditions of the nervous system, is crucial. This can be achieved by modulating the 3D matrix composition and stiffness. Human ADSCs were cultured for 14 days in a 1.1 kPa polyethylene glycol-based 3D hydrogel matrix to assess effects on cell morphology, cell viability, proteome changes and spontaneous neural differentiation. Results showed that cells continued to proliferate over the 14-day period and presented a different morphology to 2D cultures, with the cells elongating and aligning with one another. The proteome analysis revealed 439 proteins changed in abundance by >1.5 fold. Cyclic nucleotide 3'-phosphodiesterase (CNPase) markers were identified using immunocytochemistry and confirmed with proteomics. Findings indicate that ADSCs spontaneously increase neural marker expression when grown in an environment with similar mechanical properties to the central nervous system.
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Affiliation(s)
- Neus Gomila Pelegri
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
- Neural Injury Research Unit, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Aleksandra M. Stanczak
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (A.M.S.); (M.P.P.)
| | - Amy L. Bottomley
- Microbial Imaging Facility, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Bruce K. Milthorpe
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
| | - Catherine A. Gorrie
- Neural Injury Research Unit, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Matthew P. Padula
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (A.M.S.); (M.P.P.)
| | - Jerran Santos
- Advanced Tissue Engineering and Stem Cell Biology Group, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (N.G.P.); (B.K.M.)
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15
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Ge B, Wei M, Bao B, Pan Z, Elango J, Wu W. The Role of Integrin Receptor's α and β Subunits of Mouse Mesenchymal Stem Cells on the Interaction of Marine-Derived Blacktip Reef Shark ( Carcharhinus melanopterus) Skin Collagen. Int J Mol Sci 2023; 24:ijms24119110. [PMID: 37298062 DOI: 10.3390/ijms24119110] [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: 03/28/2023] [Revised: 04/25/2023] [Accepted: 05/10/2023] [Indexed: 06/12/2023] Open
Abstract
Marine collagen (MC) has recently attracted more attention in tissue engineering as a biomaterial substitute due to its significant role in cellular signaling mechanisms, especially in mesenchymal stem cells (MSCs). However, the actual signaling mechanism of MC in MSC growth, which is highly influenced by their molecular pattern, is poorly understood. Hence, we investigated the integrin receptors (α1β1, α2β1, α10β1, and α11β1) binding mechanism and proliferation of MCs (blacktip reef shark collagen (BSC) and blue shark collagen (SC)) compared to bovine collagen (BC) on MSCs behavior through functionalized collagen molecule probing for the first time. The results showed that BSC and SC had higher proliferation rates and accelerated scratch wound healing by increasing migratory rates of MSCs. Cell adhesion and spreading results demonstrated that MC had a better capacity to anchor MSCs and maintain cell morphology than controls. Living cell observations showed that BSC was gradually assembled by cells into the ECM network within 24 h. Interestingly, qRT-PCR and ELISA revealed that the proliferative effect of MC was triggered by interacting with specific integrin receptors such as α2β1, α10β1, and α11β1 of MSCs. Accordingly, BSC accelerated MSCs' growth, adhesion, shape, and spreading by interacting with specific integrin subunits (α2 and β1) and thereby triggering further signaling cascade mechanisms.
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Affiliation(s)
- Baolin Ge
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Mingjun Wei
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Bin Bao
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Zhilin Pan
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jeevithan Elango
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
- Department of Biomaterials Engineering, Faculty of Health Sciences, UCAM-Universidad Católica San Antonio de Murcia, Guadalupe, 30107 Murcia, Spain
| | - Wenhui Wu
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
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16
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Ostadi Moghaddam A, Arshee MR, Lin Z, Sivaguru M, Phillips H, McFarlin BL, Toussaint KC, Wagoner Johnson AJ. Orientation-dependent indentation reveals the crosslink-mediated deformation mechanisms of collagen fibrils. Acta Biomater 2023; 158:347-357. [PMID: 36638936 PMCID: PMC10039649 DOI: 10.1016/j.actbio.2023.01.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/18/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023]
Abstract
The spatial arrangement and interactions of the extracellular matrix (ECM) components control the mechanical behavior of tissue at multiple length scales. Changes in microscale deformation mechanisms affect tissue function and are often hallmarks of remodeling and disease. Despite their importance, the deformation mechanisms that modulate the mechanical behavior of collagenous tissue, particularly in indentation and compression modes of deformation, remain poorly understood. Here, we develop an integrated computational and experimental approach to investigate the deformation mechanisms of collagenous tissue at the microscale. While the complex deformation arising from indentation with a spherical probe is often considered a pitfall rather than an opportunity, we leverage this orientation-dependent deformation to examine the shear-regulated interactions of collagen fibrils and the role of crosslinks in modulating these interactions. We specifically examine tendon and cervix, two tissues rich in collagen with quite different microstructures and mechanical functions. We find that interacting, crosslinked collagen fibrils resist microscale longitudinal compressive forces, while widely used constitutive models fail to capture this behavior. The reorientation of collagen fibrils tunes the compressive stiffness of complex tissues like cervix. This study offers new insights into the mechanical behavior of collagen fibrils during indentation, and more generally, under longitudinal compressive forces, and illustrates the mechanisms that contribute to the experimentally observed orientation-dependent mechanical behavior. STATEMENT OF SIGNIFICANCE: Remodeling and disease can affect the deformation and interaction of tissue constituents, and thus mechanical function of tissue. Yet, the microscale deformation mechanisms are not well characterized in many tissues. Here, we develop a combined experimental-computational approach to infer the microscale deformation mechanisms of collagenous tissues with very different functions: tendon and cervix. Results show that collagen fibrils resist microscale forces along their length, though widely-used constitutive models do not account for this mechanism. This deformation process partially modulates the compressive stiffness of complex tissues such as cervix. Computational modeling shows that crosslink-mediated shear deformations are central to this unexpected behavior. This study offers new insights into the deformation mechanisms of collagenous tissue and the function of collagen crosslinkers.
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Affiliation(s)
- A Ostadi Moghaddam
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - M R Arshee
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Z Lin
- School of Engineering, Brown University, Providence, RI 02912, USA
| | - M Sivaguru
- Flow Cytometry and Microscopy to Omics, Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - H Phillips
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - B L McFarlin
- Department of Women, Children and Family Health Science, University of Illinois College of Nursing, Chicago, IL 60612, USA
| | - K C Toussaint
- School of Engineering, Brown University, Providence, RI 02912, USA
| | - A J Wagoner Johnson
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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17
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Pereira I, Lopez-Martinez MJ, Villasante A, Introna C, Tornero D, Canals JM, Samitier J. Hyaluronic acid-based bioink improves the differentiation and network formation of neural progenitor cells. Front Bioeng Biotechnol 2023; 11:1110547. [PMID: 36937768 PMCID: PMC10020230 DOI: 10.3389/fbioe.2023.1110547] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction: Three-dimensional (3D) bioprinting is a promising technique for the development of neuronal in vitro models because it controls the deposition of materials and cells. Finding a biomaterial that supports neural differentiation in vitro while ensuring compatibility with the technique of 3D bioprinting of a self-standing construct is a challenge. Methods: In this study, gelatin methacryloyl (GelMA), methacrylated alginate (AlgMA), and hyaluronic acid (HA) were examined by exploiting their biocompatibility and tunable mechanical properties to resemble the extracellular matrix (ECM) and to create a suitable material for printing neural progenitor cells (NPCs), supporting their long-term differentiation. NPCs were printed and differentiated for up to 15 days, and cell viability and neuronal differentiation markers were assessed throughout the culture. Results and Discussion: This composite biomaterial presented the desired physical properties to mimic the ECM of the brain with high water intake, low stiffness, and slow degradation while allowing the printing of defined structures. The viability rates were maintained at approximately 80% at all time points. However, the levels of β-III tubulin marker increased over time, demonstrating the compatibility of this biomaterial with neuronal cell culture and differentiation. Furthermore, these cells showed increased maturation with corresponding functional properties, which was also demonstrated by the formation of a neuronal network that was observed by recording spontaneous activity via Ca2+ imaging.
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Affiliation(s)
- Inês Pereira
- Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Maria J. Lopez-Martinez
- Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking, Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - Aranzazu Villasante
- Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
| | - Clelia Introna
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Creatio - Production and Validation Center of Advanced Therapies, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Research Foundation Clinic Barcelona-August Pi i Sunyer Biomedical Research Institute (FRCB-IDIBAPS), Barcelona, Spain
| | - Daniel Tornero
- Research Foundation Clinic Barcelona-August Pi i Sunyer Biomedical Research Institute (FRCB-IDIBAPS), Barcelona, Spain
- Laboratory of Neuronal Stem Cells and Cerebral Damage, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
| | - Josep M. Canals
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Creatio - Production and Validation Center of Advanced Therapies, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Research Foundation Clinic Barcelona-August Pi i Sunyer Biomedical Research Institute (FRCB-IDIBAPS), Barcelona, Spain
| | - Josep Samitier
- Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking, Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
- *Correspondence: Josep Samitier,
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18
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Wu C, Pu Y, Zhang Y, Liu X, Qiao Z, Xin N, Zhou T, Chen S, Zeng M, Tang J, Pi J, Wei D, Sun J, Luo F, Fan H. A Bioactive and Photoresponsive Platform for Wireless Electrical Stimulation to Promote Neurogenesis. Adv Healthc Mater 2022; 11:e2201255. [PMID: 35932207 DOI: 10.1002/adhm.202201255] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/14/2022] [Indexed: 02/05/2023]
Abstract
Delivering electrical signals to neural cells and tissue has attracted increasing attention in the treatment of nerve injuries. Unlike traditional wired electrical stimulation, wireless and remote light stimulation provides less invasive and longer-lasting interfaces, holding great promise in the treatment of nerve injuries and neurodegenerative diseases, as well as human-computer interaction. Additionally, a bioactive matrix that bridges the injured gap and induces nerve regeneration is essential for injured nerve repair. However, it is still challenging to construct a 3D biomimetic cell niche with optoelectrical responsiveness. Herein, a bioactive platform for remote and wireless optoelectrical stimulation is established by incorporating hydrophilic poly(3-hexylthiophene) nanoparticles (P3HT NPs) into a biomimetic hydrogel matrix. Moreover, the hydrogel matrix is modified by varying the composition and/or the crosslinking degree to meet the needs of different application scenarios. When exposed to pulsed green light, P3HT NPs in hydrogels convert light signals into electrical signals, resulting in the generation of tens of picoampere photocurrent, which is proved to promote the growth of cortical neurons that covered by hydrogels and the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) encapsulated in hydrogels. This work is of great significance for the design of next-generation neural electrodes and scaffolds.
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Affiliation(s)
- Chengheng Wu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China.,Institute of Regulatory Science for Medical Devices, Sichuan University, Chengdu, Sichuan, 610065, China
| | - Yiyao Pu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Yusheng Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Xiaoyin Liu
- Department of Neurosurgery, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zi Qiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Nini Xin
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Ting Zhou
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Suping Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Mingze Zeng
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Jiajia Tang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Jinkui Pi
- Core Facilities of West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Dan Wei
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Jing Sun
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
| | - Fang Luo
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, China
| | - Hongsong Fan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan, 610064, China
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19
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Girão AF, Serrano MC, Completo A, Marques PAAP. Is Graphene Shortening the Path toward Spinal Cord Regeneration? ACS NANO 2022; 16:13430-13467. [PMID: 36000717 PMCID: PMC9776589 DOI: 10.1021/acsnano.2c04756] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Along with the development of the next generation of biomedical platforms, the inclusion of graphene-based materials (GBMs) into therapeutics for spinal cord injury (SCI) has potential to nourish topmost neuroprotective and neuroregenerative strategies for enhancing neural structural and physiological recovery. In the context of SCI, contemplated as one of the most convoluted challenges of modern medicine, this review first provides an overview of its characteristics and pathophysiological features. Then, the most relevant ongoing clinical trials targeting SCI, including pharmaceutical, robotics/neuromodulation, and scaffolding approaches, are introduced and discussed in sequence with the most important insights brought by GBMs into each particular topic. The current role of these nanomaterials on restoring the spinal cord microenvironment after injury is critically contextualized, while proposing future concepts and desirable outputs for graphene-based technologies aiming to reach clinical significance for SCI.
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Affiliation(s)
- André F. Girão
- Centre
for Mechanical Technology and Automation (TEMA), Department of Mechanical
Engineering, University of Aveiro (UA), Aveiro, 3810-193, Portugal
- Instituto
de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Calle Sor Juana Inés de la
Cruz 3, Madrid, 28049, Spain
- (A.F.G.)
| | - María Concepcion Serrano
- Instituto
de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Calle Sor Juana Inés de la
Cruz 3, Madrid, 28049, Spain
- (M.C.S.)
| | - António Completo
- Centre
for Mechanical Technology and Automation (TEMA), Department of Mechanical
Engineering, University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - Paula A. A. P. Marques
- Centre
for Mechanical Technology and Automation (TEMA), Department of Mechanical
Engineering, University of Aveiro (UA), Aveiro, 3810-193, Portugal
- (P.A.A.P.M.)
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20
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Khan HM, Liao X, Sheikh BA, Wang Y, Su Z, Guo C, Li Z, Zhou C, Cen Y, Kong Q. Smart biomaterials and their potential applications in tissue engineering. J Mater Chem B 2022; 10:6859-6895. [PMID: 36069198 DOI: 10.1039/d2tb01106a] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Smart biomaterials have been rapidly advancing ever since the concept of tissue engineering was proposed. Interacting with human cells, smart biomaterials can play a key role in novel tissue morphogenesis. Various aspects of biomaterials utilized in or being sought for the goal of encouraging bone regeneration, skin graft engineering, and nerve conduits are discussed in this review. Beginning with bone, this study summarizes all the available bioceramics and materials along with their properties used singly or in conjunction with each other to create scaffolds for bone tissue engineering. A quick overview of the skin-based nanocomposite biomaterials possessing antibacterial properties for wound healing is outlined along with skin regeneration therapies using infrared radiation, electrospinning, and piezoelectricity, which aid in wound healing. Furthermore, a brief overview of bioengineered artificial skin grafts made of various natural and synthetic polymers has been presented. Finally, by examining the interactions between natural and synthetic-based biomaterials and the biological environment, their strengths and drawbacks for constructing peripheral nerve conduits are highlighted. The description of the preclinical outcome of nerve regeneration in injury healed with various natural-based conduits receives special attention. The organic and synthetic worlds collide at the interface of nanomaterials and biological systems, producing a new scientific field including nanomaterial design for tissue engineering.
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Affiliation(s)
- Haider Mohammed Khan
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Xiaoxia Liao
- Department of Burn and Plastic Surgery, West China School of Medicine, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Bilal Ahmed Sheikh
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Yixi Wang
- Department of Burn and Plastic Surgery, West China School of Medicine, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Zhixuan Su
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.,National Engineering Research Centre for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Chuan Guo
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Zhengyong Li
- Department of Burn and Plastic Surgery, West China School of Medicine, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Changchun Zhou
- College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.,National Engineering Research Centre for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Ying Cen
- Department of Burn and Plastic Surgery, West China School of Medicine, West China Hospital, Sichuan University, 610041, Chengdu, China.
| | - Qingquan Kong
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China.
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21
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Yi B, Xu Q, Liu W. An overview of substrate stiffness guided cellular response and its applications in tissue regeneration. Bioact Mater 2022; 15:82-102. [PMID: 35386347 PMCID: PMC8940767 DOI: 10.1016/j.bioactmat.2021.12.005] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 02/06/2023] Open
Abstract
Cell-matrix interactions play a critical role in tissue repair and regeneration. With gradual uncovering of substrate mechanical characteristics that can affect cell-matrix interactions, much progress has been made to unravel substrate stiffness-mediated cellular response as well as its underlying mechanisms. Yet, as a part of cell-matrix interaction biology, this field remains in its infancy, and the detailed molecular mechanisms are still elusive regarding scaffold-modulated tissue regeneration. This review provides an overview of recent progress in the area of the substrate stiffness-mediated cellular responses, including 1) the physical determination of substrate stiffness on cell fate and tissue development; 2) the current exploited approaches to manipulate the stiffness of scaffolds; 3) the progress of recent researches to reveal the role of substrate stiffness in cellular responses in some representative tissue-engineered regeneration varying from stiff tissue to soft tissue. This article aims to provide an up-to-date overview of cell mechanobiology research in substrate stiffness mediated cellular response and tissue regeneration with insightful information to facilitate interdisciplinary knowledge transfer and enable the establishment of prognostic markers for the design of suitable biomaterials.
Substrate stiffness physically determines cell fate and tissue development. Rational design of scaffolds requires the understanding of cell-matrix interactions. Substrate stiffness depends on scaffold molecular-constituent-structure interaction. Substrate stiffness-mediated cellular responses vary in different tissues.
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22
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Xu Z, Li Y, Li P, Sun Y, Lv S, Wang Y, He X, Xu J, Xu Z, Li L, Li Y. Soft substrates promote direct chemical reprogramming of fibroblasts into neurons. Acta Biomater 2022; 152:255-272. [PMID: 36041647 DOI: 10.1016/j.actbio.2022.08.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 08/13/2022] [Accepted: 08/23/2022] [Indexed: 11/01/2022]
Abstract
Fibroblasts can be directly reprogrammed via a combination of small molecules to generate induced neurons (iNs), bypassing intermediate stages. This method holds great promise for regenerative medicine; however, it remains inefficient. Recently, studies have suggested that physical cues may improve the direct reprogramming of fibroblasts into neurons, but the underlying mechanisms remain to be further explored, and the physical factors reported to date do not exhibit the full properties of the extracellular matrix (ECM). Previous in vitro studies mainly used rigid polystyrene dishes, while one of the characteristics of the native in-vivo environment of neurons is the soft nature of brain ECM. The reported stiffness of brain tissue is very soft ranging between 100 Pa and 3 kPa, and the effect of substrate stiffness on direct neuronal reprogramming has not been explored. Here, we show for the first time that soft substrates substantially improved the production efficiency and quality of iNs, without needing to co-culture with glial cells during reprogramming, producing more glutamatergic neurons with electrophysiological functions in a shorter time. Transcriptome sequencing indicated that soft substrates might promote glutamatergic neuron reprogramming through integrins, actin cytoskeleton, Hippo signalling pathway, and regulation of mesenchymal-to-epithelial transition, and competing endogenous RNA network analysis provided new targets for neuronal reprogramming. We demonstrated that soft substrates may promote neuronal reprogramming by inhibiting microRNA-615-3p-targeting integrin subunit beta 4. Our findings can aid the development of regenerative therapies and help improve our understanding of neuronal reprogramming. STATEMENT OF SIGNIFICANCE: : First, we have shown that low stiffness promotes direct reprogramming on the basis of small molecule combinations. To the best of our knowledge, this is the first report on this type of method, which may greatly promote the progress of neural reprogramming. Second, we found that miR-615-3p may interact with ITGB4, and the soft substrates may promote neural reprogramming by inhibiting microRNA (miR)-615-3p targeting integrin subunit beta 4 (ITGB4). We are the first to report on this mechanism. Our findings will provide more functional neurons for subsequent basic and clinical research in neurological regenerative medicine, and will help to improve the overall understanding of neural reprogramming. This work also provides new ideas for the design of medical biomaterials for nerve regeneration.
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Affiliation(s)
- Ziran Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yan Li
- Division of Orthopedics and Biotechnology, Department for Clinical Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
| | - Pengdong Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong, China.
| | - Yingying Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Stomatology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yin Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Xia He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Pathology, Shanxi Bethune Hospital, Taiyuan 030032, China.
| | - Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Burns Surgery, The First Hospital of Jilin University, Changchun 130000, China.
| | - Zhixiang Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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23
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Chen S, Wu C, Zhou T, Wu K, Xin N, Liu X, Qiao Z, Wei D, Sun J, Luo H, Zhou L, Fan H. Aldehyde-methacrylate-hyaluronan profited hydrogel system integrating aligned and viscoelastic cues for neurogenesis. Carbohydr Polym 2022; 278:118961. [PMID: 34973776 DOI: 10.1016/j.carbpol.2021.118961] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/21/2021] [Accepted: 11/28/2021] [Indexed: 02/05/2023]
Abstract
Either oriented architecture or viscoelasticity is pivotal to neurogenesis, thus, native neural extracellular matrix derived-hyaluronan hydrogels with nano-orientation and viscoelasticity recapitulated might be instructive for neurogenesis, however it is still unexploited. Herein, based on aldehyde-methacrylate difunctionalized hyaluronan, by integrating imine kinetic modulation and microfluidic biofabrication, we construct a hydrogel system with orthogonal viscoelasticity and nano-topography. We then find the positive synergy effects of matrix nano-orientation and viscoelasticity not only on neurites outgrowth and elongation of neural cells, but also on neuronal differentiation of stem cells. Moreover, by implanting viscoelastic and nano-aligned hydrogels into lesion sites, we demonstrate the enhanced repair of spinal cord injury, including ameliorated pathological microenvironment, facilitated endogenous neurogenesis and functional axons regeneration as well as motor function restoration. This work supplies universal platform for preparing neuronal inducing hyaluronan-based hydrogels which might serve as promising therapeutic strategies for nerve injury.
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Affiliation(s)
- Suping Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Chengheng Wu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Ting Zhou
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Kai Wu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Nini Xin
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Xiaoyin Liu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zi Qiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Dan Wei
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Jing Sun
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Hongrong Luo
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
| | - Hongsong Fan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, Sichuan, China.
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24
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Zhang C, Lü D, Zhang F, Wu Y, Zheng L, Zhang X, Li Z, Sun S, Long M. Gravity-Vector Induces Mechanical Remodeling of rMSCs via Combined Substrate Stiffness and Orientation. Front Bioeng Biotechnol 2022; 9:724101. [PMID: 35198547 PMCID: PMC8859489 DOI: 10.3389/fbioe.2021.724101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/30/2021] [Indexed: 11/23/2022] Open
Abstract
Distinct physical factors originating from the cellular microenvironment are crucial to the biological homeostasis of stem cells. While substrate stiffness and orientation are known to regulate the mechanical remodeling and fate decision of mesenchymal stem cells (MSCs) separately, it remains unclear how the two factors are combined to manipulate their mechanical stability under gravity vector. Here we quantified these combined effects by placing rat MSCs onto stiffness-varied poly-dimethylsiloxane (PDMS) substrates in upward (180°), downward (0°), or edge-on (90°) orientation. Compared with those values onto glass coverslip, the nuclear longitudinal translocation, due to the density difference between the nucleus and the cytosol, was found to be lower at 0° for 24 h and higher at 90° for 24 and 72 h onto 2.5 MPa PDMS substrate. At 0°, the cell was mechanically supported by remarkably reduced actin and dramatically enhanced vimentin expression. At 90°, both enhanced actin and vimentin expression worked cooperatively to maintain cell stability. Specifically, perinuclear actin stress fibers with a large number, low anisotropy, and visible perinuclear vimentin cords were formed onto 2.5 MPa PDMS at 90° for 72 h, supporting the orientation difference in nuclear translocation and global cytoskeleton expression. This orientation dependence tended to disappear onto softer PDMS, presenting distinctive features in nuclear translocation and cytoskeletal structures. Moreover, cellular morphology and focal adhesion were mainly affected by substrate stiffness, yielding a time course of increased spreading area at 24 h but decreased area at 72 h with a decrease of stiffness. Mechanistically, the cell tended to be stabilized onto these PDMS substrates via β1 integrin–focal adhesion complexes–actin mechanosensitive axis. These results provided an insight in understanding the combination of substrate stiffness and orientation in defining the mechanical stability of rMSCs.
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Affiliation(s)
- Chen Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Dongyuan Lü
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Fan Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Yi Wu
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Lu Zheng
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyu Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Zhan Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Shujin Sun
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Mian Long
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Mian Long,
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25
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Ozgun A, Lomboni D, Arnott H, Staines WA, Woulfe J, Variola F. Biomaterial-based strategies for in vitro neural models. Biomater Sci 2022; 10:1134-1165. [PMID: 35023513 DOI: 10.1039/d1bm01361k] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In vitro models have been used as a complementary tool to animal studies in understanding the nervous system's physiological mechanisms and pathological disorders, while also serving as platforms to evaluate the safety and efficiency of therapeutic candidates. Following recent advances in materials science, micro- and nanofabrication techniques and cell culture systems, in vitro technologies have been rapidly gaining the potential to bridge the gap between animal and clinical studies by providing more sophisticated models that recapitulate key aspects of the structure, biochemistry, biomechanics, and functions of human tissues. This was made possible, in large part, by the development of biomaterials that provide cells with physicochemical features that closely mimic the cellular microenvironment of native tissues. Due to the well-known material-driven cellular response and the importance of mimicking the environment of the target tissue, the selection of optimal biomaterials represents an important early step in the design of biomimetic systems to investigate brain structures and functions. This review provides a comprehensive compendium of commonly used biomaterials as well as the different fabrication techniques employed for the design of neural tissue models. Furthermore, the authors discuss the main parameters that need to be considered to develop functional platforms not only for the study of brain physiological functions and pathological processes but also for drug discovery/development and the optimization of biomaterials for neural tissue engineering.
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Affiliation(s)
- Alp Ozgun
- Department of Mechanical Engineering, Faculty of Engineering, University of Ottawa, Ottawa, Canada. .,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - David Lomboni
- Department of Mechanical Engineering, Faculty of Engineering, University of Ottawa, Ottawa, Canada. .,Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - Hallie Arnott
- Department of Mechanical Engineering, Faculty of Engineering, University of Ottawa, Ottawa, Canada. .,Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - William A Staines
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - John Woulfe
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.,The Ottawa Hospital, Ottawa, Canada
| | - Fabio Variola
- Department of Mechanical Engineering, Faculty of Engineering, University of Ottawa, Ottawa, Canada. .,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.,Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada.,The Ottawa Hospital, Ottawa, Canada.,Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada
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26
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Sala MR, Skalli O, Sabri F. Optimal structural and physical properties of aerogels for promoting robust neurite extension in vitro. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 135:112682. [DOI: 10.1016/j.msec.2022.112682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/15/2022] [Accepted: 01/21/2022] [Indexed: 01/02/2023]
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27
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Samanipour R, Tahmooressi H, Rezaei Nejad H, Hirano M, Shin SR, Hoorfar M. A review on 3D printing functional brain model. BIOMICROFLUIDICS 2022; 16:011501. [PMID: 35145569 PMCID: PMC8816519 DOI: 10.1063/5.0074631] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/31/2021] [Indexed: 05/08/2023]
Abstract
Modern neuroscience increasingly relies on 3D models to study neural circuitry, nerve regeneration, and neural disease. Several different biofabrication approaches have been explored to create 3D neural tissue model structures. Among them, 3D bioprinting has shown to have great potential to emerge as a high-throughput/high precision biofabrication strategy that can address the growing need for 3D neural models. Here, we have reviewed the design principles for neural tissue engineering. The main challenge to adapt printing technologies for biofabrication of neural tissue models is the development of neural bioink, i.e., a biomaterial with printability and gelation properties and also suitable for neural tissue culture. This review shines light on a vast range of biomaterials as well as the fundamentals of 3D neural tissue printing. Also, advances in 3D bioprinting technologies are reviewed especially for bioprinted neural models. Finally, the techniques used to evaluate the fabricated 2D and 3D neural models are discussed and compared in terms of feasibility and functionality.
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Affiliation(s)
| | - Hamed Tahmooressi
- Department of Mechanical Engineering, University of British Columbia, Kelowna, British Columbia V1V 1V7, Canada
| | - Hojatollah Rezaei Nejad
- Department of Electrical and Computer Engineering, Tufts University, 161 College Avenue, Medford, Massachusetts 02155, USA
| | | | - Su-Royn Shin
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02139, USA
- Authors to whom correspondence should be addressed: and
| | - Mina Hoorfar
- Faculty of Engineering, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada
- Authors to whom correspondence should be addressed: and
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28
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Karacan I, Milthorpe B, Ben-Nissan B, Santos J. Stem Cells and Proteomics in Biomaterials and Biomedical Applications. SPRINGER SERIES IN BIOMATERIALS SCIENCE AND ENGINEERING 2022:125-157. [DOI: 10.1007/978-981-16-7435-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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29
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Mandal S, Dube T, Mohapatra AK, Choudhury S, Khanam F, Yadav P, Chauhan VS, Mishra J, Panda JJ. Engineered Biocompatible and Stable Dipeptide Hydrogel with Tunable Mechanical and Cell Growth Properties to Embolden Neuroglial Cell Growth. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10290-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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30
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Potjewyd G, Kellett K, Hooper N. 3D hydrogel models of the neurovascular unit to investigate blood-brain barrier dysfunction. Neuronal Signal 2021; 5:NS20210027. [PMID: 34804595 PMCID: PMC8579151 DOI: 10.1042/ns20210027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
The neurovascular unit (NVU), consisting of neurons, glial cells, vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)) together with the surrounding extracellular matrix (ECM), is an important interface between the peripheral blood and the brain parenchyma. Disruption of the NVU impacts on blood-brain barrier (BBB) regulation and underlies the development and pathology of multiple neurological disorders, including stroke and Alzheimer's disease (AD). The ability to differentiate induced pluripotent stem cells (iPSCs) into the different cell types of the NVU and incorporate them into physical models provides a reverse engineering approach to generate human NVU models to study BBB function. To recapitulate the in vivo situation such NVU models must also incorporate the ECM to provide a 3D environment with appropriate mechanical and biochemical cues for the cells of the NVU. In this review, we provide an overview of the cells of the NVU and the surrounding ECM, before discussing the characteristics (stiffness, functionality and porosity) required of hydrogels to mimic the ECM when incorporated into in vitro NVU models. We summarise the approaches available to measure BBB functionality and present the techniques in use to develop robust and translatable models of the NVU, including transwell models, hydrogel models, 3D-bioprinting, microfluidic models and organoids. The incorporation of iPSCs either without or with disease-specific genetic mutations into these NVU models provides a platform in which to study normal and disease mechanisms, test BBB permeability to drugs, screen for new therapeutic targets and drugs or to design cell-based therapies.
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Affiliation(s)
- Geoffrey Potjewyd
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Katherine A.B. Kellett
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Nigel M. Hooper
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, U.K
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31
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Poorna MR, Jayakumar R, Chen JP, Mony U. Hydrogels: A potential platform for induced pluripotent stem cell culture and differentiation. Colloids Surf B Biointerfaces 2021; 207:111991. [PMID: 34333302 DOI: 10.1016/j.colsurfb.2021.111991] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 01/02/2023]
Abstract
Induced pluripotent stem cells (iPSCs) can be used to generate desired types of cells that belong to the three germ layers (i.e., ectoderm, endoderm and mesoderm). These cells possess great potential in regenerative medicine. Before iPSCs are used in various biomedical applications, the existing xenogeneic culture methods must be improved to meet the technical standards of safety, cost effectiveness, and ease of handling. In addition to commonly used 2D substrates, a culture system that mimics the native cellular environment in tissues will be a good choice when culturing iPS cells and differentiating them into different lineages. Hydrogels are potential candidates that recapitulate the native complex three-dimensional microenvironment. They possess mechanical properties similar to those of many soft tissues. Moreover, hydrogels support iPSC adhesion, proliferation and differentiation to various cell types. They are xeno-free and cost-effective. In addition to other substrates, such as mouse embryonic fibroblast (MEF), Matrigel, and vitronectin, the use of hydrogel-based substrates for iPSC culture and differentiation may help generate large numbers of clinical-grade cells that can be used in potential clinical applications. This review mainly focuses on the use of hydrogels for the culture and differentiation of iPSCs into various cell types and their potential applications in regenerative medicine.
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Affiliation(s)
- M R Poorna
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi 682041, India
| | - R Jayakumar
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi 682041, India
| | - Jyh-Ping Chen
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan, ROC; Department of Plastic and Reconstructive Surgery and Craniofacial Research Center, Chang Gung Memorial Hospital, Linkou, Kwei-San, Taoyuan 33305, Taiwan, ROC; Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33305, Taiwan, ROC.
| | - Ullas Mony
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi 682041, India; Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India.
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Rinoldi C, Zargarian SS, Nakielski P, Li X, Liguori A, Petronella F, Presutti D, Wang Q, Costantini M, De Sio L, Gualandi C, Ding B, Pierini F. Nanotechnology-Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID-19 Vaccines. SMALL METHODS 2021; 5:e2100402. [PMID: 34514087 PMCID: PMC8420172 DOI: 10.1002/smtd.202100402] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/04/2021] [Indexed: 05/07/2023]
Abstract
In recent years, the main quest of science has been the pioneering of the groundbreaking biomedical strategies needed for achieving a personalized medicine. Ribonucleic acids (RNAs) are outstanding bioactive macromolecules identified as pivotal actors in regulating a wide range of biochemical pathways. The ability to intimately control the cell fate and tissue activities makes RNA-based drugs the most fascinating family of bioactive agents. However, achieving a widespread application of RNA therapeutics in humans is still a challenging feat, due to both the instability of naked RNA and the presence of biological barriers aimed at hindering the entrance of RNA into cells. Recently, material scientists' enormous efforts have led to the development of various classes of nanostructured carriers customized to overcome these limitations. This work systematically reviews the current advances in developing the next generation of drugs based on nanotechnology-assisted RNA delivery. The features of the most used RNA molecules are presented, together with the development strategies and properties of nanostructured vehicles. Also provided is an in-depth overview of various therapeutic applications of the presented systems, including coronavirus disease vaccines and the newest trends in the field. Lastly, emerging challenges and future perspectives for nanotechnology-mediated RNA therapies are discussed.
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Affiliation(s)
- Chiara Rinoldi
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Seyed Shahrooz Zargarian
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Pawel Nakielski
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
| | - Xiaoran Li
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Anna Liguori
- Department of Chemistry “Giacomo Ciamician” and INSTM UdR of BolognaUniversity of BolognaVia Selmi 2Bologna40126Italy
| | - Francesca Petronella
- Institute of Crystallography CNR‐ICNational Research Council of ItalyVia Salaria Km 29.300Monterotondo – Rome00015Italy
| | - Dario Presutti
- Institute of Physical ChemistryPolish Academy of Sciencesul. M. Kasprzaka 44/52Warsaw01‐224Poland
| | - Qiusheng Wang
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Marco Costantini
- Institute of Physical ChemistryPolish Academy of Sciencesul. M. Kasprzaka 44/52Warsaw01‐224Poland
| | - Luciano De Sio
- Department of Medico‐Surgical Sciences and BiotechnologiesResearch Center for BiophotonicsSapienza University of RomeCorso della Repubblica 79Latina04100Italy
- CNR‐Lab. LicrylInstitute NANOTECArcavacata di Rende87036Italy
| | - Chiara Gualandi
- Department of Chemistry “Giacomo Ciamician” and INSTM UdR of BolognaUniversity of BolognaVia Selmi 2Bologna40126Italy
- Interdepartmental Center for Industrial Research on Advanced Applications in Mechanical Engineering and Materials TechnologyCIRI‐MAMUniversity of BolognaViale Risorgimento 2Bologna40136Italy
| | - Bin Ding
- Innovation Center for Textile Science and TechnologyDonghua UniversityWest Yan'an Road 1882Shanghai200051China
| | - Filippo Pierini
- Department of Biosystems and Soft MatterInstitute of Fundamental Technological ResearchPolish Academy of Sciencesul. Pawińskiego 5BWarsaw02‐106Poland
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Klarmann GJ, Gaston J, Ho VB. A review of strategies for development of tissue engineered meniscal implants. BIOMATERIALS AND BIOSYSTEMS 2021; 4:100026. [PMID: 36824574 PMCID: PMC9934480 DOI: 10.1016/j.bbiosy.2021.100026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/17/2021] [Accepted: 08/25/2021] [Indexed: 12/09/2022] Open
Abstract
The meniscus is a key stabilizing tissue of the knee that facilitates proper tracking and movement of the knee joint and absorbs stresses related to physical activity. This review article describes the biology, structure, and functions of the human knee meniscus, common tears and repair approaches, and current research and development approaches using modern methods to fabricate a scaffold or tissue engineered meniscal replacement. Meniscal tears are quite common, often resulting from sports or physical training, though injury can result without specific contact during normal physical activity such as bending or squatting. Meniscal injuries often require surgical intervention to repair, restore basic functionality and relieve pain, and severe damage may warrant reconstruction using allograft transplants or commercial implant devices. Ongoing research is attempting to develop alternative scaffold and tissue engineered devices using modern fabrication techniques including three-dimensional (3D) printing which can fabricate a patient-specific meniscus replacement. An ideal meniscal substitute should have mechanical properties that are close to that of natural human meniscus, and also be easily adapted for surgical procedures and fixation. A better understanding of the organization and structure of the meniscus as well as its potential points of failure will lead to improved design approaches to generate a suitable and functional replacement.
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Affiliation(s)
- George J. Klarmann
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA,The Geneva Foundation, 917 Pacific Ave., Tacoma, WA 98402, USA,Corresponding author at: USU-4D Bio³ Center, 9410 Key West Ave., Rockville, MD 20850, USA.
| | - Joel Gaston
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA,The Geneva Foundation, 917 Pacific Ave., Tacoma, WA 98402, USA
| | - Vincent B. Ho
- 4D Bio³ Center, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
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Cadena M, Ning L, King A, Hwang B, Jin L, Serpooshan V, Sloan SA. 3D Bioprinting of Neural Tissues. Adv Healthc Mater 2021; 10:e2001600. [PMID: 33200587 PMCID: PMC8711131 DOI: 10.1002/adhm.202001600] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/19/2020] [Indexed: 02/06/2023]
Abstract
The human nervous system is a remarkably complex physiological network that is inherently challenging to study because of obstacles to acquiring primary samples. Animal models offer powerful alternatives to study nervous system development, diseases, and regenerative processes, however, they are unable to address some species-specific features of the human nervous system. In vitro models of the human nervous system have expanded in prevalence and sophistication, but still require further advances to better recapitulate microenvironmental and cellular features. The field of neural tissue engineering (TE) is rapidly adopting new technologies that enable scientists to precisely control in vitro culture conditions and to better model nervous system formation, function, and repair. 3D bioprinting is one of the major TE technologies that utilizes biocompatible hydrogels to create precisely patterned scaffolds, designed to enhance cellular responses. This review focuses on the applications of 3D bioprinting in the field of neural TE. Important design parameters are considered when bioprinting neural stem cells are discussed. The emergence of various bioprinted in vitro platforms are also reviewed for developmental and disease modeling and drug screening applications within the central and peripheral nervous systems, as well as their use as implants for in vivo regenerative therapies.
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Affiliation(s)
- Melissa Cadena
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Liqun Ning
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Alexia King
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Boeun Hwang
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Linqi Jin
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
| | - Vahid Serpooshan
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Steven A. Sloan
- Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30322, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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35
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Physical and Mechanical Characterization of Fibrin-Based Bioprinted Constructs Containing Drug-Releasing Microspheres for Neural Tissue Engineering Applications. Processes (Basel) 2021. [DOI: 10.3390/pr9071205] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Three-dimensional bioprinting can fabricate precisely controlled 3D tissue constructs. This process uses bioinks—specially tailored materials that support the survival of incorporated cells—to produce tissue constructs. The properties of bioinks, such as stiffness and porosity, should mimic those found in desired tissues to support specialized cell types. Previous studies by our group validated soft substrates for neuronal cultures using neural cells derived from human-induced pluripotent stem cells (hiPSCs). It is important to confirm that these bioprinted tissues possess mechanical properties similar to native neural tissues. Here, we assessed the physical and mechanical properties of bioprinted constructs generated from our novel microsphere containing bioink. We measured the elastic moduli of bioprinted constructs with and without microspheres using a modified Hertz model. The storage and loss modulus, viscosity, and shear rates were also measured. Physical properties such as microstructure, porosity, swelling, and biodegradability were also analyzed. Our results showed that the elastic modulus of constructs with microspheres was 1032 ± 59.7 Pascal (Pa), and without microspheres was 728 ± 47.6 Pa. Mechanical strength and printability were significantly enhanced with the addition of microspheres. Thus, incorporating microspheres provides mechanical reinforcement, which indicates their suitability for future applications in neural tissue engineering.
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Lomboni DJ, Steeves A, Schock S, Bonetti L, De Nardo L, Variola F. Compounded topographical and physicochemical cueing by micro-engineered chitosan substrates on rat dorsal root ganglion neurons and human mesenchymal stem cells. SOFT MATTER 2021; 17:5284-5302. [PMID: 34075927 DOI: 10.1039/d0sm02170a] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Given the intertwined physicochemical effects exerted in vivo by both natural and synthetic (e.g., biomaterial) interfaces on adhering cells, the evaluation of structure-function relationships governing cellular response to micro-engineered surfaces for applications in neuronal tissue engineering requires the use of in vitro testing platforms which consist of a clinically translatable material with tunable physiochemical properties. In this work, we micro-engineered chitosan substrates with arrays of parallel channels with variable width (20 and 60 μm). A citric acid (CA)-based crosslinking approach was used to provide an additional level of synergistic cueing on adhering cells by regulating the chitosan substrate's stiffness. Morphological and physicochemical characterization was conducted to unveil the structure-function relationships which govern the activity of rat dorsal root ganglion neurons (DRGs) and human mesenchymal stem cells (hMSCs), ultimately singling out the key role of microtopography, roughness and substrate's stiffness. While substrate's stiffness predominantly affected hMSC spreading, the modulation of the channels' design affected the neuronal architecture's complexity and guided the morphological transition of hMSCs. Finally, the combined analysis of tubulin expression and cell morphology allowed us to cast new light on the predominant role of the microtopography over substrate's stiffness in the process of hMSCs neurogenic differentiation.
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Affiliation(s)
- David J Lomboni
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - Alexander Steeves
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - Sarah Schock
- Department of Cellular and Molecular Medicine, University of Ottawa, Canada and The Children's Hospital of Eastern Ontario (CHEO) Research Institute, Canada
| | - Lorenzo Bonetti
- Department of Chemistry, Materials and Chemical Engineering, "G. Natta", Politecnico di Milano, Italy
| | - Luigi De Nardo
- Department of Chemistry, Materials and Chemical Engineering, "G. Natta", Politecnico di Milano, Italy
| | - Fabio Variola
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada and Department of Cellular and Molecular Medicine, University of Ottawa, Canada and The Children's Hospital of Eastern Ontario (CHEO) Research Institute, Canada
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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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38
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Peng Y, Chu S, Yang Y, Zhang Z, Pang Z, Chen N. Neuroinflammatory In Vitro Cell Culture Models and the Potential Applications for Neurological Disorders. Front Pharmacol 2021; 12:671734. [PMID: 33967814 PMCID: PMC8103160 DOI: 10.3389/fphar.2021.671734] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/29/2021] [Indexed: 12/17/2022] Open
Abstract
Cell cultures are used in pharmaceutical, medical and biological sciences. Due to the ethical and cost limitations of in vivo models, the replaceable cell model that is more closely related to the characteristics of organisms, which has broad prospects and can be used for high-throughput drug screening is urgent. Neuronal and glial cell models have been widely used in the researches of neurological disorders. And the current researches on neuroinflammation contributes to blood-brain barrier (BBB) damage. In this review, we describe the features of healthy and inflamed BBB and summarize the main immortalized cell lines of the central nervous system (PC12, SH-SY5Y, BV2, HA, and HBMEC et al.) and their use in the anti-inflammatory potential of neurological disorders. Especially, different co-culture models of neuroinflammatory, in association with immune cells in both 2D and 3D models are discussed in this review. In summary, 2D co-culture is easily practicable and economical but cannot fully reproduce the microenvironment in vivo. While 3D models called organs-on-chips or biochips are the most recent and very promising approach, which made possible by bioengineering and biotechnological improvements and more accurately mimic the BBB microenvironment.
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Affiliation(s)
- Ye Peng
- School of Pharmacy, Minzu University of China, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shifeng Chu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yantao Yang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Zhao Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zongran Pang
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Naihong Chen
- School of Pharmacy, Minzu University of China, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
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39
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Carvalho IC, Mansur HS, Leonel AG, Mansur AAP, Lobato ZIP. Soft matter polysaccharide-based hydrogels as versatile bioengineered platforms for brain tissue repair and regeneration. Int J Biol Macromol 2021; 182:1091-1111. [PMID: 33892028 DOI: 10.1016/j.ijbiomac.2021.04.116] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/12/2021] [Accepted: 04/17/2021] [Indexed: 01/08/2023]
Abstract
Acute or chronic brain injuries promote deaths and the life-long debilitating neurological status where, despite advances in therapeutic strategies, clinical outcome hardly achieves total patient recovery. In recent decades, brain tissue engineering emerged as an encouraging area of research for helping in damaged central nervous system (CNS) recovery. Polysaccharides are abundant naturally occurring biomacromolecules with a great potential enhancement of advanced technologies in brain tissue repair and regeneration (BTRR). Besides carrying rich biological information, polysaccharides can interact and communicate with biomolecules, including glycosaminoglycans present in cell membranes and many signaling moieties, growth factors, chemokines, and axon guidance molecules. This review includes a comprehensive investigation of the current progress on designing and developing polysaccharide-based soft matter biomaterials for BTRR. Although few interesting reviews concerning BTRR have been reported, this is the first report specifically focusing on covering multiple polysaccharides and polysaccharide-based functionalized biomacromolecules in this emerging and intriguing field of multidisciplinary knowledge. This review aims to cover the state of art challenges and prospects of this fascinating field while presenting the richness of possibilities of using these natural biomacromolecules for advanced biomaterials in prospective neural tissue engineering applications.
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Affiliation(s)
- Isadora C Carvalho
- Center of Nanoscience, Nanotechnology and Innovation - CeNano(2)I, Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 Belo Horizonte/M.G., Brazil
| | - Herman S Mansur
- Center of Nanoscience, Nanotechnology and Innovation - CeNano(2)I, Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 Belo Horizonte/M.G., Brazil.
| | - Alice G Leonel
- Center of Nanoscience, Nanotechnology and Innovation - CeNano(2)I, Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 Belo Horizonte/M.G., Brazil
| | - Alexandra A P Mansur
- Center of Nanoscience, Nanotechnology and Innovation - CeNano(2)I, Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 Belo Horizonte/M.G., Brazil
| | - Zelia I P Lobato
- Department of Preventive Veterinary Medicine, Veterinary School, Federal University of Minas Gerais - UFMG, Brazil
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40
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Luo Y, Xue F, Liu K, Li B, Fu C, Ding J. Physical and biological engineering of polymer scaffolds to potentiate repair of spinal cord injury. MATERIALS & DESIGN 2021; 201:109484. [DOI: 10.1016/j.matdes.2021.109484] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
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41
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Cao R, Zhan A, Ci Z, Wang C, She Y, Xu Y, Xiao K, Xia H, Shen L, Meng D, Chen C. A Biomimetic Biphasic Scaffold Consisting of Decellularized Cartilage and Decalcified Bone Matrixes for Osteochondral Defect Repair. Front Cell Dev Biol 2021; 9:639006. [PMID: 33681223 PMCID: PMC7933472 DOI: 10.3389/fcell.2021.639006] [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: 12/08/2020] [Accepted: 01/26/2021] [Indexed: 11/24/2022] Open
Abstract
It is challenging to develop a biphasic scaffold with biomimetic compositional, structural, and functional properties to achieve concomitant repair of both superficial cartilage and subchondral bone in osteochondral defects (OCDs). This study developed a biomimsubchondraletic biphasic scaffold for OCD repair via an iterative layered lyophilization technique that controlled the composition, substrate stiffness, and pore size in each phase of the scaffold. The biphasic scaffold consisted of a superficial decellularized cartilage matrix (DCM) and underlying decalcified bone matrix (DBM) with distinct but seamlessly integrated phases that mimicked the composition and structure of osteochondral tissue, in which the DCM phase had relative low stiffness and small pores (approximately 134 μm) and the DBM phase had relative higher stiffness and larger pores (approximately 336 μm). In vitro results indicated that the biphasic scaffold was biocompatible for bone morrow stem cells (BMSCs) adhesion and proliferation, and the superficial DCM phase promoted chondrogenic differentiation of BMSCs, as indicated by the up-regulation of cartilage-specific gene expression (ACAN, Collagen II, and SOX9) and sGAG secretion; whereas the DBM phase was inducive for osteogenic differentiation of BMSCs, as indicated by the up-regulation of bone-specific gene expression (Collagen I, OCN, and RUNX2) and ALP deposition. Furthermore, compared with the untreated control group, the biphasic scaffold significantly enhanced concomitant repair of superficial cartilage and underlying subchondral bone in a rabbit OCD model, as evidenced by the ICRS macroscopic and O’Driscoll histological assessments. Our results demonstrate that the biomimetic biphasic scaffold has a good osteochondral repair effect.
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Affiliation(s)
- Runfeng Cao
- Department of Cardiothoracic Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China
| | - Anqi Zhan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China.,Research Institute of Plastic Surgery, Weifang Medical College, Shandong, China
| | - Zheng Ci
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China.,Research Institute of Plastic Surgery, Weifang Medical College, Shandong, China
| | - Cheng Wang
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yunlang She
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yong Xu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kaiyan Xiao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China
| | - Huitang Xia
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China.,Research Institute of Plastic Surgery, Weifang Medical College, Shandong, China
| | - Li Shen
- Department of Cardiothoracic Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Depeng Meng
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
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42
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Rmaidi A, Zelzer M, Sindji L, Dima R, Boury F, Delorme N, Montero-Menei CN. Impact of the physico-chemical properties of polymeric microspheres functionalized with cell adhesion molecules on the behavior of mesenchymal stromal cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 121:111852. [DOI: 10.1016/j.msec.2020.111852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/17/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022]
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43
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Wang S, Hashemi S, Stratton S, Arinzeh TL. The Effect of Physical Cues of Biomaterial Scaffolds on Stem Cell Behavior. Adv Healthc Mater 2021; 10:e2001244. [PMID: 33274860 DOI: 10.1002/adhm.202001244] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/09/2020] [Indexed: 02/06/2023]
Abstract
Stem cells have been sought as a promising cell source in the tissue engineering field due to their proliferative capacity as well as differentiation potential. Biomaterials have been utilized to facilitate the delivery of stem cells in order to improve their engraftment and long-term viability upon implantation. Biomaterials also have been developed as scaffolds to promote stem cell induced tissue regeneration. This review focuses on the latter where the biomaterial scaffold is designed to provide physical cues to stem cells in order to promote their behavior for tissue formation. Recent work that explores the effect of scaffold physical properties, topography, mechanical properties and electrical properties, is discussed. Although still being elucidated, the biological mechanisms, including cell shape, focal adhesion distribution, and nuclear shape, are presented. This review also discusses emerging areas and challenges in clinical translation.
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Affiliation(s)
- Shuo Wang
- Department of Biomedical Engineering New Jersey Institute of Technology Newark NJ 07102 USA
| | - Sharareh Hashemi
- Department of Biomedical Engineering New Jersey Institute of Technology Newark NJ 07102 USA
| | - Scott Stratton
- Department of Biomedical Engineering New Jersey Institute of Technology Newark NJ 07102 USA
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44
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Matta R, Yousafzai MS, Murrell M, Gonzalez AL. Endothelial cell secreted metalloproteinase-2 enhances neural stem cell N-cadherin expression, clustering, and migration. FASEB J 2021; 35:e21311. [PMID: 33417253 DOI: 10.1096/fj.202002302rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 11/11/2022]
Abstract
Neuroblasts have a clustered phenotype critical for their unidirectional migration, which in part is dependent on signaling from microvascular endothelial cells (EC) and pericytes (PC). Diffusible signals secreted by vascular cells have been demonstrated to increase survival, proliferation, and differentiation of subventricular zone resident neural stem cells (NSC); however, the signals that promote the necessary initiating step of NSC clustering are undefined. To investigate the role of vascular cells in promoting NSC clustering and directing migration, we created a 3-D hydrogel that mimics the biomechanics, biochemistry, and architectural complexity of brain tissue. We demonstrate that EC, and not PC, have a crucial role in NSC clustering and migration, further verified through microfluidic chamber systems and traction force microscopy. Ablation of the extended NSC aggregate arm halts aggregate movement, suggesting that clustering is a prerequisite for migration. When cultured with EC, NSC clustering occurs and NSC coincidentally increase their expression of N-cadherin, as compared to NSC cultured alone. NSC-presented N-cadherin expression was increased following exposure to EC secreted metalloproteinase-2 (MMP2). We demonstrate that inhibition of MMP2 prevented NSC N-cadherin surface expression and subsequent NSC clustering, even when NSC were in direct contact with EC. Furthermore, with exogenous activation of EGFR, which serves as a downstream activator of N-cadherin cleavage, NSC form clusters. Our results suggest that EC secretion of MMP2 promotes NSC clustering through N-cadherin expression. The insight gained about the mechanisms by which EC promote NSC migration may enhance NSC therapeutic response to sites of injury.
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Affiliation(s)
- Rita Matta
- Biomedical Engineering Department, Yale University, New Haven, CT, USA
| | - Muhammad Sulaiman Yousafzai
- Biomedical Engineering Department, Yale University, New Haven, CT, USA.,Systems Biology Institute, Yale University, West Haven, CT, USA
| | - Michael Murrell
- Biomedical Engineering Department, Yale University, New Haven, CT, USA.,Systems Biology Institute, Yale University, West Haven, CT, USA.,Physics Department, Yale University, New Haven, CT, USA
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Sun Y, Liu J, Xu Z, Lin X, Zhang X, Li L, Li Y. Matrix stiffness regulates myocardial differentiation of human umbilical cord mesenchymal stem cells. Aging (Albany NY) 2020; 13:2231-2250. [PMID: 33318310 PMCID: PMC7880396 DOI: 10.18632/aging.202244] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/20/2020] [Indexed: 05/07/2023]
Abstract
Myocardial infarction is a cardiovascular disease with high mortality. Human umbilical cord mesenchymal stem cells (hUC-MSCs) with strong self-renewal capacity and multipotency, provide the possibility of replacing injured cardiomyocytes. hUC-MSCs were cultured on polyacrylamide hydrogels with stiffnesses corresponding to Young's modulus of 13-16kPa and 62-68kPa which mimic the stiffnesses of healthy heart tissue and fibrotic myocardium. The expression of early myocardial markers Nkx2.5, GATA4, Mesp1 and the mature myocardial markers cTnT, cTnI, α-actin were detected by RT-PCR and Western Blot, which showed that soft matrix (13-16 kPa) tended to induce the differentiation of hUC-MSCs into myocardium, compared with stiff matrix (62-68 kPa). Piezos are mechanically sensitive non-selective cation channels. The expression of Piezo1 increased with the stiffness gradient of 1-10kPa, 13-16kPa, 35-38kPa and 62-68kPa on the 1st day, but Piezo2 expression was irregular. The expression of integrin β1 and calcium ions were also higher on stiff substrate than on soft substrate. hUC-MSCs tend to differentiate into myocardium on the matrix stiffness of 13-16 kPa. The relationship among matrix stiffness, Piezo1 and myocardial differentiation needs further validation.
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Affiliation(s)
- Yingying Sun
- Department of Stomatology, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jingwei Liu
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Ziran Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaoxuan Lin
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
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Walimbe T, Panitch A. Best of Both Hydrogel Worlds: Harnessing Bioactivity and Tunability by Incorporating Glycosaminoglycans in Collagen Hydrogels. Bioengineering (Basel) 2020; 7:E156. [PMID: 33276506 PMCID: PMC7711789 DOI: 10.3390/bioengineering7040156] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 01/13/2023] Open
Abstract
Collagen, the most abundant protein in mammals, has garnered the interest of scientists for over 50 years. Its ubiquitous presence in all body tissues combined with its excellent biocompatibility has led scientists to study its potential as a biomaterial for a wide variety of biomedical applications with a high degree of success and widespread clinical approval. More recently, in order to increase their tunability and applicability, collagen hydrogels have frequently been co-polymerized with other natural and synthetic polymers. Of special significance is the use of bioactive glycosaminoglycans-the carbohydrate-rich polymers of the ECM responsible for regulating tissue homeostasis and cell signaling. This review covers the recent advances in the development of collagen-based hydrogels and collagen-glycosaminoglycan blend hydrogels for biomedical research. We discuss the formulations and shortcomings of using collagen in isolation, and the advantages of incorporating glycosaminoglycans (GAGs) in the hydrogels. We further elaborate on modifications used on these biopolymers for tunability and discuss tissue specific applications. The information presented herein will demonstrate the versatility and highly translational value of using collagen blended with GAGs as hydrogels for biomedical engineering applications.
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Affiliation(s)
- Tanaya Walimbe
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA;
| | - Alyssa Panitch
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA;
- Department of Surgery, University of California Davis Health, Sacramento, CA 95817, USA
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Kim S, Lee M. Rational design of hydrogels to enhance osteogenic potential. CHEMISTRY OF MATERIALS : A PUBLICATION OF THE AMERICAN CHEMICAL SOCIETY 2020; 32:9508-9530. [PMID: 33551566 PMCID: PMC7857485 DOI: 10.1021/acs.chemmater.0c03018] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Bone tissue engineering (BTE) encompasses the field of biomaterials, cells, and bioactive molecules to successfully guide the growth and repair of bone tissue. Current BTE strategies rely on delivering osteogenic molecules or cells via scaffolding materials. However, growth factor- and stem cell-based treatments have several limitations, such as source restriction, low stability, difficulties in predicting long-term efficacy, and high costs, among others. These issues have promoted the development of material-based therapy with properties of accessibility, high stability, tunable efficacy, and low-cost production. Hydrogels are widely used in BTE applications because of their unique hydrophilic nature and tunable physicochemical properties to mimic the native bone environment. However, current hydrogel materials are not ideal candidates due to minimal osteogenic capability on their own. Therefore, recent studies of BTE hydrogels attempt to counterbalance these issues by modifying their biophysical properties. In this article, we review recent progress in the design of hydrogels to instruct osteogenic potential, and present strategies developed to precisely control its bone healing properties.
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Affiliation(s)
- Soyon Kim
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Min Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
- Department of Bioengineering, University of California, Los Angeles, USA
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Choudhary P, Gupta A, Singh S. Therapeutic Advancement in Neuronal Transdifferentiation of Mesenchymal Stromal Cells for Neurological Disorders. J Mol Neurosci 2020; 71:889-901. [PMID: 33047251 DOI: 10.1007/s12031-020-01714-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022]
Abstract
Neurodegenerative disorders have become the leading cause of chronic pain and death. Treatments available are not sufficient to help the patients as they only alleviate the symptoms and not the cause. In this regard, stem cells therapy has emerged as an upcoming option for the replacement of dead and damaged neurons. Stem cells, in general, are characterized as cells exhibiting potency properties, i.e., on being subjected to specific conditions they transform into cells of another lineage. Of all the types, mesenchymal stem cells (MSCs) are known for their pluripotent nature without the obstacle of ethical concern surrounding the procurement of other cell types. Although fibroblasts are quite similar to MSCs morphologically, certain markers like CD73, CD 90 are specific to MSCs, making both the cell types distinguishable from each other. This is implemented while procuring MSCs from a plethora of sources like umbilical cord blood, adipose tissue, bone marrow, etc. Among these, bone marrow MSCs are the most widely used type for neural regeneration. Neural regeneration is achieved via transdifferentiation. Several studies have either transplanted the stem cells into rodent models or have carried out transdifferentiation in vitro. The process involves a combination of growth factors, pre-treatment factors, and neuronal differentiation inducing mediums. The results obtained are characterized by neuron-like morphology, expression of markers, along with electrophysical activity in some. Recent attempts involve exploring biomaterials that may mimic the native ECM and therefore can be directly introduced at the site of interest. The review gives a brief description of MSCs, their sources and markers, and the different attempts that have been made towards achieving the goal of differentiating MSCs into neurons.
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Affiliation(s)
- Princy Choudhary
- Applied Science Department, Indian Institute of Information Technology, Allahabad, UP, India
| | - Ayushi Gupta
- Applied Science Department, Indian Institute of Information Technology, Allahabad, UP, India
| | - Sangeeta Singh
- Applied Science Department, Indian Institute of Information Technology, Allahabad, UP, India.
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Hung HS, Yu AYH, Hsieh SC, Kung ML, Huang HY, Fu RH, Yeh CA, Hsu SH. Enhanced Biocompatibility and Differentiation Capacity of Mesenchymal Stem Cells on Poly(dimethylsiloxane) by Topographically Patterned Dopamine. ACS APPLIED MATERIALS & INTERFACES 2020; 12:44393-44406. [PMID: 32697572 DOI: 10.1021/acsami.0c05747] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Controlling the behavior of mesenchymal stem cells (MSCs) through topographic patterns is an effective approach for stem cell studies. We, herein, reported a facile method to create a dopamine (DA) pattern on poly(dimethylsiloxane) (PDMS). The topography of micropatterned DA was produced on PDMS after plasma treatment. The grid-topographic-patterned surface of PDMS-DA (PDMS-DA-P) was measured for adhesion force and Young's modulus by atomic force microscopy. The surface of PDMS-DA-P demonstrated less stiff and more elastic characteristics compared to either nonpatterned PDMS-DA or PDMS. The PDMS-DA-P evidently enhanced the differentiation of MSCs into various tissue cells, including nerve, vessel, bone, and fat. We further designed comprehensive experiments to investigate adhesion, proliferation, and differentiation of MSCs in response to PDMS-DA-P and showed that the DA-patterned surface had good biocompatibility and did not activate macrophages or platelets in vitro and had low foreign body reaction in vivo. Besides, it protected MSCs from apoptosis as well as excessive reactive oxygen species (ROS) generation. Particularly, the patterned surface enhanced the differentiation capacity of MSCs toward neural and endothelial cells. The stromal cell-derived factor-1α/CXantiCR4 pathway may be involved in mediating the self-recruitment and promoting the differentiation of MSCs. These findings support the potential application of PDMS-DA-P in either cell treatment or tissue repair.
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Affiliation(s)
- Huey-Shan Hung
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
- Translational Medicine Research, China Medical University Hospital, Taichung 40402, Taiwan, R.O.C
| | - Alex Yang-Hao Yu
- Ministry of Health & Welfare, Changhua Hospital, Changhua 51341, Taiwan, R.O.C
| | - Shu-Chen Hsieh
- Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, R.O.C
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, R.O.C
| | - Hsiu-Yuan Huang
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Ru-Huei Fu
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
- Translational Medicine Research, China Medical University Hospital, Taichung 40402, Taiwan, R.O.C
| | - Chun-An Yeh
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei 10617, Taiwan, R.O.C
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Ciccone G, Dobre O, Gibson GM, Rey JM, Gonzalez-Garcia C, Vassalli M, Salmeron-Sanchez M, Tassieri M. What Caging Force Cells Feel in 3D Hydrogels: A Rheological Perspective. Adv Healthc Mater 2020; 9:e2000517. [PMID: 32696605 DOI: 10.1002/adhm.202000517] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/29/2020] [Indexed: 12/30/2022]
Abstract
It has been established that the mechanical properties of hydrogels control the fate of (stem) cells. However, despite its importance, a one-to-one correspondence between gels' stiffness and cell behavior is still missing from literature. In this work, the viscoelastic properties of poly(ethylene-glycol) (PEG)-based hydrogels are investigated by means of rheological measurements performed at different length scales. The outcomes of this work reveal that PEG-based hydrogels show significant stiffening when subjected to a compressional deformation, implying that conventional bulk rheology measurements may overestimate the stiffness of hydrogels by up to an order of magnitude. It is hypothesized that this apparent stiffening is caused by an induced "tensional state" of the gel network, due to the application of a compressional normal force during sample loading. Moreover, it is shown that the actual stiffness of the hydrogels is instead accurately determined by means of both passive-video-particle-tracking (PVPT) microrheology and nanoindentation measurements, which are inherently performed at the cell's length scale and in absence of any externally applied force in the case of PVPT. These results underpin a methodology for measuring hydrogels' linear viscoelastic properties that are representative of the mechanical constraints perceived by cells in 3D hydrogel cultures.
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Affiliation(s)
- Giuseppe Ciccone
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
| | - Oana Dobre
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
- Centre for the Cellular Microenvironment, University of Glasgow, G12 8LT, UK
| | - Graham M Gibson
- SUPA, School of Physics and Astronomy, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Jose Manuel Rey
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
- Centre for the Cellular Microenvironment, University of Glasgow, G12 8LT, UK
| | - Cristina Gonzalez-Garcia
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
- Centre for the Cellular Microenvironment, University of Glasgow, G12 8LT, UK
| | - Massimo Vassalli
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
- Centre for the Cellular Microenvironment, University of Glasgow, G12 8LT, UK
| | - Manuel Salmeron-Sanchez
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
- Centre for the Cellular Microenvironment, University of Glasgow, G12 8LT, UK
| | - Manlio Tassieri
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8LT, UK
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